Articles de revues : « Peripheral neuropathy, murine models, bortezomib, multiple myeloma »

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Berenson, James R., Ori Yellin, Ravi Patel, Chien-Shing Chen, Ralph Vincent Boccia, Donald Colbourn, Honghao (Hank) Yang et al. « A Phase II Study of Pegylated Liposomal Doxorubicin, Bortezomib and Dexamethasone (DVD) for Patients with Previously Untreated Multiple Myeloma (MM). » Blood 114, n^o 22 (20 novembre 2009) : 4936. http://dx.doi.org/10.1182/blood.v114.22.4936.4936.

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Abstract Abstract 4936 Despite recent advances in the treatment of MM, the disease remains incurable and many of the most effective, newer combination therapies are accompanied by significant side effects that have a major negative impact on the patient's quality of life. Pegylated liposomal doxorubicin (PLD) and bortezomib have shown anti-MM efficacy in the laboratory and for the treatment of previously treated MM patients, leading to FDA approval for patients who have failed one prior therapy. Using our severe combined immunodeficiency-hu murine models of human MM, we have previously demonstrated that lower doses of PLD administered daily are more effective and better tolerated than higher amounts given weekly. Moreover, the combination of bortezomib and dexamethasone has been shown to be effective for previously untreated MM patients. Prior studies by our group have shown that combining chemotherapy including PLD with bortezomib administered at 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle rather than the standard 1.3 mg/m2 on the same days of a 21-day schedule is effective for MM patients with relapsed or refractory disease and associated with a reduction in the incidence and severity of peripheral neuropathy. Thus, we conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the combination of intravenously administered dexamethasone, bortezomib and PLD (DVD). The treatment consisted of intravenous administration of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and finally 5.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. To date, 22 (of 35 planned) patients have been enrolled with a median age of 64 years (range, 42-79 years). The majority of those on study (68 %) were diagnosed with International Staging System II or III MM. Four patients are too early to assess for response. To date, among the 18 evaluable patients, 16 (89%) have shown objective responses to the DVD regimen, including 2 complete responses (11%), 8 partial responses (44%) and 6 minimal responses (33%). The other 2 patients (11%) had stable disease, with one of these subjects showing a continuing reduction in M-protein after 2 cycles of therapy to date. Thus, disease control was achieved in all patients. To date, no patient has shown progressive disease after 2+ - 12+ months of follow-up. Six patients experienced grade 3 adverse events and one patient with a prior history of pulmonary interstitial fibrosis developed a grade 4 toxicity (shortness of breath). Grade 3 adverse events in three of the six patients were judged not to be related to the study treatment. The most common grade 3 adverse event was reversible neutropenia (n=2). To date, only 2 patients (9%) have developed peripheral neuropathy (grade 1). Notably, there have been no cases of stomatitis or hand-foot syndrome. Thus, these results suggest that the DVD regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib and PLD is a well tolerated treatment that produces high response rates for previously untreated patients with multiple myeloma. Disclosures Berenson: Millennium Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Speakers Bureau. Hilger:Millennium Pharmaceutcals: Employment.

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Dave, Ami Atulkumar, Jaime K. Lewis et Agne Paner. « Retrospective review of chronic pain causes and management in multiple myeloma patients. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : e20552-e20552. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e20552.

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e20552 Background: The survival of patients with multiple myeloma has improved dramatically since the introduction of proteasome inhibitors such as bortezomib, which can have the adverse effect of peripheral neuropathy. This study retrospectively examines causes of chronic pain in myeloma patients and the modalities and duration of treatments used for pain control. Methods: Rush University Medical Center multiple myeloma patients who were diagnosed and treated between 2000-2019 were included. Outcome measures were abstracted from the medical record and included: classes of pain medication used, duration of treatment, prevalence of peripheral neuropathy symptoms, and use of adjunct treatment modalities. Descriptive statistical models including Chi-square and Fisher’s exact test were used for categorical variable analysis. Results: In all, 134 patients were included, of which 75.4% (N = 101) patients received at least one cycle of bortezomib. 42.5% (N = 57) patients were seen in palliative clinic. 72.9% (N = 97) reported bone pain symptoms. A total of 73.7% (N = 98) patients experienced peripheral neuropathy symptoms. 86.1% (N = 87) of patients who received bortezomib reported neuropathy, as compared to 34.4% (N = 11) of patients who did not have bortezomib therapy (OR 11.8, p < 0.0001). 66.4% (N = 67) patients who received bortezomib took anticonvulsants as compared to 31.3% (N = 10) of those who did not receive bortezomib (OR 4.3, p < 0.0005). Patients were on anticonvulsant therapy for a mean of 32.6 months (SD = 26.7) with no significant difference in the bortezomib group. 79.7% (N = 106) patients took opioid medications. Norco was the most commonly used opioid (N = 55) and average duration of use was 36.6 months (SD = 34). 18.8% (N = 25) took antidepressant medications such as TCAs or SNRIs for pain, and all of these patients received bortezomib therapy (p = 0.0003). 36.6% (N = 45) of patients received radiation and 16.5% (N = 22) underwent kyphoplasty. 70.7% (N = 94) patients attended at least one physical therapy session. There was no statistically significant difference in radiation or kyphoplasty utilization between patients who had received bortezomib and those who had not, but there was a significant difference in physical therapy (OR 4.9, p < 0.0001). Conclusions: Patients who received bortezomib as part of their myeloma treatment were more likely to experience peripheral neuropathy and required anticonvulsant therapy more frequently. It is important to better understand and define the health burden of chronic pain and use of pain medications in patients with multiple myeloma.

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Mavis, Cory, Juan Gu, Joseph Skitzki, Francisco Hernandez et Myron S. Czuczman. « Ixazomib, An Investigational Orally Bioavailable Proteasome Inhibitor, Increases p21 Expression Inducing Caspase-Dependent Cell Death, Cell-Cycle Arrest, and In B-Cell Lymphoma Pre-Clinical Models ». Blood 122, n^o 21 (15 novembre 2013) : 1828. http://dx.doi.org/10.1182/blood.v122.21.1828.1828.

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Abstract Pharmacological inhibition of the proteasome with bortezomib (BTZ) has translated into an improved clinical outcome in patients with multiple myeloma and mantle cell lymphoma. Despite the observed clinical activity, BTZ anti-tumor activity in B-cell lymphoma has been partially hindered by treatment-related toxicities (peripheral neuropathy) preventing further dose escalation and emergence of acquired resistance. To further develop therapeutic strategies targeting the proteasome system, we studied the anti-tumor activity and mechanisms-of-action of ixazomib (MLN2238), a reversible proteasome inhibitor, in pre-clinical lymphoma models. Previously we demonstrated that ixazomib is active in various lymphoma pre-clinical in vitro models and that is capable of inducing cancer cell death in a caspase-independent manner. To further explore the effects of ixazomib, we investigated its anti-tumor activity in murine lymphoma models and investigated the mechanisms responsible for cell death observed in our pre-clinical models. For in vivo studies, 6-8 week old severe combined immunodeficiency (SCID) mice were inoculated via tail vein injection (iv) with mantle cell lymphoma Granta cells (day 0) and assigned to observation, ixazomib (iv) (at 6mg/kg/dose on days +1, 4, 8, 11, 15 and 18) or BTZ (ip) (at 0.8mg/kg/dose on days +1, 4, 8, 11, 15, and 18). Differences in survival (measured as the time to limb paralysis development) were evaluated by log-rank test across treatment arms. In addition, we studied the role of p21 in the anti-tumor activity of ixazomib. A panel of rituximab-sensitive (RSCL) and -resistant cell lines (RRCL) was exposed to ixazomib. Changes in cell cycle distribution and expression levels of key cell cycle regulatory proteins were evaluated by Western blotting and flow cytometry respectively. To further define the role of p21 in ixazomib activity, transient p21 knock down was achieved using electroporation with a pooled p21 siRNA. Down regulation of p21 was confirmed by Western blotting. Following transient p21 knock down, RSCL or RRCL were exposed to ixazomib and changes in cell viability were determined using the cell titer glo assay. Finally, RSCL and RRCL were exposed to ixazomib (10nM) +/- the cell cycle inhibitor roscovitine (10nM) and viability was determined by measuring changes in ATP content. As single agent, ixazomib prolonged the survival of Granta-bearing SCID mice when compared to control or BTZ (median=24 vs. 27 vs. 35 days; P = 0.012). In addition, in vitro exposure of lymphoma cell lines to ixazomib resulted in p21 and cell cycle arrest in G1 (RSCL) or G2/M (RRCL). Transient knock down of p21 rescued both Raji RSCL and RRCL from the cytotoxic effects of ixazomib when compared to controls. Moreover, in vitro exposure of RSCL to ixazomib in the presence to roscovitine resulted in synergistic effects on cell viability. Together our data suggests that ixazomib is more effective than BTZ in controlling mantle cell lymphoma growth in vivo. In addition, MLN2238 anti-tumor activity appears to be mediated partially by the stabilization of p21. (Ixazomib was obtained from Millennium Pharmaceuticals, Inc. Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund.) Disclosures: Czuczman: Genetech, Onyx, Celgene, Astellas, Millennium, Mundipharma: Advisory Committees Other.

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Uy, Geoffrey L., Matthew S. Holt, Nicholas M. Fisher, Steven M. Devine, Michael H. Tomasson, John F. DiPersio et Ravi Vij. « Bortezomib Alters Peripheral Blood Lymphocyte Subsets in Patients with Multiple Myeloma. » Blood 106, n^o 11 (16 novembre 2005) : 2387. http://dx.doi.org/10.1182/blood.v106.11.2387.2387.

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Abstract Bortezomib (VELCADE®) is a potent inhibitor of the proteasome which exerts its antimyeloma effect in part by blocking the activation of NF-κB. As NF-κB is critical for lymphocyte development and survival, there is great interest in harnessing the potential immunomodulatory effects of bortezomib. In murine hematopoietic transplantation models, bortezomib inhibits in vitro mixed lymphocyte responses and promotes the apoptosis of alloreactive T cells protecting against acute graft-versus-host disease. However, no data exists on the in vivo effects of bortezomib on human T cells. To characterize the effects of bortezomib on immune function, we profiled peripheral blood lymphocytes subsets and T cell associated cytokines in 39 patients with multiple myeloma. Two cycles of bortezomib 1.3 mg/m2 were administered by intravenous infusion on days 1, 4, 8, and 11 of a 21-day treatment cycle. The patients had received prior induction chemotherapy and would proceed to autologous transplant following treatment with bortezomib. Study population consists of 23 male and 16 female patients with the median age of 56 years (range 38–69). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (28), IgA (10), light chain only (1), with stage I (1), II (12), or stage III (26) disease. Peripheral blood was collected at baseline (cycle 1, day 1) and at one week after the last dose of bortezomib (cycle 2, day 18) and analyzed for lymphocyte subsets by standard multicolor flow cytometry. Th1 and Th2 serum cytokines were measured at the same timepoints using a multiplexed cytometric bead array (BD Biosciences). Following treatment with bortezomib, no significant changes were detected in either Th1 or Th2 serum cytokine levels: IL-2 (p=0.116), TNF-alpha (p=0.854), IFN-gamma (p=0.070), IL-4 (p=0.240), IL-6 (0.236), IL-10 (0.151) as analyzed by Wilcoxon signed ranks test. Analysis of lymphocyte subsets using a paired student’s T-test demonstrated a 38% decrease in CD56+ NK cells (p=0.02) and a 26% increase in CD4/CD8 ratio (p=0.0006) which appears to be secondary to a decrease in CD8+ cytotoxic T-cells (p=0.054). (Table 1.) In conclusion, we observe an alteration of lymphocyte subsets following only two cycles of bortezomib. Further analysis of the effects of long term treatment with bortezomib is warranted. These studies may provide insights into the role of bortezomib as an immunomodulatory agent. Peripheral Blood Lymphocyte Subsets Pre-bortezomib (/mm 3 ) Post-bortezomib(/mm 3 ) Difference(/mm 3 ) P-value CD2 1446 1259 −187 0.085 CD3 1273 1160 −113 0.28 CD4 842 802 −40 0.54 CD8 412 337 −75 0.055 CD19 90 94 4 0.86 CD20 87 95 8 0.78 CD56 206 148 −58 0.022 CD4/CD8 ratio 2.53 3.19 0.66 0.0006

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Kuhn, Deborah J., Sally A. Hunsucker, Qing Chen, Peter M. Voorhees, Marian Orlowski et Robert Z. Orlowski. « Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors ». Blood 113, n^o 19 (7 mai 2009) : 4667–76. http://dx.doi.org/10.1182/blood-2008-07-171637.

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Abstract Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, nonspecific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a proteasomal variant found predominantly in cells of hematopoietic origin that differs from the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immunoproteasomes, we screened a rationally designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-001, preferentially targeted the β1i subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, proapoptotic proteins, and activated caspase-mediated apoptosis. IPSI-001 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-001 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide antimyeloma activity with greater specificity and less toxicity than current inhibitors.

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Ikeda, Hiroshi, Teru Hideshima, Mariateresa Fulciniti, Giulia Perrone, Naoya Miura, Hiroshi Yasui, Yutaka Okawa et al. « PI3K/p110δ is a novel therapeutic target in multiple myeloma ». Blood 116, n^o 9 (2 septembre 2010) : 1460–68. http://dx.doi.org/10.1182/blood-2009-06-222943.

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In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110δ signaling in multiple myeloma (MM). Knockdown of p110δ by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110δ specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110δ potently induced autophagy. The in vivo inhibition of p110δ with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110δ is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

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Steinberg, Jeffrey A., Jing Shen, Eric Sanchez, Haiming Chen, Zhi-Wei Li, Jacqueline Hilger et James R. Berenson. « Alpha Lipoic Acid (ALA) Inhibits the Anti-Myeloma Effects of Bortezomib. » Blood 114, n^o 22 (20 novembre 2009) : 3832. http://dx.doi.org/10.1182/blood.v114.22.3832.3832.

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Abstract Abstract 3832 Poster Board III-768 Introduction ALA is an antioxidant often used in the management of peripheral neuropathy (PN) for patients with multiple myeloma (MM). A clinical trial evaluating ALA in diabetic neuropathy showed this drug to be effective for patients with both somatic and autonomic neuropathies. It also normalized the endoneural blood flow, reduced oxidative stress and improved vascular dysfunction. Bortezomib (Velcade®), the first-in-class proteasome inhibitor (PI), which is approved for the treatment of patients with MM, may cause PN. As a result, patients are often treated empirically with ALA. In this study, we investigated whether ALA has any impact on the anti-MM effects of bortezomib. Methods First, cells from the MM cell lines RPMI8226 and MM1S (1×105 cells per 100μl) were treated with ALA alone to determine whether ALA had any effects on their growth as determined with an MTS assay. MM cells were plated in a 96-well plate using serum-free media. The cells were treated with either media alone or ALA at concentrations ranging from 1 to 1000 μM for 48 hours. The acidity of ALA at these doses was determined and if the pH was less than 7, we neutralized it using NaOH. Second, we measured the proliferation of cells exposed to bortezomib alone and combinations of a fixed concentration of bortezomib and escalating concentrations of ALA. Results The exposure of cells to ALA alone had a stimulatory effect on the growth of both MM cell lines in vitro. ALA alone at 1000 μM resulted in an increase in cell viability of MM1S cells by approximately 10% when compared to the control group. ALA alone also stimulated the growth of RPMI8226 cells but at much lower concentrations than observed for MM1S. Compared to untreated cells, there was an increase in cell viability with ALA at concentrations as low as 1 μM and a concentration dependent increase at concentrations of 1, 10, 100, and 1000 μM in RPMI8226 cells. At the highest concentration (1000 μM) of ALA, cell viability increased 150% when compared to RPMI8226 cells incubated with media alone. Next, we evaluated the effect of ALA on bortezomib's anti-MM activity. As a single agent, bortezomib reduced MM1S (20 nM) and RPMI8226 (5 nM) cell viability by 93% and 70% respectively. When ALA was added at a clinically achievable concentration (100 μM) to bortezomib (RPMI8226, 5 nM; MM1S, 20 nM), a reduction in the anti-MM effects of bortezomib on these cell lines was observed when compared to bortezomib treatment alone. Compared to bortezomib alone, the combination of ALA plus bortezomib doubled cell viability (increased RPMI8226 and MM1S cell viability from 32.5% to 65% and 7.5% to 15%, respectively). These negative effects of ALA on bortezomib's anti-MM activity were consistently observed in multiple experiments involving both of these cell lines evaluating concentrations of ALA ranging from 100 to 1000 μM and bortezomib ranging from 5 to 20 nM. Conclusions Our data suggest that ALA has the potential to antagonize the anti-MM effects of bortezomib based on our in vitro results using MM cell lines. Thus, it is possible that ALA could negatively impact the therapeutic benefit of bortezomib for MM patients and this requires further study especially if ALA is accepted as an intervention in bortezomib-related neuropathy. We are currently completing studies evaluating primary MM patients' tumor cells in vitro and our human MM xenograft models in vivo to further validate this impact of ALA on bortezomib's anti-MM activity and whether changes in treatment schedule of these drugs may prevent this inhibitory effect from occurring. In addition, because part of bortezomib's anti-tumor effects are related to reactive oxygen species (ROS) levels, we are evaluating whether the inhibitory effects of ALA on this PI may be overcome by increasing intracellular ROS levels. Disclosures: Hilger: Millennium Pharmaceutcals: Employment. Berenson:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Moreau, Philippe, Asher A. Chanan-Khan, Andrew W. Roberts, Amit B. Agarwal, Thierry Facon, Shaji Kumar, Cyrille Touzeau et al. « Venetoclax Combined with Bortezomib and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma ». Blood 128, n^o 22 (2 décembre 2016) : 975. http://dx.doi.org/10.1182/blood.v128.22.975.975.

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Abstract Background: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

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Ricci, Deborah S., Reyna Favis, Yu Sun, Helgi van de Velde, Erin Broderick, Michael Meyers, Jean-Luc Harousseau, Hervé Avet-Loiseau, Paul G. Richardson et Jesús F. San Miguel. « Pharmacogenomic (PGx) Analysis of Bortezomib-Associated Peripheral Neuropathy in the Phase 3 VISTA Trial of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Multiple Myeloma. » Blood 114, n^o 22 (20 novembre 2009) : 3875. http://dx.doi.org/10.1182/blood.v114.22.3875.3875.

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Abstract Abstract 3875 Poster Board III-811 We investigated genotyping of 172 candidate gene loci (2016 SNPs) related to hereditary neuropathy, energy production and fast axonal transport, nociception and pain transmission, mitochondria, neurogenesis, neuroprotection, immune function, and bortezomib (Velcade®) mechanism of action. Our aim was to identify predictive classifiers for peripheral neuropathy (PN) in multiple myeloma (MM) following treatment with bortezomib in the phase 3 VISTA trial of bortezomib plus melphalan–prednisone (VMP, N=344) vs MP (N=338) in previously untreated MM patients ineligible for high-dose therapy (median age 71 years). We collected whole blood samples from 323 patients who provided consent for this analysis, from 99/151 participating clinical centers. Samples were transferred to a central laboratory for DNA extraction. After quality control for DNA integrity and quantity, DNA from 139 patients on the VMP arm (VISTA PGx subset) was included in this case-control candidate gene study. A custom array was developed by Illumina (San Diego, CA) for this analysis. Patient characteristics of the VISTA PGx subset were similar to those of the overall population. Of the PGx subset, 51.8% had reported PN events (36.0% grade ≥2). We sought to confirm VISTA findings in an independent cohort of patients in the IFM2005-01 phase 3 study of bortezomib–dexamethasone (Vel/Dex) vs VAD in previously untreated MM patients aged ≤65 years eligible for high-dose therapy (median age 57 years); 215 samples were collected from consenting patients on the Vel/Dex arm, of whom 46% had reported PN events (23.7% grade ≥2) including peripheral neuropathies, dysesthesia, and paresthesia. The VISTA analysis included cases and matched controls with result correlations to clinical adverse event descriptions of “peripheral sensory neuropathy”, “peripheral neuropathy NEC”, and/or “neuralgia”, or any occurrence of these three adverse events. Multiple covariates were included in single-marker association analyses using logistic regression in SAS (PROC LOGISTIC, SAS, v9.1) under three different genotypic models (additive, dominant, recessive) followed by FDR correction. No SNPs had significant associations with the terms above. However, analysis for time to onset of PN using Cox regression and the log rank test in SAS (PROC PHREG PROC TPHREG and PROC LIFETEST, SAS v9.1) using the same models and multiple testing corrections methods identified two SNPs significantly associated with shorter time to onset of any PN (rs4553808; CTLA4; FDR=0.002) and time to onset of grade ≥2 PN (rs1474642; PSMB1; FDR =0.014). Both of these associations were found in the recessive model so that 8.3% of patients with PN following bortezomib treatment have the homozygous recessive genotype of CTLA4 and 6% of patients with grade ≥2 PN have the recessive PSMB1 genotype. Both of these associations were also significant under Bonferroni's correction method. Two additional SNPs were identified that had significant association with grade ≥2 PN (rs12568757; CTSS, FDR=0.027) and with grade ≥3 PN (rs11974610; GJE1; FDR=0.041) but these were not significant under Bonferroni's method. These results suggest an immune-related influence for PN development involving genes associated with immune function (CTLA4, CTSS) and reflexive coupling within Schwann cells (GJE1). Mutations in the target (PSMB1) subunit suggest an influence with drug binding as well. When we investigated associations with these SNPs in the IFM2005-01 dataset, no significant associations were found in the analysis of time to onset of PN following multiple testing corrections; however, rs4553808 (CTLA4) had the same trend of association with time to onset of grade ≥2 PN in the recessive model (p=0.105). The differences in association were likely due to differences between the VISTA and IFM2005-01 study populations (e.g. neuropathy status at entry, rate of onset of PN, age, and baseline characteristics including β2-microglobulin, albumin, and diabetes status). This is the first report of an association between genes associated with immune function (e.g. CTLA4) and time to onset of bortezomib-associated PN. Although the clinical utility of this study is limited due to the low number of genes investigated and the exploratory nature of this analysis, further genome-wide studies may result in a predictive classifier for bortezomib-associated PN applicable to the clinic. This work is currently ongoing. Disclosures: Ricci: Johnson & Johnson: Employment, Equity Ownership. Favis:Johnson & Johnson: Employment, Equity Ownership, Research Funding. Sun:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Broderick:Johnson & Johnson: Employment. Meyers:Johnson & Johnson: Employment, Equity Ownership. Harousseau:Janssen Cilag: Honoraria; Celgene: Honoraria. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; OrthoBiotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Schueler, Julia B., Dagmar Wider, Kerstin Klingner, Gabrielle Melanie Siegers, Annette M. May, Johannes M. Waldschmidt, Alexander Keller, Justus Duyster, Ralph M. Waesch et Monika Engelhardt. « Novel Patient Derived Multiple Myeloma Model Reflects Sensitivity Towards Anticancer Treatment in Multiple Myeloma Patients ». Blood 126, n^o 23 (3 décembre 2015) : 3004. http://dx.doi.org/10.1182/blood.v126.23.3004.3004.

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Abstract Background Appropriate animal models for hematological malignancies are highly attractive, because they allow the study of the tumor biology and underlying disease mechanisms. They also constitute a major prerequisite for rapid bench-to-bedside translation of investigational anticancer therapies. To validate our multiple myeloma patient (pt)-derived xenograft (MM PDX) model (Schueler et al, Expert Opin Biol Ther, 2013), we systematically analyzed a panel of MM PDX with regard to their sensitivity towards standard of care treatment and compared these data with the pts' clinical outcome. Methods Bone marrow (BM) cells of 11 MM pts were implanted intratibialy (i.t.) into 103 NOD/Shi-scid/IL-2Rγnull (NOG) mice (n= 6-18 / pt sample). Mice were treated according to pts' therapy with VCD (Bortezomib, Cyclophosphamide, Dexamethasone), or to evaluate additional treatment options with Rd (Lenalidomide, Dexamethasone). Tumor growth and antitumoral activity in mice were assessed in tumor-bearing mice and compared to untreated control mice as well as to pts' response. Tumor growth in the mouse model was monitored by whole-body fluorescence-based in-vivo-imaging (IVI) using CF750-labeled α-HLA ABC antibody before and during treatment as well as 24h after last treatment cycle as described (Schueler J. PLOSone 2013). Mock-injected animals served as negative controls. Engraftment of human MM cells in murine organs was confirmed by flow cytometry and patho-histological analyses (immunostaining) at the end of the study. Results The pt cohort included a typical MM clientele for referral centers, with a median age of 75 years (range 56-85), median BM infiltration of 80% (20-90), and high- and standard-risk cytogenetics in 5 and 6 pts, respectively. All pts had advanced disease with Durie&Salmon stage III and active/symptomatic MM. All pts received VCD after diagnosis and BM sampling. MM cell engraftment could reliably be determined from experimental day 10 on in all 11 MM PDX models, at all assessed sites, namely within the BM, spleen and peripheral blood (PB) of recipient mice. Individual pt samples displayed distinct tumor growth patterns in vivo. Fluorescence intensity of engrafted murine organs ranged from 2- to 15-fold compared to mock injected control mice. Mean IVI signals in BM of recipient mice were 10-fold higher as compared to spleen signals, qualifying the BM niche as the preferred homing localization of pts' MM cells. Of note, both injected and non-injected BM sites were infiltrated by MM cells 10 days after tumor cell injection. Engraftment of human MM cells in the respective murine organs was confirmed by flow cytometry (HLA ABC, CD138, CD38) and histology and verified MM engraftment via both methods, confirming prior reports (Schüler PLOSone 2013; Groen Blood 2012;120:e9-16, Overdijk MAbs. 2015;7:311-21). The murine engraftment capacity was independent of MM type, disease stage, BM infiltration and cytogenetics of the donor pt. VCD was applied to 9 different MM PDX models and induced partial remission (PR; defined as at least 50% reduction of murine tumor load in BM, spleen and/or PB) in 5 out of 9 tested MM PDX models, whereas 2 cases each showed stable disease (SD) or progression (PD). The response rates in the mouse avatars mirrored the clinical outcome of the respective MM pts in 8/9 cases; only one MM pt showed serological and clinical PR, whereas the corresponding mice displayed SD. Rd induced PR in 1 and PD in a second MM PDX model, underlining the feasibility of MM PDX for drug screening approaches. Conclusions Due to the complex tumor biology, murine models of MM are still challenging. Our data support the preclinical rationale to use i.t.-injected NOG mice, since they closely resemble clinical MM with respect to symptoms, disseminated disease sites and response to anticancer treatment. Possible applications for the MM mouse avatars include development of new anticancer drugs as well as definition of biomarker strategies and selection of treatment options for individual pts with relapsed/refractory MM. The data of our preclinical study may serve as a useful future strategy to guide treatment decisions in refractory pts. The suitability as a drug development tool will be additionally determined performing treatment experiments with novel agents, e.g. elotuzumab or daratumumab. Disclosures Schueler: Oncotest GmbH: Employment. Klingner:Oncotest GmbH: Employment.

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Magrangeas, Florence, Rowan Kuiper, Hervé Avet-loiseau, Wilfried Gouraud, Catherine Guérin, Henri Der Sakissian, Jérôme Suhard et al. « A Genome Wide Association Study Reveals Genetic Predisposition for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma By Variation in the PREP1-Cbs Locus ». Blood 124, n^o 21 (6 décembre 2014) : 2057. http://dx.doi.org/10.1182/blood.v124.21.2057.2057.

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Abstract Introduction: Bortezomib has become an important part of myeloma therapy, despite the occurrence of toxicities such as bortezomib induced peripheral neuropathy (BiPN). Since effective prophylactic treatment is lacking, onset of BiPN can only be remedied by dose reduction or stop of treatment. Here, using a genome-wide genotyping method, we investigated the potential genetic predisposition to BiPN in MM patients who received bortezomib-dexamethasone (VD) induction therapy prior to autologous stem-cell transplantation (ASCT). Methods: We performed a genome-wide association study using the Affymetrix SNP 6.0 platform. In total 469 cases from the IFM 2005-01, IFM2007-02 clinical trials or routine diagnostic were included as discovery cohort. Another 114 samples from the HOVON-65/GMMG-HD4 trial were used as validation. Patients with BiPN grade 2 or higher after initiation of bortezomib treatment were assigned as cases (n=155 in discovery, n=40 in validation) and the remaining patients that did not developed BiPN were considered controls (n=314 in discovery, n=74 in validation). Additional exclusion criteria were a minor allele frequency ≤ 5%, genotype frequency < 95% or Hardy Weinberg equilibrium p-value <1 x 10-5; 371,075 tagging SNPs were thus included for analysis. Association of SNPs to BiPN was tested using a Cochran-Armitage trend test. Six SNPs were found with parametric p-value < 1 x 10-5. These SNPs were validated using the validation cohort. Results: Of three loci identified by six SNPs in the discovery cohort, one previously unreported gene locus (rs2839629) remained associated to BiPN in the validation data set. This locus at 21q22.3 had odd ratios of 1.89 (p<1x10-6) and 2.02 (p = 0.02) in the discovery and validation cohorts, respectively. It is localized in the 3’ UTR of PBX/knotted 1 homeobox 1 (PKNOX1; alias PREP1), which encodes for a homeodomain transcription factor. Amongst others, PKNOX1 may modulate levels of chemokine monocyte chemoattractant protein-1 (MCP-1). MCP-1 is universally increased in different models of peripheral neuropathic pain and may be considered as a biomarker of chronic pain (Zhang and de Koninck, J. Neurochem. 97:772-783 (2006)). Haplotype analysis revealed a strong linkage disequilibrium (LD, r2 = 0.87) to the neighbouring gene CBS which encodes an endogenous H2S-producing enzyme. The CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models (Takahashi et al., Pain, 150, 183-191, 2010). Conclusions: Our data provides evidence for susceptibility to BiPN in MM by variation in the PREP1-CBS locus, and suggests a new potential target in neuro-protective strategies of treatment. Validation of this finding may allow for the identification of patients at increased risk of BiPN which may benefit alternative treatments such as carfilzomib and better clinical management of this toxicity. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Moreau:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Sanchez, Larysa, Xavier Leleu, Jennifer Beaumont, Hailin Yu, Stacie Hudgens, Holger W. Auner, Hang Quach et al. « Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone ». Blood 136, Supplement 1 (5 novembre 2020) : 39–41. http://dx.doi.org/10.1182/blood-2020-141319.

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Introduction: The BOSTON study is a Phase 3 trial comparing the novel triplet regimen of once weekly oral selinexor with once weekly bortezomib and dexamethasone (SVd) versus standard twice weekly Vd in patients with multiple myeloma (MM) after 1-3 prior therapies. The SVd regimen conferred a 47% increase in median progression-free survival (PFS) and time to next therapy (TTNT), higher overall response rates (ORR) and deeper responses compared to Vd. Furthermore, this is the first trial of a bortezomib-based triplet therapy (i.e., SVd) that showed lower rates of overall and Grade ≥2 peripheral neuropathy (PN) compared with doublet Vd while conferring a longer PFS, and the regimen requires ~35% fewer clinic visits than standard twice weekly Vd. This abstract reports analyses of the patient reported outcomes (PROs) in BOSTON to evaluate patterns in therapy-induced PN symptoms, pain and function. Methods: PROs were assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-CIPN20 questionnaires. The QLQ-CIPN20 assesses patients' experience of symptoms and functional limitations related to chemotherapy induced PN (CIPN) and has 3 subscales: sensory, motor, and autonomic. The QLQ-C30 includes several functional and symptom scales and focuses on physical functioning, role functioning, and pain subscales as pre-specified domains of interest. Mixed effects repeated measures models were fit to the longitudinal data to estimate differences over time. Meaningful change thresholds derived using anchor- and distribution-based methods or estimated from the literature were used to identify patients who had experienced a meaningful worsening of symptoms or deterioration in functioning. Time to definitive deterioration was defined as the time from randomization to the first occurrence of meaningful deterioration that was not followed by subsequent improvement. Cox proportional hazard models compared the hazard rates between arms adjusted for baseline questionnaire score, randomization stratification factors (prior PI therapy, number of prior anti-MM regimens, R-ISS stage at MM) and prior bortezomib exposure. Results: A total of 402 patients were enrolled in the trial; 388 completed a baseline QLQ-CIPN20 assessment and are included in these analyses. Based on the mixed model repeated measures analysis (Table 1), a benefit was demonstrated for SVd in change from baseline to Day 106 for sensory (-5.3 points difference, p=0.0006) and pain (-6.6, p=0.007) scores. Patients in the SVd arm had a greater increase in autonomic symptom scores (+5.0, p=0.022). The number of patients with definitive deterioration in QLQ-CIPN20 sensory symptoms was greater in the Vd arm (86 patients, 45.7%) compared to 52 (27.7%) patients in the SVd arm (Table 2). The median time to deterioration was 20.7 months (95% confidence interval [CI]: 15.4, not estimable [NE]) in the SVd arm compared to 12.5 months (95% CI: 7.8, 19.9) in the Vd arm. The adjusted hazard ratio (HR) comparing time to deterioration in sensory scores between SVd and Vd arms was 0.53 (95% CI: 0.38, 0.75; p = 0.0004). Worsening of motor symptoms also trended in favor of SVd with a HR = 0.72 (p=0.052). Roughly half of the patients in each treatment arm experienced worsening autonomic symptoms (54.6% and 48.4%, SVd and Vd respectively) with no significant difference between arms (HR=1.14, p=0.37). While not statistically significant, fewer SVd patients had definitive deteriorations in pain and physical function compared to Vd patients, with similar or extended time to deterioration (Table 2). Conclusions: In the setting of a significant increase in PFS and TTNT, patients with MM after at least one prior therapy who received weekly SVd reported lower sensory symptom and pain scores but higher autonomic symptom scores. Further, patients treated with twice weekly Vd experienced a more rapid rate of sensory symptom worsening and a trend to more rapid worsening of motor symptoms, compared to patients treated with SVd. The improved pain scores in patients treated with SVd may be related to superior disease control. The reduction in PN-related pain and sensory symptoms observed with SVd in the setting of increased PFS and TTNT supports a potentially improved patient experience and decreased health care burden and long term morbidity. Disclosures Leleu: Janssen: Honoraria; BMS-celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Oncopeptide: Honoraria; AbbVie: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria. Beaumont:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Yu:Clinical Outcomes Solutions: Current Employment; Karyopharm Therapeutics: Consultancy. Hudgens:Clinical Outcomes Solutions: Current Employment; Sierra Oncology: Consultancy; Karyopharm Therapeutics: Consultancy. Auner:Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Quach:Sanofi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria. Delimpasi:Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; GENESIS: Honoraria. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Hajek:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Garg:Janssen, Takeda, Celgene, Novartis, Sanofi: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chai:Karyopharm Therapeutics Inc: Current Employment. Ma:Karyopharm: Current Employment, Current equity holder in private company. Tang:Karyopharm Therapeutics: Current Employment. Leong:AbbVie: Ended employment in the past 24 months; Karyopharm Therapeutics: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding.

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Bagal, Bhausaheb, Anant Gokarn, Avinash Bonda, Swapnil Chavan, Sachin Punatar, Lingaraj Nayak, Sadhana Kannan et al. « Bortezomib in Combination with Cyclophosphamide and G-CSF for Hematopoietic Stem Cell Mobilization in Patients with Multiple Myeloma ». Blood 132, Supplement 1 (29 novembre 2018) : 2067. http://dx.doi.org/10.1182/blood-2018-99-116886.

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Abstract Background: Proteasome inhibitors (PI) have become integral part of front-line treatment of multiple myeloma. Murine model experiments have shown mobilization of hematopoietic stem cells from bone marrow to peripheral blood after PI administration via down regulation of very late antigen 4 (VLA-4) which mediate adherence of hematopoietic stem cells to the bone marrow microenvironment via interaction with vascular cell adhesion molecule (VCAM-1). Human studies with bortezomib in combination with G-CSF for mobilization have yielded encouraging results with no additional toxicity and no malignant plasma cell mobilization was observed. Cyclophosphamide based chemo-mobilization offers advantage in term of higher stem cell yield and is able to overcome adverse impact of prior lenalidomide therapy on stem cell harvest. In the current study we added bortezomib to cyclophosphamide-GCSF (B-Cy-GCSF) chemo-mobilization regimen to study the effect of bortezomib on stem cell harvest and compared this with our earlier protocol of only cyclophosphamide-GCSF (Cy-GCSF) mobilization. Methods: Patients of multiple myeloma aged between 18 to 70 years were eligible for the study in the period between March 2016- June 2018. Patients after induction therapy achieving at least partial response and having no more than grade 1 peripheral neuropathy were enrolled. Patients received bortezomib at a dose of 1.3 mg/m2 on day 1, 4, 8 and 11 and cyclophosphamide (Cy) was administered at a dose of 1 g/m2 on day 8 and 9 followed by G-CSF 10µg/kg in two divided doses from day 11 onwards till target stem cell collection of at least 5 X 106/Kg. The peripheral blood CD34 (PB CD34) counts were monitored from day 14 and harvest was initiated when it reached above 20 cells/µL. The peak PB CD34 count achieved, the number of days of harvest required, the CD34 dose yield and the engraftment kinetics were recorded and compared with earlier patients who had undergone Cy-GCSF chemo-mobilization. These patients had received Cy 1 g/m2 on d1 and d2, G-CSF 10 mcg/kg from d4 onwards and PBCD34 monitored from d7 onwards. Result: A total of 37 patients were enrolled between March 2016 and June 2018. Median age of study cohort was 46 years (range 27-63) and 27 (73 %) were males. Median lines of therapy received were 1 (range 1 to 2) and 8 (21.6 %) had received lenalidomide prior to stem cell harvest. The median peak peripheral blood CD34 cell counts 71.3 cells /µL (range 27.5 -306). Median CD34 cells collected were 9.21 X 106 /Kg (range 4.95-17.1). Target CD34 cell collection was achieved after a median of one day harvest (range 1-2). Median time to neutrophil and platelet engraftment was 11.5 and 13.5 days respectively. These results were compared with 88 patients who had undergone Cy-GCSF chemo-mobilization earlier at our center from May 2008 till February 2016 as seen in Table1 . In Cy- G-CSF cohort, median number of harvest required for target CD34 was 2 (range 1-4) and median CD34 cell yield was 8.2 X 106/Kg (0.4-24.2). Target CD34 cells yield of 5 X 106/Kg was achieved with single apheresis in 58.6% of patients after B-Cy-GCSF mobilization as compared to 44.3% in Cy-G-CSF group, although this was not statistically significant (p=0.1). While 3(3.4 %) had failed chemo-mobilization after Cy-GCSF, none of patients in bortezomib group had mobilization failure. Conclusion: Patients undergoing B-Cy-GCSF mobilization have higher stem cell yield and required less days of harvest. This strategy should be explored in a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

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Voorhees, Peter M., Cristina Gasparetto, Keren Osman, Kristy Richards, Madlyn Ferraro, Reynaldo Garcia, Jennifer MacLean et al. « Results of a Phase I Study of Vorinostat In Combination with Pegylated Liposomal Doxorubicin and Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma ». Blood 116, n^o 21 (19 novembre 2010) : 1955. http://dx.doi.org/10.1182/blood.v116.21.1955.1955.

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Abstract Abstract 1955 Introduction: The histone deacetylase inhibitor vorinostat has additive to synergistic activity in combination with anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore sought to evaluate the safety of vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in patients with relapsed and/or refractory MM. Patients and Methods: Treatment consisted of PLD 30mg/m2 on D4, bortezomib 1.3mg/m2 on D1,4,8,11 and escalating doses of vorinostat from either D4-11 or D1-14 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients could remain on therapy until disease progression or unacceptable toxicity. Key eligibility criteria: relapsed and/or refractory MM, ANC≥1.0×109/L. plts≥100×109/L, CrCl≥30mL/min, adequate hepatic and cardiac function. The primary objective of the study was to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen. Results: 20 patients have enrolled at the following dose levels: The median age was 60 (range 44–73), median time from diagnosis 42.5 months (9 to 117), and median number of prior lines of therapy 2 (1 to 7). 90% of patients received prior immunomodulatory drugs, 65% bortezomib, 65% autologous stem cell transplantation, and 50% anthracyclines. 55% of patients were relapsed; 45% relapsed and refractory. 9 of 13 patients had disease resistant to prior bortezomib-based therapy. Grade 3 and 4 neutropenia was seen in 35% and 5% of patients, respectively, while grade 3/4 lymphopenia and thrombocytopenia were seen in 30%/5% and 10%/20%, respectively. Two grade 3 infections were seen, 1 of which was attributable to study treatment, but no ≥grade 4 infections were encountered. Common non-hematologic toxicities of all grades regardless of attribution included fatigue (70%), anorexia (55%), nausea (80%), vomiting (60%), diarrhea (85%), constipation (70%) and peripheral neuropathy (75%), most of which was grade 1 or 2 in severity. Grade 3 fatigue, peripheral neuropathy and hand foot syndrome were seen in 10% of patients each, while grade 3 diarrhea was seen in 20%. 1 DLT of transient atrial flutter with grade 4 systolic dysfunction was seen at dose level 3. Two of six patients suffered DLTs at dose level 4 consisting of grade 4 thrombocytopenia without bleeding sequelae, thus establishing dose level 3 as the MTD. Serious adverse events included the above mentioned systolic dysfunction and a limited episode of diastolic dysfunction in one patient. No deaths have occurred on study. Using International Myeloma Working Group criteria, 38% of patients have had ≥VGPR and 61% ≥PR. Only 2 of 18 evaluable patients have had progressive disease on treatment. 7 of 10 patients with relapsed disease had ≥PRs, 6 of which were VGPRs, whereas 4 of 8 patients with relapsed and refractory disease responded. 4 of 5 bortezomib-naïve patients responded to treatment and 4 of 4 patients with bortezomib-pretreated but sensitive disease had PRs or better. 3 of 9 patients with bortezomib-refractory disease had ≥PRs but MRs were seen in an additional 3. Conclusions: The MTD of vorinostat in combination with PLD and bortezomib was 400mg on D4-11. Constitutional, gastrointestinal, and neurologic toxicities were common, but predominantly grade 1 and 2 in severity, and largely manageable. Responses were seen in patients with bortezomib-resistant and -sensitive disease. Dose level 3 has been expanded to include an additional 12 patients. Our results support further clinical testing of this combination in patients with MM. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: Vorinostat for the treatment of myeloma. Gasparetto:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Richards:Cephalon: Speakers Bureau; Merck/Shering-Plough: Consultancy. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hurd:Celgene: Research Funding.

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Ahn, Won-Gyun, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky et al. « Abstract 416 : A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 416. http://dx.doi.org/10.1158/1538-7445.am2022-416.

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Abstract The existing proteasome inhibitors, such as bortezomib and ixazomib, are effective in multiple myeloma, but have little activity against solid tumors. These are covalent boronic acid-based compounds and are associated with undesired side effects, mainly hematologic toxicity and peripheral neuropathy. A variety of improved covalent proteasome inhibitors have been developed, but lack of oral availability and low distribution in tumors make them ineffective in solid tumors. In addition, they still have a narrow therapeutic window due to unexpected adverse effects such as cardiac and pulmonary toxicity. We report a non-covalent and rapidly reversible proteasome inhibitor as a potential anti-cancer agent against solid tumors as well as multiple myeloma. These novel inhibitors, called QL compounds, are non-covalent chymotrypsin-like selective proteasome inhibitors that can be taken orally. They effectively inhibited tumor growth in multiple myeloma xenograft model without hematologic toxicity through improved PK properties, especially partition of compound between plasma and RBC. Moreover, this improved PK properties of the QL compounds allowed for sufficient distribution outside the blood compartment and induced tumor growth inhibition in some types of solid cancer xenograft models that were sensitive to proteasome inhibition. These results indicate that non-covalent and rapidly reversible proteasome inhibitors are an ideal strategy for multiple myeloma and potential agents for solid tumors. Citation Format: Won-Gyun Ahn, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky, Axel Choidas, Ayesha Pasha, Bert Klebl, Robert Huber, Michael Hamacher, Kiyean Nam. A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 416.

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Raje, Noopur, Edward Anthony Faber, Paul G. Richardson, Gary J. Schiller, Raymond J. Hohl, Adam D. Cohen, Andres Forero et al. « Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma ». Blood 120, n^o 21 (16 novembre 2012) : 447. http://dx.doi.org/10.1182/blood.v120.21.447.447.

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Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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Jakubowiak, Andrzej J., Don M. Benson, William Bensinger, David S. Siegel, Todd M. Zimmerman, Ann Mohrbacher, Paul G. Richardson, Daniel EH Afar, Anil K. Singhal et Kenneth C. Anderson. « Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma : Updated Results of a Phase 1 Study ». Blood 116, n^o 21 (19 novembre 2010) : 3023. http://dx.doi.org/10.1182/blood.v116.21.3023.3023.

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Abstract Abstract 3023 Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods: The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on days 1 and 11 in combination with bortezomib (1.3 mg/m2 IV) administered on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone 20 mg PO was added for patients with disease progression after cycle 2 or 3 on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles. Patients with stable disease or better after 4 cycles continued treatment until disease progression or unexpected toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses were assessed during each cycle using European Group for Bone Marrow Transplantation (EBMT) criteria. Results: The 28 enrolled patients had a median time since MM diagnosis of 3.5 years and had received a median of 2 prior therapies; 11 patients (39%) had received prior bortezomib, 4 (14%) were refractory to bortezomib, and 12 (43%) were refractory to their last therapy. Three patients each received the 2.5, 5, and 10 mg/kg doses of elotuzumab and 19 received 20 mg/kg. No DLTs were observed during cycle 1 and the MTD was not reached. After a median of 6 cycles of therapy (range, 1–25 cycles), 2 patients remain on therapy. Serious adverse events related to elotuzumab were 1 grade 3 chest pain and 1 grade 3 gastroenteritis. The most frequent grade 3/4 AEs were lymphopenia (25%), fatigue (14%), thrombocytopenia, neutropenia, hyperglycemia, peripheral neuropathy, and pneumonia (11%), and leukopenia and anemia (7%). Twenty-seven patients completed at least 2 cycles of therapy or progressed earlier and were therefore evaluable for response (Table). An objective response (≥ PR) was observed in 13/27 (48%) evaluable patients, including 7% CR and 41% PR. A clinical response (≥ MR) was seen in 17/27 (63%) evaluable patients. Notably, a partial response was seen in 2 (50%) of 4 patients refractory to prior bortezomib. The objective response rate (ORR) was 60% (6/10), 50% (6/12), and 20% (1/5) in patients who had received 1, 2, or 3 previous lines of therapy, respectively. Analysis of bone marrow plasma cells indicated that 10 and 20 mg/kg elotuzumab doses resulted in complete or near complete saturation of CS1 sites by elotuzumab. Median time to progression was 9.46 months in the overall population as well as in the bortezomib-naïve population. Conclusions: The combination of elotuzumab and bortezomib had a manageable safety profile. Key toxicities attributable to elotuzumab appeared to be related to infusion reactions. The combination showed promising efficacy with an ORR of 48% and a clinical response rate of 63%. Notably, activity was seen in bortezomib-refractory patients (ORR = 50%). The median time to progression was 9.46 months for both the overall and the bortezomib-naïve populations. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson, Centocor Ortho Biotech: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor Ortho Biotech: Speakers Bureau. Off Label Use: Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study. Bensinger:Millennium Pharmaceuticals, Celgene Corp., Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Zimmerman:Millennium, Celgene: Speakers Bureau. Mohrbacher:Millennium: Speakers Bureau. Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Afar:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Millennium, Celgene, Novartis, Onyx, Merck, Bristol-Myers Squibb: Consultancy; Acetylon: Stock Options; Acetylon: Membership on an entity's Board of Directors or advisory committees.

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Flint, Oliver P., Jae Kwagh, Faye Wang, Frederic Moulin, Jan Oberdoerster, David Berman et Bruce Car. « Tanespimycin Prevents Bortezomib Toxicity and Preserves Neuronal Morphology in Primary Rat Dorsal Root Ganglion Cultures. » Blood 114, n^o 22 (20 novembre 2009) : 2847. http://dx.doi.org/10.1182/blood.v114.22.2847.2847.

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Abstract Abstract 2847 Poster Board II-823 INTRODUCTION: Tanespimycin, an inhibitor of Hsp90, is in phase 3 clinical trials in combination with bortezomib in patients with relapsed/refractory multiple myeloma (MM). The combination of tanespimycin and bortezomib produces synergistic antitumor activity and enhanced proteasome inhibition in primary MM cells (Mitsiades, Blood, 2006). In a phase 1/2 study in 72 patients with relapsed/refractory myeloma, tanespimycin + bortezomib produced durable responses in patients including bortezomib-refractory patients. Bortezomib-induced peripheral neuropathy (PN) is the key dose-limiting toxicity in patients with MM. In rat models of bortezomib-induced PN, tanespimycin is neuroprotective and can reverse bortezomib-induced PN. No Grade 3/4 PN was reported in the phase 1/2 study. OBJECTIVE: To explore the mechanism of tanespimycin-mediated neuroprotection from bortezomib-induced neurotoxicity in primary rat dorsal root ganglion (DRG) cells. METHODS: Differentiated DRG cultures prepared from rat fetuses were treated for up to 24 hours with tanespimycin alone, bortezomib alone, or the combination of tanespimycin + bortezomib. Total cell ATP, caspase 3/7 induction, calpain activity, and chymotrypsin-like activity of the proteasome were analyzed as measures of cell viability, apoptosis, neuron-specific protease activity, and proteasome function, respectively. Neuronal morphology was evaluated by light microscopy. RESULTS: At concentrations ≥100 nM, both bortezomib and tanespimycin induced a rapid increase in apoptosis (up to a fivefold increase in caspase activity) associated with reduced cell viability (based on ATP levels) to 20% of control values. In addition, bortezomib at ≥100 nM visibly shortened neurite extensions from DRG cell bodies. When DRG cells were co-exposed to both tanespimycin (500 nM) and bortezomib (320 nM–2.5 μM), the inhibitory effects of bortezomib on cell viability and neurite extension were ameliorated. At concentrations as low as 100 nM, tanespimycin completely and reproducibly abrogated the induction of caspase activity at all bortezomib concentrations tested (ie, 0.15–100 μM). When administered alone, bortezomib and tanespimycin had opposite effects on proteasome and calpain activity; bortezomib inhibited all proteasome and calpain activity at concentrations >1 μM, while tanespimycin (100 nM–10 μM) induced calpain and proteasome activity by up to fivefold and threefold, respectively. When DRG cells were exposed to both bortezomib (<1 μM) and tanespimycin, tanespimycin (10 nM–1 μM) induction of the proteasome ameliorated bortezomib proteasome inhibition. Similarly, but to a lesser extent, tanespimycin also overcame the bortezomib-induced inhibition of calpain activity. CONCLUSION: In primary rat DRG cells, tanespimycin prevented bortezomib-induced apoptosis and loss of cell viability in cultures and restored neuronal morphology. These neuroprotective effects of tanespimycin are consistent with the effects observed in rat models of bortezomib-induced PN and with the lack of severe PN observed in patients in the phase 1/2 study of tanespimycin + bortezomib in MM. The mechanism for the protective effect of tanespimycin on bortezomib-induced neuronal toxicity in MM is currently being explored. Disclosures: Flint: Bristol-Myers Squibb: Employment, Equity Ownership. Moulin:Bristol-Myers Squibb: Employment. Oberdoerster:Bristol-Myers Squibb: Employment. Berman:Bristol-Myers Squibb: Employment.

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Ghobrial, Irene, Abdel Kareem A. Azab, Jacob P. Laubach, Ranjit Banwait, Meghan Rourke, Phong Quang, Nikhil C. Munshi et al. « Phase I Trial of Plerixafor and Bortezomib as a Chemosensitization Strategy In Relapsed or Relapsed/Refractory Multiple Myeloma ». Blood 116, n^o 21 (19 novembre 2010) : 1943. http://dx.doi.org/10.1182/blood.v116.21.1943.1943.

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Abstract Abstract 1943 Introduction: Plerixafor (Mozobil®), a potent CXCR4 inhibitor, is approved in combination with G-CSF to mobilize hematopoietic stem cells (HSCs) for autologous transplantation in multiple myeloma (MM) and non Hodgkin's lymphoma (NHL). Another area of investigation consists of exploring whether disruption of the CXCR4 pathway by plerixafor could potentiate the effect of chemotherapy in active disease. This study aimed to establish the maximum tolerated dose (MTD) of plerixafor in combination with bortezomib in patients who have active relapse/refractory MM. This was informed by preclinical studies showing that plerixafor induces de-adhesion of MM cells with sensitization to combination therapy with bortezomib in pre-clinical animal models. Methods: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) measurable disease, 3) not receiving chemotherapy> 3weeks, or biological/novel therapy for MM > 2 weeks. Patients with active disease received plerixafor at the recommended dose sc on days 1–6 of every cycle. Dose levels include 0.16, 0.24, 0.32, 0.40, and 0.48 mg/kg. Bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Dose levels include 1.0 and 1.3 mg/m2. Bortezomib was given 60–90 minutes after plerixafor. Patients were assessed after every cycle. Patients who had response or stable disease went on to receive a total of 8 cycles without planned maintenance therapy. 4 dose levels were initially planned at a maximum of 0.24 mg/kg plerixafor. The protocol was then modified to include 3 higher doses of plerixafor, to further evaluate the hypothesis that higher doses may induce better chemosensitization. To examine the in vivo effect of plerixafor and bortezomib on de-adhesion of MM cells and other accessory cells of bone marrow, blood samples were obtained from patients at 0, 2, 4 and 24 hours post-plerixafor injection on days 1 and 3, and time points 0, 2, and 4 hours on days 6, 10 and 13 of cycle 1 and examined for the presence of plasma cells or CD34+ cells using flow cytometry. Results: Thirteen patients have been treated to date, three in each cohort with cohort 5 currently enrolling. The median age is 60, the median lines of prior therapy is 2. All of the patients received prior bortezomib. Three patients were assessed by light chain, two patients had extramedullary disease. The median number of cycles on therapy was 5 (1-8). None of the patients came off study due to toxicity. To date, there have been no dose-limiting toxicities. Overall, the combination is very well tolerated. Grade 3 possibly related toxicities include lymphopenia (30%), hypophosphatemia (15%), anemia (8%), and hyponatremia (8%). No grade 2 or higher neuropathy has been noted in these patients. Twelve patients are evaluable for response, including 1 (8%) complete remission (CR) and 1 (8%) minimal response (MR), with an overall response rate including MR of 2 (16%) in this relapsed/refractory population. In addition, 8 (66%) patients had stable disease (SD), and 2 (18%) had progressive disease (PD). We also examined the number of plasma cells, CD34+ HSCs, and other accessory bone marrow cells (including endothelial progenitor cells and plasmacytoid dendritic cells) in the peripheral blood. Analysis of these samples is ongoing, but preliminary data indicate de-adhesion of plasma cells. Conclusions: : The combination of plerixafor and bortezomib is very well tolerated with minimal neuropathy or other toxicities. The responses observed are encouraging in this relapsed/refractory population. The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo indicates that these cells can be separated from their protective stromal environment which may make them more sensitive to chemotherapy. This study was supported by R01CA133799-01, and by Genzyme. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Martin, Thomas G., Sumeet Panjabi, Jiandong Kerr, Michael G. Martin et Mark S. Walker. « Association Of Treatment Induced Peripheral Neuropathy (TIPN) With Treatment Patterns and Outcomes In Patients (pts) With Newly Diagnosed Multiple Myeloma (NDMM) ». Blood 122, n^o 21 (15 novembre 2013) : 1750. http://dx.doi.org/10.1182/blood.v122.21.1750.1750.

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Abstract Background Peripheral neuropathy (PN) is associated with multiple myeloma (MM) and often exacerbated by anti-MM treatments. TIPN poses significant morbidity and may result in therapy modifications. The impact of TIPN on treatment patterns and outcomes is not well studied in “real world” settings. We examined the association between TIPN in NDMM with treatment changes and efficacy outcomes in community oncology practices. Methods This was a retrospective review of clinical practice data from 12 US practices. Included pts had NDMM between 1/1/2008 and 7/1/2010, received anti-MM therapy and were ≥ 18 years of age at initiation of front line therapy. Inclusion was stratified with approximately half of the sample having TIPN from initial therapy (i.e. before 1stdocumented disease progression), as confirmed through review of medical records. Front line therapies were classified as those that included: 1) Lenalidomide (L), 2) Thalidomide (T), 3) Bortezomib ± Thalidomide (B), 4) Lenalidomide + Bortezomib (LB), and 5) Other regimens (O). Multivariate Cox regression models were used to identify pt level risk factors for TIPN, including regimen. Cox models with time varying covariates were used to predict: a) time to dose reduction; b) time to delay, discontinuation or switch; c) time to progression (TTP), and d) overall survival (OS). TIPN was modeled as a binary, time varying predictor of each outcome (pt observation split by non-TIPN and TIPN intervals), controlling for demographic and clinical characteristics, and treatment regimen. Results Mean age of sampled patients (n=229) was 66.6 years (range 40-91), 49.3% were female, 58.5% Caucasian, and 34.9% African American. Of 229 pts, 112 experienced TIPN during front line therapy. Of the 117 without TIPN, 23 (19.7%) experienced PN during front line that was not attributed to treatment. Relevant comorbidities were higher in the TIPN than non-TIPN pts but not significantly different; diabetes (26.8% v 21.4%, p =0.360) and renal disease (26.8% v 20.5%, p=0.28). TIPN severity during front line treatment was reported as severe (22.3%), moderate (25.9%), mild (25.0%), and unknown (26.8%). Front line treatment included B: 110 (48.0%), L: 36 (15.7%), O: 31 (13.5%), T: 30 (13.1%) and LB: 22 (9.6%), with B uniformly administered IV rather than SC. TIPN occurred in 69.6% of B containing vs. 30.4% of non-B containing regimens. Median duration of front line treatment ranged from 5.1 (O) to 6.74 months (R). Overall, 94 pts (41.0%) had dose reductions, and 117 pts (51.1%) had a delay, discontinuation or switch in therapy. Of the 117, 62 continued with front line therapy after the delay, discontinuation or switch. Overall median TTP was 27.7 months, and median OS was 47.9 months. Median time to TIPN in TIPN patients was 4.52 months. Regimen was a significant predictor of time to TIPN (p = .0056), with L (HR = .323, p = .0009) and O (HR = .455, p = .037) at lower risk than B. Table 1 shows that time varying TIPN was associated with dose reduction and treatment delay, discontinuation, or switch. Each analysis controlled for gender, age, presence of any relevant comorbidity, performance status, stage of disease, and regimen. For analysis of dose reduction, the only other significant pt level predictor was comorbid disease (HR = 1.903, p = .006). Other pt level covariates were not associated with predicting delay, discontinuation or switch. Gender was a significant predictor of TTP (HR = .643, p = .017), indicating lower risk for males. For analysis of OS, comorbid disease and age were significant (HR = 1.7, p = .02; 1 year HR = 1.035, p = .002, respectively), as was stage (p = .0038), with more advanced stage tending to be associated with higher risk. Conclusions This retrospective study of TIPN in MM showed that occurrence of TIPN was associated with increased risk of dose reduction, and of treatment delay, discontinuation or switch. TIPN was not significantly associated with TTP or OS, likely because most treatment modifications (including dose reduction) did not involve complete treatment discontinuation. Regimen combinations with a lower neurotoxicity burden should be considered in NDMM patients. Disclosures: Panjabi: Onyx Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Rowley, Scott D., David Siegel, Michele L. Donato, Andrew L. Pecora, Tatyana Feldman, Stuart Goldberg, Andre Goy et Aisha Masood. « Combination Melphalan and Bortezomib Conditioning with Autologous Hematopoietic Stem Cell Support in Patients with Advanced Multiple Myeloma. A Phase I/II Study. » Blood 114, n^o 22 (20 novembre 2009) : 1214. http://dx.doi.org/10.1182/blood.v114.22.1214.1214.

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Abstract Abstract 1214 Poster Board I-236 Bortezomib is an active agent in the treatment of multiple myeloma (MM) and shows additive or synergistic effects when combined with various chemotherapeutics in pre-clinical and clinical models. We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan with autologous peripheral blood stem cell transplantation (PBSCT) in patients (pts) with disease progression or less than partial response after a prior PBSCT (tandem transplant). Primary exclusion criteria are active infection at time of PBSCT, cardiac amyloid deposition, and creatinine clearance of <20 ml/min. Peripheral neuropathy of less than grade 4 is not an exclusion. Bortezomib is given on days -4 and -1 with melphalan 200 mg/m2 (actual weight) given on day -2 before PBSCT. All pts are given oral ice during the melphalan infusion to prevent oral mucositis. For the phase I study, bortezomib was given at rising doses of 1.0, 1.3, and 1.6 mg/m2. Three pts were to be enrolled at each dose level, with an additional 3 pts enrolled in case of a serious toxicity event at any level. An additional 20 pts are being enrolled in the phase II portion of the study. Twelve pts (median age, 59 yrs) were treated in the phase I study with 6 pts treated at the 1.0 mg/m2 level after 1 pt experienced an SAE of prolonged diarrhea, and 3 pts treated at each of the subsequent levels. Eleven pts had 1 prior and 1 pt tandem prior cycles of dose-intense melphalan with PBSCT. All pts experienced the expected pancytopenia requiring red cell and/or platelet support. Ten pts had febrile neutropenia with bacteremia identified in 3 pts. One pt had mild tumor lysis. Mucositis was minimal and comparable to PBSCT with melphalan alone. All pts engrafted at a median time to ANC>500/uL of 11 days (range, 9-19) and plt>20,000/uL of 14 days (range, 11-27). No other SAEs occurred in the phase I study beyond the usual events of high-dose therapy. No neurological SAEs, including severe peripheral neuropathies, were observed. A bortezomib dose of 1.6 mg/m2 was chosen for the phase II study. Eleven pts (median age, 57 yrs) are now treated in the phase II study. Three pts had disease progression and 8 pts had less than PR after a prior PBSCT. All pts experienced pancytopenia and 10 engrafted with median time to ANC>500/uL of 10 days (range, 8-13) and plt>20,000 11 days (range, 9-65). Seven pts had febrile neutropenia with 3 pts with positive blood cultures and 1 pt with RSV bronchitis. Three SAEs are reported in the phase II portion: 1 pt expired of complications of Candida krusei infection and 1 of MRSA sepsis (before ANC recovery). A third pt developed tumor lysis requiring dialysis. One pt had a dysphoric reaction to anti-emetics and did not receive the 2nd bortezomib dose. No neurological SAEs attributable to this regimen were observed in this population. Pts underwent restaging studies at monthly intervals after transplantation with marrow examination at 3 and 12 months (mos). Response classification is in accordance to standard definitions. Three pts underwent subsequent allogeneic PBSC and 2 pts died of transplant-related complications and are not evaluable for response. Two pts succumbed to progressive disease. The remaining 16 pts are in ongoing follow-up. Eight pts including 6 of 11 pts with stable disease or minimal response after prior dose-intense melphalan achieved a CR. Six pts remain in continuous CR at 11+ to 23+ mos (median, 15+ mos) after PBSCT with 2 pts having disease progression at 12 and 26 mo after PBSCT. These data indicate that bortezomib can be added to dose-intense melphalan in this schedule with acceptable toxicities. Strikingly, 8 of 20 pts achieved CR after minimal response to dose-intense melphalan alone or disease progression after a prior PBSCT, and 2 pts showed tumor lysis, indicating a synergistic effect of adding bortezomib to dose-intense melphalan. This regimen will now be studied in a larger cross-over study of tandem PBSCT to assess relative response to the two regimens. Disclosures: Off Label Use: Bortezomib is indicated in the treatment of multiple myeloma. This study involved the use of bortezomib in combination with dose-intense melphalan with stem cell transplantation.. Siegel:Millenium: Consultancy, Research Funding, Speakers Bureau. Goy:Millenium: Speakers Bureau.

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Rosiñol, Laura, Albert Oriol, Maria Victoria Mateos, Anna Sureda, Pedro García-Sánchez, Norma Gutiérrez, Adrián Alegre et al. « Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma : Efficacy and Clinical Implications of Tumor Response Kinetics ». Journal of Clinical Oncology 25, n^o 28 (1 octobre 2007) : 4452–58. http://dx.doi.org/10.1200/jco.2007.12.3323.

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PurposeThis is the first study in which bortezomib and dexamethasone were administered on an alternating basis as up-front therapy in multiple myeloma (MM). We investigated the efficacy and kinetics of response to each drug and safety.Patients and MethodsPatients with newly diagnosed MM who were less than 66 years old were treated with bortezomib at 1.3 mg/m2on days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 to 12, and 17 to 20 (cycles 2, 4, and 6), followed by autologous stem-cell transplantation (ASCT). Responses were evaluated by modified European Bone Marrow Transplantation criteria. Random effects models were used to analyze the tumor response kinetics.ResultsForty patients were enrolled. Partial response (PR) or greater was 65% (12.5% complete response [CR], 10% very good PR [VGPR], and 42.5% PR) plus 17.5% minor response. Time to response was rapid, with 82% serum M-protein reduction achieved within the first two cycles. The M-protein decrease was similar with dexamethasone and with bortezomib (P = .48). Chromosome 13 deletion, t(4;14), and t(14;16) did not have a negative impact on response. Toxicity was low, with no grade 3 to 4 peripheral neuropathy and no grade 2 to 4 thrombocytopenia. The response rate after ASCT was 88%, with 33% CR (negative immunofixation) plus 22% VGPR.ConclusionBortezomib alternating with dexamethasone is a highly effective induction regimen with low toxicity. The kinetic study has shown a high degree of heterogeneity in response and rapid effect from both agents, supporting the use of a short induction regimen before ASCT in MM.

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Weber, Donna M., Sundar Jagannath, Amitabha Mazumder, Ronald Sobecks, Gary J. Schiller, Maria Gavino, Chantelle Sumbler et al. « Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma. » Blood 110, n^o 11 (16 novembre 2007) : 1172. http://dx.doi.org/10.1182/blood.v110.11.1172.1172.

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Abstract Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated antiproliferative and proapoptotic activity alone and in combination with the proteasome inhibitor bortezomib in preclinical multiple myeloma (MM) models. In a Phase I study, vorinostat also demonstrated modest single agent activity in patients (pts) with relapsed or refractory MM. Patients and Methods: We conducted a Phase I trial of oral vorinostat (200 mg bid or 400 mg daily × 14 days (d1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on d 4, 8, 11 and 15 or 0.9, 1.1, or 1.3 mg/m2 i.v. on d 1, 4, 8 and 11. Cycles were repeated every 21 d for a maximum of 8 cycles until progressive disease (PD) or intolerable toxicity. Pts with active relapsed or refractory MM who had not received bortezomib in the preceding 3 months and with adequate hematologic, hepatic, and renal function, and ECOG performance status of 0–2 were eligible. The primary objective was to determine the maximum tolerated dose (MTD). Activity (utilizing EBMT criteria) and safety of the combination regimen were also assessed. Results: Twenty pts have been enrolled: median age, 61 years (range 52–76), median number prior systemic therapies, 3 (range 1–14), prior therapy with bortezomib (4 pts). Eighteen pts have received ≥ 1 dose and were evaluable for safety as of 7/1/07. One pt (cohort 3) experienced a dose-limiting toxicity (DLT, Table). The MTD has not been reached. The most common drug-related toxicities of any grade were nausea (56%), thrombocytopenia (50%), diarrhea (39%), vomiting (39%), fatigue (39%), and anemia (22%). Grade ≥ 3 drug-related adverse events were thrombocytopenia (33%, none associated with bleeding), peripheral neuropathy (11%), neutropenia (11%, none associated with fever), diarrhea (6%), diverticulitis (6%), fatigue (6%), increased AST (6%), memory changes (6%), nausea (6%), vomiting (6%), and upper respiratory infection (6%). Eight pts discontinued treatment, 3 due to PD and 5 due to adverse experiences [fatigue (2), nausea (2), diverticulitis (1)]. Of 17 evaluable pts for efficacy, all had measurable response or stable disease; 4 had a partial response, 2 had a minimal response, and 11 stable disease. Among 3 evaluable pts previously treated with bortezomib, 1 achieved a partial response and 1, minimal response. Pts at the highest dose level were not yet evaluable for response. Conclusion: Although accrual continues to determine the MTD, the combination of vorinostat and bortezomib is well tolerated and effective in this group of heavily pretreated pts with refractory/relapsed MM. Table Cohort Vorinostat Dose (mg) Bortezomib Dose (mg/m2) N # of Cycles DLTs Best Response MR = minimal response; NE = not evaluable; PR = partial response; SD = stable disease. *Days 4, 8, 11 and 15. †Days 1, 4, 8 and 11. ‡Treatment cycle in progress. 1 200 0.7* 3 3, 3, 14 - SD (2), PR 2 200 0.9* 3 4, 5, 6 - SD (2), PR 3 400 0.9† 6 2, 3, 5, 6, 6, 6 Transient AST elevation SD (3), MR, PR (2) 4 400 1.1† 5 3, 3, 4, 5, 11 - SD (4), MR 5 400 1.3† 3 1‡, 1‡, 2 - NE (3)

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Bahlis, Nizar J., Rami Kotb, Michael Sebag, Heather J. Sutherland, Richard LeBlanc, Darrell White, Christopher P. Venner et al. « Selinexor in Combination with Bortezomib and Dexamethasone (SdB) Demonstrates Significant Activity in Patients with Refractory Multiple Myeloma (MM) Including Proteasome-Inhibitor Refractory Patients : Results of the Phase I Stomp Trial ». Blood 128, n^o 22 (2 décembre 2016) : 977. http://dx.doi.org/10.1182/blood.v128.22.977.977.

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Abstract Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (dex) has demonstrated potent anti-cancer activity in patients with heavily pretreated MM. While the development of proteasome inhibitors (PIs) has transformed the treatment of MM, acquired resistance to PIs limit their efficacy. Preclinical studies have shown that selinexor, when combined with bortezomib, can restore sensitivity of bortezomib-resistant MM to this drug, inducing tumor growth inhibition and increasing survival in MM models in mice. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dex (SdB) in patients (pts) with refractory MM. Methods - This phase 1b/2 dose escalation study using a standard 3+3 design, was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for SdB. The study included pts with refractory MM, after ≥ 1 prior therapy. Pts with prior PI relapsed and/or refractory disease were included, provided the patient's MM was not refractory to bortezomib as last therapy. Selinexor was independently dosed escalated in once-weekly (QW, starting at 80 mg; N=7, 100 mg N=6 pts) or twice-weekly (BIW, starting at 60 mg; N=3, 80 mg N=6 pts) regimens. Bortezomib (1.3 mg/m2 sc) was administered either once-weekly or twice-weekly and dex was given orally 40 mg QW or 20 mg BIW. Results - As of July 25th, 2016, enrollment in the dose escalation cohorts has been completed with 22 pts (12 male /10 female). The median age is 65 years (range, 46 - 74), with a median of 4 (range, 1 - 12) prior treatment regimens. One dose limiting toxicity (Grade 4 thrombocytopenia without bleeding) in the 80 mg BIW cohort was observed but the MTD has not been reached. Common related grade 1/2 adverse events (AEs) include: fatigue 41%, nausea 41%, anorexia 36%, and weight loss 18%. Grade 3/4 AEs include: thrombocytopenia 41%, anemia 18%, and neutropenia 18%. One case of grade 1 peripheral neuropathy in the 80 mg BIW cohort was reported. All pts were evaluable for response. The ORR (≥partial response, PR) was 77% with ≥VGPR 27% (1 pt in CR and 5 pts in VGPR) and 11 PRs. There were 3 minor responses (14%), 1 stable disease, 1 progressive disease (5% each). Seven of the 12 pts with PI-refractory MM responded (ORR 58%). A summary of response by PI treatment history is shown in Table 1. Ten patients have remained on study >4 months, including 7 patients still on trial (longest >9 months). Based on tolerability and anti-MM activity, RP2D of SdB is selinexor 100 mg, bortezomib 1.3 mg/m2 and dex 40 mg, all given once weekly. At the RP2D, all six pts achieved ≥PR (ORR 100%). Conclusions - Selinexor in combination with bortezomib and dex is well tolerated and highly active in refractory MM. Toxicities are manageable and similar to selinexor or bortezomib monotherapy. Peripheral neuropathy is uncommon, consistent with the use of weekly bortezomib sc and the lack of neuropathy with selinexor. Overall, the SdB regimens induced an ORR of 77% with ≥VGPR of 27%. In patients with PI-refractory MM, the ORR was 58%, indicating that the addition of selinexor restores sensitivity to bortezomib. These results confirm the preclinical data supporting synergistic effects of selinexor when combined with PIs. This promising, once-weekly treatment regimen may provide deeper and more durable responses in pts with relapsed / refractory MM, including those with PI-refractory disease. Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Disclosures Bahlis: Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria. Sebag:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Sutherland:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Amgen: Honoraria; J+J: Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Kouroukis:Amgen: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Takeda: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding.

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Ghobrial, Irene M., Ranjit Banwait, Abdel Kareem Azab, Phong Quang, Jacob P. Laubach, Amanda Donovan, Meghan Bagshaw et al. « Phase I Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma ». Blood 118, n^o 21 (18 novembre 2011) : 1874. http://dx.doi.org/10.1182/blood.v118.21.1874.1874.

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Abstract Abstract 1874 INTRODUCTION: This study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Genzyme Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. METHODS: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy > 3 weeks, or biological therapy for MM > 2 weeks prior to study treatment. Eight cohorts with different doses and two treatment schedules were planned. In cohorts 1–5, patients received plerixafor at the recommended dose sq on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. To test the hypothesis that higher doses and a different schedule might induce better chemosensitization, in cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Bortezomib was given 60–90 minutes after plerixafor. Patients were assessed after every cycle by modified EBMT/UC criteria. Patients who had a response or stable disease went on to receive a total of 8 cycles with maintenance therapy for patients with at least a minimal response (MR). To examine the in vivo effect of plerixafor and bortezomib on de-adhesion of MM cells and other accessory cells of the bone marrow, peripheral blood samples were obtained from the patients at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. RESULTS: Twenty-five patients were enrolled in this phase I trial from June 2009 to May 2011. Median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). Overall, the combination proved to be well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). One patient came off treatment due to grade 2 painful neuropathy at cycle 5. Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR) and 3 (13%) MR, with an overall response rate (including MR) of 5 (22%) in this relapsed and refractory population. In addition, 15 (65%) patients achieved stable disease (SD), with just 3 (13%) having progressive disease (PD) as their best response. We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3, but less mobilization occurred on the following days. Hematopoietic stem cell mobilization occurred at 4 hours on days 1 and 3, and was less observed with subsequent doses of plerixafor consistent with prior studies. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are encouraging in this relapsed and refractory population. The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo in most of the patients indicates that chemosensitization can potentially be achieved in patients with MM using this approach. Further studies are warranted and a phase 2 trial is underway. This study was supported by R01CA133799-01, and by Genzyme Corporation. Disclosures: Ghobrial: Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Plerixafor in myeloma. Munshi:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy; Celgene: Consultancy. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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Voorhees, Peter M., Cristina Gasparetto, Kristy L. Richards, Reynaldo Garcia, John S. Strader, Madlyn Ferraro, Jennifer MacLean et al. « Vorinostat in Combination with Pegylated Liposomal Doxorubicin and Bortezomib for Patients with Relapsed/Refractory Multiple Myeloma : Results of a Phase I Study. » Blood 114, n^o 22 (20 novembre 2009) : 306. http://dx.doi.org/10.1182/blood.v114.22.306.306.

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Abstract Abstract 306 Introduction: Histone deacetylase inhibitors potentiate the efficacy of anthracyclines and proteasome inhibitors in preclinical models of multiple myeloma (MM). We therefore conducted a phase I clinical trial to evaluate the safety of the histone deacetylase inhibitor, vorinostat, in combination with pegylated liposomal doxorubicin (PLD) and bortezomib for patients with relapsed/refractory MM. Patients and Methods: Patients received bortezomib at 1.3mg/m2 on days 1, 4, 8, and 11; PLD at 30mg/m2 on day 4, and escalating doses of vorinostat (200 to 400mg once daily) on days 4 through 11 of a 3-week cycle. Dose escalation followed a standard “3 + 3” design. Patients remained on therapy until disease progression or unacceptable toxicity. Eligibility criteria included an ANC of ≥1.0×109/L, platelets of ≥100×109/L, a CrCl of ≥30 mL/min., and adequate hepatic and cardiac function. The primary objectives of the study were to establish dose limiting toxicities (DLTs) in cycle 1 and the maximum tolerated dose (MTD) for future phase II testing. Results: Nine patients have enrolled thus far at vorinostat dose levels of 200mg (n=3), 300mg (n=4), and 400mg (n=2). Six patients had relapsed disease, while 3 had relapsed disease that was refractory to their last prior therapy. The median age was 56 (range 44–73), median time from diagnosis was 66 months (range 28 to 117), and median prior number of lines of therapy was 2 (1 to 7). Six of 9 patients received prior bortezomib, 3 of whom were refractory, 7 of 9 had received anthracyclines, 9 of 9 were treated with corticosteroids, 8 of 9 were treated with immunomodulatory agents, and 7 of 9 had undergone autologous stem cell transplantation. One patient was removed from the study at the 300mg vorinostat dose level due to a grade 3 infusion reaction with the first dose of PLD and was not evaluable for DLT or response. Otherwise, there have been no DLTs, serious adverse events, or deaths to date. Common non-hematologic toxicities of all grades have included fatigue (44%), constipation (67%), diarrhea (67%), nausea (56%), vomiting (33%), and peripheral neuropathy (56%), the majority of which were grade 1 and 2 in severity. Grade 3 sensory neuropathy was seen in 2 patients. Common hematologic toxicities of all grades have included neutropenia (44%), lymphopenia (44%), and thrombocytopenia (67%). Grade 3/4 neutropenia, lymphopenia and thrombocytopenia were seen in 2, 3, and 2 patients, respectively. Dose reductions for non-hematologic toxicities have been necessary for 3 patients thus far. Using International Myeloma Working Group criteria, 6 out of 7 evaluable patients have responded to treatment, including 1 complete remission (CR), 1 very good partial remission, and 4 partial remissions (PRs). The only non-responder was assigned to the 200mg vorinostat dose level. PRs were seen in 2 of 3 patients with bortezomib-refractory disease. Conclusions: At the dose levels tested thus far, the addition of vorinostat to the PLD/bortezomib backbone is safe and efficacious in relapsed/refractory MM patients, including those with bortezomib-refractory disease. Cumulative constitutional, gastrointestinal, and neurologic toxicities are common but manageable, and will need to be considered when determining the optimal phase II dose moving forward. Enrollment into the 400mg dose cohort continues. Disclosures: Voorhees: Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Off Label Use: Vorinostat for the treatment of multiple myeloma. Gasparetto:Millennium Pharmaceuticals: Consultancy, Speakers Bureau. Richards:Cephalon, Inc.: Speakers Bureau. Garcia:Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. MacLean:Novartis: Speakers Bureau. Foster:Genzyme: Consultancy, Research Funding. Shea:Otsuka: Research Funding; Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Research Funding; Genzyme: Consultancy, Research Funding; Genetech: Consultancy. Rizvi:Merck: Employment.

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Rosiñol, L., A. Oriol, M. Mateos, A. Sureda, J. Díaz-Mediavilla, C. Herrero, X. Liu, H. Van de Velde, J. San Miguel et J. Bladé. « Final results of a phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma (MM) : Efficacy and clinical implications of tumor response ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 8024. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8024.

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8024 Background: Dexamethasone-based combinations are the standard induction regimens for younger patients with MM prior ASCT. This is the first study in which bortezomib and dexamethasone were administered on an alternating basis. Aims: efficacy and kinetics of response. Methods: patients with newly diagnosed MM under the age of 66 years were treated with bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1–4, 9–12 and 17–20 (cycles 2, 4 and 6), followed by ASCT with melphalan-200. Responses were evaluated by the EBMT criteria but a VGPR was included. Random effects models were utilized to analyze the tumor response kinetics to bortezomib and dexamethasone with the absolute value of M-protein overtime and decrease by cycle. Because the nonlinearity in the change of M-protein overtime, a piecewise linear model was employed. Results: between August, 2005 and March, 2006, 40 patients (median age 57) were enrolled. The response rate was 82% with 12% CR plus 10% VGPR. The response was quick with 82% M-protein reduction achieved with the first 2 cycles. There was no further decrease of the mean M-protein in cycles 5 and 6. The M-protein decrease was not different with dexamethasone and with bortezomib (p=0.48). Chromosome 13 deletion as well as t(4;14) and t(14;16) did not had a negative impact on response. Toxicity was very low: ten (25%) patients had mild peripheral neuropathy (grade 1:9 cases, grade 2:1 case) and 11 grade 1 thrombocytopenia. Grade 3 toxicity was observed in 7 patients (neutropenia 6, skin/liver 1 case). No patient developed grade 4 toxicity. In all patients stem cells could be adequately collected (median of CD34+ 5 ×106/Kg). The overall response rate after ASCT was 90% with 40% CR plus 20% VGPR. Conclusions: Bortezomib alternating with dexamethasone is highly effective as up-front therapy in patients with MM, and is associated with a very low toxicity. The results of the tumor response kinetics analysis support a short program of alternating bortezomib and dexamethasone (i.e., maximum of 4 cycles) as an effective and safe therapy for younger myeloma patients prior ASCT. [Table: see text]

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Kohler, Siegfried, Stefanie Märschenz, Ulrike Grittner, Tobias Alexander, Falk Hiepe et Andreas Meisel. « Bortezomib in antibody-mediated autoimmune diseases (TAVAB) : study protocol for a unicentric, non-randomised, non-placebo controlled trial ». BMJ Open 9, n^o 1 (janvier 2019) : e024523. http://dx.doi.org/10.1136/bmjopen-2018-024523.

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IntroductionThe clinical characteristics of autoantibody-mediated autoimmune diseases are diverse. Yet, medical treatment and the associated complications are similar, that is, the occurrence of long-term side effects and the problem that a significant proportion of patients are non-responders. Therefore, new therapeutic options are needed. Bortezomib, a proteasome inhibitor, is effective in the treatment of multiple myeloma and data from experimental models and case reports suggest an effect in the treatment of autoantibody-mediated autoimmunity. In our study, we will determine the effect of bortezomib treatment on a shared surrogate parameter for clinical efficacy, namely change in autoantibody levels, which we chose as primary parameter.Methods and analysisWe designed a phase IIa trial with altogether n=18 treatment-refractory patients suffering from myasthenia gravis, systemic lupus erythematosus and rheumatoid arthritis that will be treated with bortezomib add-on to pre-existing therapy. Primary endpoint is the change in autoantibody levels 6 months after therapy. Secondary endpoints include concomitant medication, disease-specific clinical scores and measures of quality of life and activities of daily living.Ethics and disseminationSafety parameters include neurophysiological and clinical signs of peripheral neuropathy as well as potential central nervous system side effects determined by olfactory and neuropsychological testing. The study has been approved by the local ethical committee and first participants have already been enrolled. This proof of concept study will contribute to improve our understanding of plasma cell-specific treatment approaches by assessing its safety and efficacy in reducing serum levels of antibodies known to mediate autoimmune disorders.We plan to publish the final results of our study in a peer reviewed journal and to present our findings at international conferences.Trial registration numberNCT02102594.

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Ghobrial, Irene M., Kenneth Shain, Courtney Hanlon, Ranjit Banwait, Abdel Kareem Azab, Jacob P. Laubach, Philippe Armand et al. « Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy In Relapsed Or Relapsed/Refractory Multiple Myeloma ». Blood 122, n^o 21 (15 novembre 2013) : 1947. http://dx.doi.org/10.1182/blood.v122.21.1947.1947.

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Abstract Introduction This study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). The phase I portion of this study was to determine the maximum tolerated dose (MTD). The phase II portion was designed to assess the toxicity profile and the proportion of overall confirmed response (CR + PR). This was based on preclinical studies demonstrating that plerixafor (Mozobil, Sanofi Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. Methods Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy > 3 weeks, or biological therapy for MM > 2 weeks prior to study treatment. Phase I included eight cohorts with different doses and two treatment schedules. In cohorts 1–5, patients received plerixafor at the recommended dose subcutaneously (sq) on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. Patients in both cohorts were assessed after every cycle by IMWG criteria. Patients who had a response or stable disease went on to receive a total of 8 cycles with maintenance therapy for patients with at least a minimal response (MR). Peripheral blood samples were obtained from the patients in the phase I portion of trial at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. Results Twenty-five patients were enrolled in the phase I portion of trial from June 2009 to May 2011. Median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). In the phase II portion, eleven patients have been treated to date. The median age is 65 (56-80), the median lines of prior therapy were 2 (1-4). The median number of cycles on therapy was 4 (1-8). Grade 4 toxicities include lymphopenia (10%) and thrombocytopenia (20%). Grade 3 toxicities include anemia (10%), thrombocytopenia (10%), lymphopenia (20%), hyperglycemia (10%), and hypophosphatemia (10%). Ten patients are evaluable for response, including 1(10%) very good partial response (VGPR) and 3 (30%) partial response (PR), with an overall response rate (VGPR + PR) of 4 (40%) in this relapsed/refractory population. In addition, 4 (40%) patients had stable disease (SD), and 2 (20%) had progressive disease (PD). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3. Conclusions The combination of plerixafor and bortezomib was generally well tolerated in this study, with minimal neuropathy or other toxicities seen to date. The responses observed are encouraging with 40% PR or better in this relapsed and refractory population including prior bortezomib therapy. This study was supported by R01CA133799-01, and by Sanofi and Millennium/Takeda Corporations. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

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Ghobrial, Irene M., Nikhil C. Munshi, Brianna N. Harris, Zheng Yuan, Nichole M. Porter, Robert L. Schlossman, Jacob P. Laubach et al. « A Phase I Safety Study of Enzastaurin Plus Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma. » Blood 114, n^o 22 (20 novembre 2009) : 1870. http://dx.doi.org/10.1182/blood.v114.22.1870.1870.

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Abstract Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Ghobrial, Irene M., Jacob P. Laubach, Kenneth H. Shain, Rachid Baz, Erica N. Boswell, Patrick M. Henrick, Abdel Kareem Azab et al. « Phase I/II Trial of Plerixafor and Bortezomib As a Chemosensitization Strategy in Relapsed or Relapsed/Refractory Multiple Myeloma ». Blood 124, n^o 21 (6 décembre 2014) : 5777. http://dx.doi.org/10.1182/blood.v124.21.5777.5777.

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Abstract INTRODUCTION: This study aimed to determine the safety and activity of plerixafor (CXCR4 inhibitor) in combination with bortezomib as a chemosensitization strategy in multiple myeloma (MM). The phase I portion of this study was to determine the maximum tolerated dose (MTD). The phase II portion was designed to assess the toxicity profile and the proportion of overall confirmed response (CR + PR). This was based on preclinical studies demonstrating that plerixafor (Mozobil, Sanofi Corporation, MA) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. METHODS: Eligibility criteria included: 1) patients with relapsed or relapsed/refractory MM with 1–5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib), 2) measurable disease, 3) not receiving chemotherapy < 3 weeks, or biological therapy for MM < 2 weeks prior to study treatment. Phase I included eight cohorts with different doses and two treatment schedules. In cohorts 1–5, patients received plerixafor at the recommended dose subcutaneously (sq) on days 1–6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. Cohort 5b–7 plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. Patients who had a response or stable disease went on to receive a total of 8 cycles followed by maintenance therapy. Peripheral blood samples were obtained from the patients in the phase I portion of trial at 0, 1, 2, 3, 4 and 24 hours post-dose on days 1 and 3, and time points 0, 2, and 4 hours post-dose on days 6, 10 and 13 of cycle 1. RESULTS: Twenty-five patients were enrolled in the phase I portion of trial and 23 patients in the phase II study. In the phase I study, the median age was 60 years (range, 44–85) and median lines of prior therapy were 2 (range, 1–4) with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 3 (1–11). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). To further explore the safety of maximum tolerated dose, three additional patients were enrolled at dose level 5b. There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). In the phase II portion, twenty-three patients have been treated to date. The median age was 70 (56-83), the median lines of prior therapy were 3 (1-5). The median number of cycles on therapy was 7 (1-12). Grade 4 toxicities include lymphopenia (9%), thrombocytopenia (17%) and pneumonia (4%). Grade 3 toxicities included anemia (9%), thrombocytopenia (17%), neutropenia (4%), lymphopenia (13%), hyperglycemia (9%), hypophosphatemia (9%), elevated ALT, AST and Lipase (4%). In the phase I study, 23 patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR) and 3 (13%) MR. In addition, 15 (65%) patients achieved stable disease (SD). For the phase II study, the response rate of PR or better was 13/23 (43%) including 4 (17%) VGPR and 6 (26%) PR in this relapsed/refractory population. In addition, 7 (39%) patients had stable disease (SD), and 3 (13%) had progressive disease (PD). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. Similar results were observed on days 1 and 3. CONCLUSIONS: The combination of plerixafor and bortezomib was very active in this study, with minimal neuropathy or other toxicities seen to date, and the regimen was generally well tolerated. The responses observed are encouraging, with 43% PR or better in this relapsed and refractory population, including patients with significant exposure to prior bortezomib therapy. Disclosures Ghobrial: Sanofi: Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other. Off Label Use: Plerixafor is not FDA approved for relapsed myeloma. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Schlossman:Millennium: Consultancy. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

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Richardson, P. G., A. Chanan-Khan, S. Lonial, A. Krishnan, M. Carroll, M. Alsina, M. Albitar, D. Berman, S. Kaplita et K. Anderson. « Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma : Final results of a phase I/II study ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : 8503. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.8503.

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8503 Background: Tanespimycin (Tan) disrupts HSP90, a key molecular chaperone for signal transduction proteins critical to myeloma (MM) growth, survival and drug resistance. Preclinical data show anti-tumor synergy between Tan and bortezomib (Bz) and suggest Tan may be neuroprotective, including reversibility of Bz-induced peripheral neuropathy (PN). A phase I study of single agent Tan in advanced MM showed favorable tolerability and modest activity. Methods: 72 patients (pts) with relapsed/refractory MM received 0.7 - 1.3 mg/m2 Bz as IVB followed by 1-hr infusion of 100 -340 mg/m2 Tan on days 1, 4, 8,11 q 21d, with 42 pts receiving the highest dose of both drugs as part of a phase II expansion. Toxicities were assessed by CTCAE v3 and response by modified EBMT criteria. Results: Of 72 pts, 72% had IgG subtype with a median age of 60 yo. Median time since MM diagnosis was 50 mos with median of 5 (1–15) prior regimens. Prior treatments included stem cell transplant (69%), thalidomide (74%), Bz (69%), lenalidomide (28%) and Hsp90 inhibitors (13%). 58 pts with measurable disease were treated at 1 or 1.3 mg/m2 Bz. Response rates (≥ MR) were 41%, 20% and 14% in the Bz-naive, -pretreated and -refractory pts respectively. In the subgroup with 1–3 prior therapies and who were Bz-naive, the response rate was 56%. Median duration of response (DOR) for all pts with response (n=14) was 10.7 mos, including 3 Bz-refractory pts who had durable PR through mos 12, 22 and 28. 3 other pts remain in response through 24 mos. Of the 72 pts, the most frequent AEs were diarrhea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%) and AST elevation (28%), which proved manageable with dose reduction and supportive care. Most frequent G3–4 AEs included thrombocytopenia (25%), diarrhea, anemia and fatigue (7% each), as well as back pain and AST elevation (4% each). Only 21% of pts had G1–2 PN; no G3–4 PN was seen. Conclusions: Tan + Bz is active and well tolerated in relapsed/refractory MM, with durable responses in Bz-naive, -pretreated and -refractory pts. Median DOR for the combination compares favorably to Bz monotherapy. Final PFS data will be presented. No severe PN has been observed, consistent with Tan's neuroprotective effect in pre-clinical models. A phase III study of Tan + Bz vs Bz is ongoing. [Table: see text]

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Jakubowiak, Andrzej J., William Bensinger, David Siegel, Todd M. Zimmerman, Jan M. Van Tornout, Carol Zhao, Anil Singhal et Kenneth Anderson. « Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies : Interim Results. » Blood 114, n^o 22 (20 novembre 2009) : 3876. http://dx.doi.org/10.1182/blood.v114.22.3876.3876.

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Abstract Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Das, Deepika Sharma, Durgadevi Ravillah, Arghya Ray, Yan Song, Paul G. Richardson, Mohit Trikha, Dharminder Chauhan et Kenneth C. Anderson. « Synergistic Anti-Myeloma Activity of a Proteasome Inhibitor Marizomib and IMiD® Immunomodulatory Drug Pomalidomide ». Blood 124, n^o 21 (6 décembre 2014) : 2099. http://dx.doi.org/10.1182/blood.v124.21.2099.2099.

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Abstract Background and Rationale: Proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that a novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities (Chauhan et al., Cancer Cell 2005, 8:407-419). We also showed that marizomib triggers synergistic anti-MM activity in combination with lenalidomide (Chauhan et al., Blood 2010, 115:834-45). Pomalidomide, like lenalidomide, is an analogue of thalidomide with potent immunomodulatory activity, and has been approved by FDA for treatment of RRMM patients who have received at least two prior therapies including lenalidomide and bortezomib and showed disease progression on or within 60 days of completion of the last therapy. Approval of treatment is based on progression-free survival. Here we utilized in vitro and in vivo models of MM to examine the anti-MM activity of combined marizomib and pomalidomide. Materials and Methods:MM celllines, patient tumor cells, and peripheral blood mononuclear cells (PBMCs) from normal healthy donors were utilized to assess the anti-MM activity of marizomib and pomalidomide. Cell viability, apoptosis, and migration assays were performed using WST/MTT, Annexin V staining, and Transwell Inserts, respectively. Synergistic/additive anti-MM activity was analyzed by isobologram analysisusing “CalcuSyn” software program. Proteasome activity was measured, as previously described (Chauhan et al., Cancer Cell 2005, 8:407-419). In vitro angiogenesis was assessed using matrigel capillary-like tube structure formation assays. MM.1S-tumor-bearing mice were treated with vehicle control, marizomib, pomalidomide or marizomib plus pomalidomide at the indicated doses for 21 days on a twice-weekly schedule for marizomib and 4 consecutive days weekly for pomalidomide. Statistical significance was determined using a Student’s t test. Pomalidomide was purchased from Selleck chemicals, USA; and marizomib was obtained from Triphase Inc., USA. Results: MM cell lines (MM.1S, MM.1R, INA-6, RPMI-8226, Dox-40, U266, LR5, ANBL6.WT, and ANBL6.BR) and primary patient MM cells were pretreated with DMSO control or with pomalidomide for 24h; marizomib was then added for an additional 24h, followed by assessment of cell viability. A significant decrease in viability of all cell lines and patient cells was observed in response to treatment with combined low doses of marizomib and pomalidomide, compared with either agent alone. Isobologram analysis confirmed the synergistic anti-MM activity of these agents (CI < 1.0). Tumor cells from 5 of 7 patients were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, the cytotoxicity of combination therapy was observed in MM cell lines sensitive and resistant to conventional (dex, doxorubicin, melphalan) and novel (bortezomib) therapies. No significant decrease in viability of PBMCs from normal healthy donors was observed in response to treatment with combined low doses of marizomib and pomalidomide, suggesting selective anti-MM activity and a favorable therapeutic index for this combination regimen. Furthermore, marizomib plus pomalidomide inhibits proliferation of MM cells even in the presence of BM stromal cells. Mechanistic studies showed that marizomib plus pomalidomide-induced apoptosis was associated with: 1) activation of caspase-8, caspase-9, caspase-3, and PARP; 2) downregulation of Cereblon, IRF4, c-Myc, and Mcl-1; and 3) enhanced inhibition of chymotrypsin-like, caspase-like and trypsin-like proteasome activities versus single agent alone. Furthermore, combined low doses of marizomib and pomalidomide blocked migration of MM cells and angiogenesis. In vivo studies using a subcutaneous human MM xenograft models show that combined low doses of marizomib and pomalidomide are well tolerated, inhibit tumor growth, and prolong survival. Conclusion: Our preclinical studies in MM disease models support a clinical trial of combined marizomib and pomalidomide to improve outcome in patients with relapsed and refractory MM. Disclosures Richardson: Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Trikha:Triphase Accelerator: Employment. Chauhan:Triphase Accelerator: Consultancy. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership.

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Raje, Noopur, Dan T. Vogl, Parameswaran N. Hari, Sundar Jagannath, Simon S. Jones, Jeffrey G. Supko, Gina Leone et al. « ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor : Interim Results Of Combination Therapy With Bortezomib In Patients With Multiple Myeloma (MM) ». Blood 122, n^o 21 (15 novembre 2013) : 759. http://dx.doi.org/10.1182/blood.v122.21.759.759.

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Abstract Background Although non-selective HDAC inhibitors are active in MM, combination therapy is limited by significant adverse effects (AEs) including severe fatigue, gastrointestinal toxicity, and myelosuppression. ACY-1215 is the first-in-class selective oral HDAC6 inhibitor that inhibits the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins. ACY-1215 has demonstrated potent synergy with bortezomib preclinically in cell and animal models of MM (Santo, Blood, 119(1):2527). Methods ACY-100 is a three part single arm, open label study with cohort dose escalation in a standard 3+3 design as monotherapy (1a) and in combination with bortezomib (1b) followed by a phase 2 extension. Eligible patients (pts) for the phase 1a and 1b portions had relapsed or relapsed and refractory MM, previously received at least two lines of therapy including a proteasome inhibitor and an immunomodulatory agent, had either progressed after or were ineligible for autologous stem cell transplant, and had adequate bone marrow reserve, hepatic function and creatinine clearance of >30 mg/mL/min. ACY-1215 was given orally days 1-5 and 8-12 of a 21 day cycle, and bortezomib days 1,4,8,11 and dexamethasone 20 mg days 1,2,4,5,8,9,11,12. Peripheral blood samples were obtained for pharmacokinetic (PK) and pharmacodynamics (PD), assessment of acetylated tubulin (HDAC6 inhibition) and acetylated histones (Class 1 HDAC inhibition). Toxicity was assessed using CTCv4.0 and responses were evaluated by modified EMBT and Uniform Criteria. Results The monotherapy portion of ACY-100 has been previously presented (Raje, Blood, V20(21):4061). Fifteen heavily pretreated pts received ACY-1215 monotherapy at doses of 40 mg to 360 mg. Most AEs were low grade and not related to ACY-1215. Two pts had grade 3 AEs, anemia and neutropenia, considered possibly related to ACY-1215. No dose limiting toxicities (DLTs) were observed. Stable disease (SD) was the best response in 6 patients. Sixteen patients as of June 28, 2013 have received ACY-1215 at doses of 40 mg to 160 mg in combination with bortezomib (1.0 mg/m2 first cohort and 1.3 mg/m2 thereafter) and dexamethasone. Median age was 60, and 16 patients had previously received up to 11 lines of therapy. The first combination cohort was expanded due to a dose limiting toxicity (DLT) of asymptomatic increase in amylase. No other DLTs have been observed. Treatment emergent adverse events were predominantly low grade. Those occurring in >25% of patients were elevated creatinine, thrombocytopenia, anemia, fatigue, elevated ALT, AST and amylase, hypokalemia, cough, decreased appetite, dyspnea, hypoalbuminemia and peripheral neuropathy; most were not considered related to ACY-1215. Grade 3-4 AEs possibly related to ACY-1215 included asymptomatic elevated amylase (2), thrombocytopenia (3), anemia (1), stomach cramps (1) and elevated creatinine (1). Of 16 patients evaluable for response, VGPR (1), PR (2), MR (1) were seen, with 5 pts achieving SD. Responding patients were on study from 2 to 17 cycles. Eleven pts were refractory to bortezomib prior to study entry. Of those the best outcome was MR (1) and SD (4), with the remaining having either progressive disease (5) or not evaluable (1). PK and PD data is available from 16 patients including the 160 mg dose level. PK for ACY-1215 is similar to the same dose levels in phase 1a monotherapy suggesting coadministration of bortezomib does not impact the PK of ACY-1215. Maximal levels were ≥ 1µM at ≥ 80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones. Conclusions ACY-1215 was well-tolerated when administered in combination with bortezomib and encouraging disease responses were observed in this heavily pretreated patient population. Future cohorts in phase 1b will explore twice daily dosing prior to start of phase 2. Disclosures: Raje: Acetylon Pharmaceuticals, Inc: Research Funding; Eli Lilly: Research Funding; Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy. Vogl:Otsuka: Consultancy; Celgene: Consultancy; Millennium: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Hari:Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Jagannath:Celgene: Honoraria; Millenium: Honoraria. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Supko:Acetylon Pharmaceuticals, Inc: Research Funding. Leone:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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Rozic, Gabriela, Paukov Lena, Jana Jakubikova, Duek Adrian, Abraham Avigdor, Arnon Nagler et Merav Leiba. « STK405759 As a Novel Tubulin Active Agent for Multiple Myeloma Therapy ». Blood 126, n^o 23 (3 décembre 2015) : 5348. http://dx.doi.org/10.1182/blood.v126.23.5348.5348.

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Abstract Background: Despite advances in treatment, multiple myeloma (MM) remains incurable due to development of drug resistance in the bone marrow microenvironment. Microtubules (MTs) are dynamic protein biopolymers formed through polymerization of heterodimers of α- and β-tubulins. Disruption of microtubules induces cell cycle arrest in G2-M phase and formation of abnormal mitotic spindles. MTs are also involved in many processes in interphase cells, including intracellular trafficking, cell motility and angiogenesis. The important functions of MT in the cells make them an attractive target for anti-myeloma drug discovery. Furan metotica is a novel class of anti-mitotic spindle drugs that inhibit kinetochore-microtubule binding and trigger a spindle checkpoint mediated arrest in mitosis, which frequently ends in cell death. We evaluated the activity of STK405759, a member of the furan metotica family, as a novel, potential antitubulin drug for MM treatment in preclinical models. Methods: Cytotoxic activity of STK405759 was evaluated by XTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Tubulin polymerization inhibition was evaluatedusing a biochemical cell free assay and by testingthe levels of soluble and polymerized tubulin in MM-treated cells using Western blot analysis. Efficacy and toxicity of the drug were checked in a murine MM xenograft model. Histochemistry was used to assay tumor apoptosis. Results: STK405759 had a potent cytotoxic activity against a wide variety of MM cell lines and patient-derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. In contrast, the viability of normal peripheral blood mononuclear cells derived from healthy donors and MM patients was not affected. Importantly, STK405759 induced cell death of RPMI MM cells co-cultured with HS-5 bone marrow stromal cells. STK405759 inhibited tubulin polymerizationin a cell free system anddecreased the level of polymerized tubulin in MM treated cells.The STK405759 anti-tubulin activity was supported by demonstration of MM cell cycle arrest followed by activation of an apoptotic default pathway. Activation of pro-caspase-8 and poly (ADP-ribose) polymerase in the cleaved forms, as well as down-regulation of the Mcl-1 anti-apoptotic protein was detected in RPMI treated cells. Combination studies of STK405759 with bortezomib, lenalidomide or dexamethasone showed significant synergistic and additive cytotoxicity in MM cells. In vivo studies revealed decreased MM tumor burden and prolonged survival of STK405759-treated mice compared to controls. STK405759 induced apoptosis of tumors cells from treated mice. Summary/Conclusion: STK405759 is an active, microtubule-targeting agent with potent anti-myeloma activity. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM. Disclosures No relevant conflicts of interest to declare.

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Moreau, Philippe, Thierry Facon, Cyrille Touzeau, Lotfi Benboubker, Martine Delain, Julie Badamo-Dotzis, Charles Phelps et al. « Phase 1b Dose Escalation Study Of Oral Quisinostat, a Histone Deacetylase Inhibitor (HDACi), In Combination With Velcade (Bortezomib) and Dexamethasone For Patients With Relapsed Multiple Myeloma (MM) ». Blood 122, n^o 21 (15 novembre 2013) : 1932. http://dx.doi.org/10.1182/blood.v122.21.1932.1932.

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Abstract Background HDACi inhibits aggresome function by acetylation of the tubulin-dynein complex that transports unfolded proteins via aggresomes to lysosomes for degradation, thereby serving as a mechanism for reversal of resistance to proteasome inhibitors. In vivo data have shown that quisinostat, a new oral pan HDACi, has a synergistic activity with bortezomib in preclinical models of MM. Methods Patients were treated with: quisinostat (Q) at escalated doses from 6 to 8 to 10 to 12 mg on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamics and pharmacokinetics. Results The study has completed enrollment and eighteen patients with relapsed MM (3, 3, 6, and 6 in the 6, 8, 10 and 12 mgQ+D+V cohorts, respectively) were enrolled: 56% male; median age of 69 (range 50-82) years; all subjects received 1 to 3 prior lines of therapy (39% received 1, 50% received 2 and 11% received 3 prior lines) and half of the patients were previously exposed and sensitive to bortezomib. To date, 17 out of 18 patients (94%) discontinued treatment, among which 5 completed 11 cycles of therapy. One patient is currently ongoing. At the highest dose level (i.e., 12 mg), 2 of 6 (33%) patients experienced dose-limiting toxicity (DLT): QTc prolongation and atrial fibrillation. The MTD was therefore established at 10 mg Q for the Q+V+D regimen. Quisinostat oral absorption was rapid, with maximum plasma concentrations achieved approximately between 1 and 3 hours after drug intake. The estimated effective half-life was between 2.5 to 15 hours. Quisinostat Cmaxand AUC were comparable to previous clinical observations and increased approximately proportional with increased dose. VELCADE exposure was in line with previous clinical observations. Most common (≥15% of patients) drug related adverse events were asthenia (56%), thrombocytopenia (56%), diarrhea (44%), oedema peripheral (39%), peripheral sensory neuropathy (39%), constipation (33%), insomnia (28%), neuralgia (28%), vomiting (28%) and nausea (28%); most of them were grade 2 or lower in toxicity. The most common (≥10% of patients) grade ≥3 drug related events included thrombocytopenia (39%), QT prolongation (11%), asthenia (11%) and insomnia (11%). Dose reduction for myelosuppression (thrombocytopenia ≥G3) was required for VELCADE in 4 patients in the 10 and 12 mg cohorts. Quisinostat dose reductions were required for asthenia G2 and G3 in 2 patients (dose level 8 and 10mg). The overall response rate was 88.2% (15 of 17 patients, 95% CI: 63.6% to 98.5%), including 1 complete response, 3 very good partial responses, and 11 partial responses. The median duration of response was 6.8 months, ranging between 2.8 and 19.6 months. The observed pharmacokinetic profiles of quisinostat and bortezomib were in line with historical data. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusion Preliminary results indicate that the MTD is 10 mg quisinostat in combination with standard doses of VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma with a high response rate and has an acceptable safety profile. Disclosures: Moreau: Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Consultancy; Millennium: Consultancy; Celgene: Consultancy. Benboubker:Celgene: Consultancy. Badamo-Dotzis:Quintiles: Employment. Phelps:Janssen: Employment, Equity Ownership. Doty:Janssen: Employment. Smit:Janssen: Employment, Equity Ownership. Fourneau:Janssen: Employment, Equity Ownership. Forslund:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

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Richardson, Paul G., Akshanth R. Polepally, Monica Motwani, Yunming Mu, Zeena Salman, Sudhir Penugonda et Philippe Moreau. « A Phase 1b, Open-Label Study of Eftozanermin Alfa in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma ». Blood 136, Supplement 1 (5 novembre 2020) : 16–17. http://dx.doi.org/10.1182/blood-2020-137037.

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Background Many patients (pts) with multiple myeloma (MM) will relapse after treatment or become refractory to all therapies currently available. For these pts, the prognosis is poor and there is a clear unmet need to identify agents with novel mechanisms of action. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has a distinct role in the induction of apoptosis in tumor cells, and activating this pathway could represent an attractive therapeutic approach. Early generation TRAIL receptor agonists had minimal efficacy in pts with MM, which may be due to suboptimal TRAIL receptor clustering. Eftozanermin alfa (formerly ABBV-621) is a next-generation TRAIL receptor agonist specifically designed to optimize receptor clustering. The ongoing first-in-human study of eftozanermin alfa (NCT03082209) demonstrated a tolerable safety profile in pts with previously treated solid tumors and hematologic malignancies. Preclinical ex vivo and in vivo models of MM indicate combinatorial activity of eftozanermin alfa with proteasome inhibitors (PIs) resulting in enhanced efficacy. The addition of eftozanermin alfa to the well-established regimen of the PI bortezomib and dexamethasone may improve efficacy outcomes in pts with relapsed/refractory (R/R) MM. Study Design and Methods This is a phase 1b, open-label, nonrandomized, multicenter study enrolling pts (≥18 years, Eastern Cooperative Oncology Group score 0-1) with R/R MM. Approximately 40 pts are planned for enrollment. The primary objectives of the study are to determine the recommended phase 2 dose (RP2D) of eftozanermin alfa when given in combination with bortezomib and dexamethasone, and to assess the efficacy of this combination on the basis of overall response rate (ORR). Secondary objectives include assessing the safety and tolerability of eftozanermin alfa with bortezomib and dexamethasone and evaluating the rate of very good partial response (VGPR) or better, the duration of response (DOR), and pharmacokinetics (PK). Key inclusion criteria are pts with R/R MM who have received at least 3 but no more than 6 prior lines of therapy (including an immunomodulatory agent, a PI, and an anti-CD38 antibody) and have documented disease progression during or after the most recent therapy. Pts must also have measurable disease per standard International Myeloma Working Group (IMWG) criteria at baseline and adequate hematologic, hepatic, and renal function. Pts will be excluded if they have primary refractory disease, received bortezomib in the most recent prior therapy, or have peripheral neuropathy grade ≥2 or grade 1 with pain. The study consists of a screening period, a treatment period, and a follow-up period; dosing schedule details are presented in Figure. After screening, pts will receive eftozanermin alfa with bortezomib and dexamethasone until unacceptable toxicity, confirmed progressive disease, or other protocol-specified reasons for discontinuation are met. Treatment may continue for maximum 12 cycles. A safety lead-in will be performed to determine the RP2D of eftozanermin alfa when combined with bortezomib and dexamethasone. Dose escalation during the safety lead-in will be guided using a Bayesian optimal interval design with a target toxicity rate of 33%. The primary efficacy endpoint is the ORR, defined as the proportion of pts with partial response or better per IMWG criteria. Other efficacy endpoints include DOR, VGPR or better rate, and progression-free and overall survival. For all binary endpoints, the estimated proportion and associated 2-sided 90% Clopper-Pearson exact confidence intervals will be provided. The time-to-event endpoints will be summarized using the Kaplan-Meier method. Safety evaluations will include assessment of dose-limiting toxicities during cycle 1 of the safety lead-in, and monitoring of adverse events, vital signs, and clinical laboratory measures throughout the study. Samples for PK analysis, biomarker assessments, and assays for antidrug and neutralizing antidrug antibodies will be obtained at protocol-specified visits. Biomarker analyses may include evaluation of death receptor 4/5 expression, chromosomal abnormalities, and minimal residual disease status. Approximately 20 sites in 6 countries are planned to be involved in the study, which is anticipated to start in September 2020. Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Polepally:AbbVie: Current Employment, Other: may hold stock or stock options.. Motwani:AbbVie: Current Employment, Current equity holder in publicly-traded company. Mu:AbbVie: Current Employment, Other: may hold stock or stock options.. Salman:AbbVie: Current Employment, Other: may hold stock or stock options.. Penugonda:AbbVie: Current Employment, Other: may hold stock or stock options.. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

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Huang, Xiangao, Kathryn Bailey, Maurizio Di Liberto, Francesco Parlati, Ruben Niesvizky, Susan Demo et Selina Chen-Kiang. « Induction of Sustained Early G1 Arrest by Selective Inhibition of CDK4 and CDK6 Primes Myeloma Cells for Synergistic Killing by Proteasome Inhibitors Carfilzomib and PR-047 ». Blood 112, n^o 11 (16 novembre 2008) : 3670. http://dx.doi.org/10.1182/blood.v112.11.3670.3670.

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Abstract Targeting the cell cycle in combination with cytotoxic killing is a rational approach to cancer therapy. Dysregulation of the cyclin-dependent kinases CDK4 and CDK6 precedes uncontrolled proliferation of myeloma cells in vivo, in particular during relapse and drug resistance. This finding reinforces the critical importance of targeting CDK4/6 in myeloma, but success with broad-spectrum CDK inhibitors has been modest. Using the only known selective inhibitor of CDK4/6, PD 0332991, we have developed a novel approach to prime chemoresistant myeloma cells for synergistic killing by diverse cytotoxic agents. We show that selective inhibition of CDK4/6 by PD 0332991 leads to sustained cell cycle arrest in early G1 in the absence of apoptosis. However, it markedly augments cytotoxic killing by PR-171 (carfilzomib), a selective inhibitor of the chymotrypsin-like activity of the proteasome, or PR-047, an orally bioavailable analog of carfilzomib. Synergistic killing of myeloma cells arrested in early G1 by carfilzomib (or PR-047) is caspase-dependent, and requires only a brief (one hour) exposure to the proteasome inhibitor at concentrations as low as 60 nM. This effect is mediated by synergistic and rapid induction of mitochondrial membrane depolarization and activation of downstream caspase-9 within 6 hours of removal of carfilzomib or PR-047. As PD 0332991 acts as an ATP-competitive inhibitor of the CDK4/6 kinase domain, inhibition of CDK4/6 and the cell cycle by PD 0332991 is reversible. Importantly, targeting CDK4/6 with PD 0332991 in combination with either carfilzomib or PR-047 leads to complete eradication of myeloma cells ex vivo, in contrast to the combination of PD 0332991 with other proteasome inhibitors. Selective inhibition of CDK4/6 in combination with carfilzomib (or PR-047), therefore, not only halts cell proliferation but also potently induces synergistic killing that is likely to eliminate cell cycle reentry and generation of resistant cells. PD 0332991 is a small molecule with bio-availability and proven tumor suppressing activity in both human myeloma xenograft and immunocompetent mouse myeloma models. It is well tolerated in humans as shown by the ongoing Phase I/II clinical trials in myeloma and previous phase I trials in mantle cell lymphoma and solid tumors. Evidence from Phase I trials of carfilzomib indicates that it is also well tolerated, in fact, the peripheral neuropathy that is commonly observed with proteasome inhibitor bortezomib appears to be less severe and possibly less frequent. Mechanism-based targeting of CDK4/6 in combination with selective proteasome inhibitors, like carfizomib and PR-047, thus represents a new and promising therapeutic strategy for multiple myeloma and potentially other hematopoietic malignancies.

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Di Liberto, Maurizio, Xiangao Huang, Jamieson Bretz, Scott A. Ely, Rediet Zewdu, David Jayabalan, Suzhen Chen et al. « Induction of Metabolic Impairment In Prolonged Early G1 Arrest Induced by CDK4/CDK6 Inhibition Sensitizes Myeloma Cells for Proteasome Inhibitor Killing During Subsequent S Phase Synchronization ». Blood 116, n^o 21 (19 novembre 2010) : 2989. http://dx.doi.org/10.1182/blood.v116.21.2989.2989.

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Abstract Abstract 2989 Sequential drug combination is a rational approach to maximize tumor killing and minimize side effects in cancer therapy. However, this is rarely achieved because the mechanism of drug action is often incompletely understood and the cell cycle specificity of individual drugs unknown. Dysregulation of cyclin-dependent kinase (CDK)4 and CDK6 is common in human cancer and precedes unrestrained proliferation of tumor cells in multiple myeloma (MM) patients, especially during refractory relapse. This highlights the critical importance of targeting CDK4/CDK6 in MM. We have now developed, for the first time, a novel therapeutic strategy to selectively inhibit CDK4/CDK6 in sequential combination with clinically relevant cytotoxic drugs for maximal tumor killing at reduced doses in MM. CDK4 and CDK6 promote reentry and progression of the cell cycle through G1. PD 0332991, the only known CDK4/CDK6-specific inhibitor, is potent, reversible and bioavailable. We showed that inhibition of CDK4/CDK6 with PD 0332991 induces early G1 arrest and upon release from the G1 block, synchronous progression to S phase and G2/M with exceptional precision and efficiency in MM cells in vitro and in animal models. This provides a unique means to determine the cell cycle targeting specificity of individual compounds for optimal combination. Simultaneous analysis of BrdU pulse-labeling (30 minutes) and DNA content per cell reveals that bortezomib, a reversible proteasome inhibitor; carfilzomib (PR-171), an irreversible selective inhibitor of the proteasom; and its oral analog ONX-0912 (PR-047) all preferentially target MM cells synchronized into S phase over those arrested in G1, but not cells in G2/M. On this basis, killing of myeloma cells by proteasome inhibitors is markedly enhanced in prolonged G1 arrest induced by PD 0332991 and further augmented during synchronous entry into and progression through S phase upon release from the G1 block, in vitro and in vivo in the native bone marrow niches. Induction of early G1 arrest by PD 0332991 requires Rb, the substrate of CDK4 and CDK6, but not p53. Importantly, the increase in carfilzomib, ONX-0912 or bortezomib mediated killing after S phase synchronization significantly surpasses the enrichment of S phase cells. It is in fact proportional to the time of prior G1 arrest. Kinetics analyses of global gene expression patterns, specific RNA and protein levels and functional shRNA interference show that prolonging early G1 arrest leads to time-dependent uncoupling of gene expression from the cell cycle. PD 0332991 withdraw rapidly restores the CDK4 and CDK6 catalytic activity and scheduled expression of cell cycle genes, hence synchronous progression to S phase and mitosis. This includes upregulation of cyclin A synthesis and Skp2 mediated ubiquitin-proteasome degradation of p27 for S phase entry, mini chromosome maintenance(MCM)s and thymidine kinase for DNA replication, and genes critical for G2/M checkpoint control and mitosis. However, it fails to fully reverse the metabolic impairment (altered glucose, nucleotide and ATP metabolism) induced in prolonged early G1 arrest. This culminates in the loss of IRF-4 required for myeloma survival and selective gain of pro-apoptotic Bim function in G1 arrest and Noxa in S phase in synergy with carfilzomib and bortezomib, which lowers the threshold for activation of the intrinsic apoptosis pathway. Selective inhibition of CDK4/CDK6 in sequential combination therapy thus not only halts tumor cell proliferation but also potently induces synergistic tumor killing. This sequential combination therapy has been implemented in a multi-center phase 1/2 clinical trial targeting CDK4/6 with PD 0332991 in combination with bortezomib and dexamethasone in relapsed refractory MM. Phase 1 data indicate that PD 0332991 is well tolerated, and directly and completely inhibits CDK4/CDK6 and the cell cycle in tumor cells in MM patients with promising clinical efficacy. Evidence from phase 2 trials of carfilzomib indicates that it is also well tolerated. The peripheral neuropathy commonly observed with bortezomib appears to be less severe and less frequent. Selective combination with carfilzomib or the oral agent ONX-0912 thus represents a promising alternative to refine targeting CDK4/6 in sequential combination therapy for multiple myeloma and potentially other cancers. Disclosures: Off Label Use: PD 0332991 is a cell cycle CDK4/CDK6 inhibitor Carfilzomib is a proteasome inhibitor. Kirk:Onyx: Employment, Equity Ownership. Randolph:Pfizer: Employment, Equity Ownership. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau.

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Nooka, Ajay K., Jonathan L. Kaufman, Madhusmita Behera, Charise Gleason, Amelia Langston, Conor Ermst Steuer, Christopher R. Flowers, Lawrence H. Boise et Sagar Lonial. « The Improved Efficacy of Bortezomib Containing Induction Regimens (BCIR) Versus Non-Bortezomib Containing Induction Regimens (NBCIR) in Transplant-Eligible Patients with Multiple Myeloma (MM) : Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) »,. Blood 118, n^o 21 (18 novembre 2011) : 3994. http://dx.doi.org/10.1182/blood.v118.21.3994.3994.

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Abstract Abstract 3994 Introduction: Patients with MM undergoing autologous stem cell transplant (ASCT) achieving complete response (CR) or very good partial response (VGPR) have prolonged progression free survival (PFS) and overall survival (OS) compared to the patients that achieve <VGPR prior to ASCT (Lahuerta JJ et al., 2008; Moreau P et al., 2011). Therefore it is of profound significance to attain the best response with induction therapies to obtain the better long-term outcomes. The response rates have significantly improved since the introduction of bortezomib, a proteasome inhibitor, in the induction therapies for myeloma. We performed a meta-analysis to evaluate the efficacy of the addition of bortezomib to the existing regimens used in induction therapy. Methods: We searched Medline, Embase, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 08/2011 for publications and abstracts to identify the phase III RCTs comparing BCIR vs. NBCIR in transplant-eligible patients with myeloma. A meta-analysis was performed using both the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the risk difference with the comparator arm to evaluate the rates of CR, ≥VGPR, ORR, PFS, OS and toxicities. Altogether, we identified 4 RCTs (two published articles and unpublished data from two RCTs including 2086 patients). The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was <.1 and I 2 statistic was > 50%. Results: Q-statistic for ORR (P =0.338; df =3; I2 = 11.1); ≥VGPR (P =0.175; df =3; I2 = 39.53); CR (P =0.677; df =3; I2 = 0) suggests homogeneity across studies. Pooled odds ratios of overall response rates (ORR), ≥VGPR, CR with BCIR vs. NBCIR were 2.619 (P <0.000; 95% CI: 2.103–3.261); 3.558 (P <0.000; 95% CI: 2.908–4.354); 2.739 (P <0.000; 95% CI: 2.072–3.621) respectively indicating BCIR result in improved efficacy. Similar results were translated post-ASCT demonstrating the superiority of BCIR over NBCIR. Post-ASCT ORR (p =0.141; df =3; I2 = 45.03); ≥VGPR (P =0.442; df =3; I2 = 0); CR (P =1.00; df =3; I2 = 0) suggest homogeneity. Pooled odds ratios of ORR, ≥VGPR, CR post-ASCT for BCIR vs. NBCIR were 1.907 (P <0.000; 95% CI: 1.431–2.639); 2.43 (P <0.000; 95% CI: 2.025–2.914); 2.406 (P <0.000; 95% CI: 1.966–2.945) respectively. The pooled hazard ratios (HR) for 3 year PFS and OS were HR 0.723 (95% CI 0.620–0.844; P =0.000); 3 year OS HR 0.789 (95% CI 0.651–0.957; P =0.016) respectively in favor of BCIR. The relative risk (RR) of selected ≥grade 3 toxicities was higher with BCIR. RR of peripheral neuropathy (PN) was 2.469 (95% CI 1.848–3.297; P =0.000) and infection with herpes-zoster virus (HZV) was 2.197 (95% CI 1.368–3.529; P =0.001). The RR of a thromboembolic event (TEE) with BCIR was 0.8 (95% CI 0.56–1.15; P =0.206). Conclusion: Our mixed model meta-analysis demonstrates that the addition of bortezomib to the induction regimens in the transplant-eligible patients with MM results in improved ORR, ≥VGPR, CR, PFS and OS compared with the NBCIR. Known bortezomib related grade 3 toxicities are higher with BCIR recommending appropriate PN monitoring and HZV prophylaxis. The pooled estimates of response and survival strongly favor inclusion of bortezomib in the induction regimens. Disclosures: Kaufman: Millenium, Onyx, Novartis, Keryx: Consultancy; Merck, Celgene: Research Funding. Gleason:Celgene, Merck, Millenium: Consultancy. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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Kirk, Christopher J., Mark K. Bennett, Tonia J. Buchholz, Susan D. Demo, Mark N. Ho, Jing Jiang, Guy J. Laidig et al. « Pharmacokinetics, Pharmacodynamics and Anti-Tumor Efficacy of PR-171, a Novel Inhibitor of the 20S Proteasome. » Blood 106, n^o 11 (16 novembre 2005) : 609. http://dx.doi.org/10.1182/blood.v106.11.609.609.

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Abstract Clinical studies using the boronic acid-based proteasome inhibitor bortezomib (VelcadeTM) have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin’s Lymphoma. Despite encouraging clinical response rates with this drug, significant toxicities, including neutropenia, thrombocytopenia and peripheral neuropathy have restricted the intensity of bortezomib dosing. PR-171 is a novel peptide epoxyketone inhibitor that selectively and irreversibly inhibits the chymotryptic subunit of the 20S proteasome. We have characterized the pharmacokinetics, pharmacodynamics and anti-tumor efficacy of PR-171 in rodents and non-human primates. PR-171 is rapidly cleared from the plasma compartment following intravenous bolus administration, with a terminal half-life in rats and monkeys of 15 and 7.2 min, respectively. Despite this rapid clearance, PR-171 administration results in a prolonged dose-dependent inhibition of the 20S proteasome in all tissues examined with the exception of brain. Single doses of PR-171 that are tolerated in mice, rats and monkeys result in greater than 90% inhibition of proteasome activity in blood and many tissues. Recovery of proteasome activity following exposure to PR-171 is dependent upon synthesis of new proteasome subunits and occurs with a t1/2 of ~ 24 hr in nucleated cells. Recovery of proteasome activity in erythrocytes is dependent upon red blood cell turnover and occurs more slowly in animals. The safety of PR-171 has been assessed in rodents using multiple dosing schedules including weekly, biweekly, daily and BID administration. In rats, daily administration of PR-171 at doses that resulted in >80% inhibition of proteasome activity in whole blood and selected tissues were well tolerated. Recovery of proteasome activity following repeated daily administrations was unchanged from that seen after a single dose. PR-171 was also well tolerated when administered daily to monkeys at equivalent doses on a body surface area comparison. A transient thrombocytopenia was noted in both rats and monkeys but neutrophil and lymphocyte counts were not decreased in response to PR-171 administration. PR-171 induced a significant anti-tumor response in beige-nu-xid (BNX) triple immunodeficient mice bearing established HS-Sultan Burkitt’s lymphoma tumors and in Balb/c mice challenged with A20 lymphoma cells. We have also demonstrated anti-tumor activity of PR-171 in several mouse models of solid tumors including syngeneic and human tumor xenograft models of colorectal cancer. These studies demonstrate the tolerability, anti-tumor activity and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies utilizing dose intensive schedules.

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Nadiminti, Kalyan, Christopher Strouse, Praveen Vikas, Lindsay Dozeman, Allyson Schultz, Sarah L. Mott, Jillna Claus et al. « Early Intensive Therapy in Multiple Myeloma Using Tandem Transplantation with Novel Conditioning and Two Years Maintenance : A Single Institution Experience ». Blood 132, Supplement 1 (29 novembre 2018) : 2152. http://dx.doi.org/10.1182/blood-2018-99-113890.

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Abstract Introduction The role of early intensive treatment of multiple myeloma, including tandem autologous stem cell transplantation( ASCT) with bortezomib, thalidomide, dexamethasone( VDT) and melphalan 200mg/m2 as a preparative regimen, followed by 2 years of combination agent maintenance therapy, is being studied. We sought to analyze a cohort of patients who received early intensive treatment at the University of Iowa between 2012 and 2016. Patients and Methods All consecutive patients who received early( < 12 months since diagnosis) tandem ASCT and have completed at least 2 years of maintenance therapy between 2012 and 2016 were included for analysis. Planned maintenance therapy consisted of a combination of VDT in 28 day cycles for year 1 and bortezomib, cyclophosphamide and dexamethasone(VCD) in 28 day cycles for year 2. Alternate regimen were used in case of toxicities. The patients were considered to have high risk cytogenetics if they had 17p deletion, t(14;16), amp 1q, or t(4;14) by FISH. Event-free (EFS) and overall survival (OS) probabilities were estimated and plotted using the Kaplan-Meier method. For EFS, time was calculated from date of first transplant to relapse or death due to any cause. Treatment-related mortality was defined as death during transplant phase or maintenance phase due to causes other than disease relapse.The effect of clinical characteristics on outcomes was evaluated using Cox regression models. Estimated effects of predictors are reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Responses were measured using IMWG consensus criteria. Results A total of 135 patients met the criteria for inclusion. Key patient characteristics are shown in table 1. The median age at first transplant was 58 years. HCT-CI was high in 68% of patients. 36% of the patients were ISS stage III, and high risk cytogenetics were present in 56%. Preparative regimen was VTD-Mel 200 in 88.9% of patients. Following the first transplant, 59% of patients had achieved CR, and following the second transplant 94.4% of patients achieved CR. At the time of median follow up, 27.4% of patients had died. The cause of death was infection (25%), organ failure (11%), relapsing myeloma (28%) or other (36%). Univariable analysis identified a statistically significant association only for age with risk of progression or death. Kaplan-Meier curves for progression free survival and overall survival in patients with high risk or low risk cytogenetics are shown in Figures 1 and 2 respectively. The hazard ratio for progression free survival and overall survival in patients with high risk vs low risk cytogenetics was 0.86 (95% confidence interval 0.45 - 1.64, p=0.65), and 0.88 (95% confidence interval 0.45 - 1.73, p=0.71), respectively. The 3 year EFS and OS of patients who received early tandem ASCT followed by 2 years of maintenance were 73% and 72%, respectively. Following the 2nd autologous transplant, 128 of 135( 94%) patients were started on maintenance therapy. VTD ( 74%) and VRD (6%) were the most common regimens used. Fifty six patients completed maintenance therapy for 1 year without regimen change, and 60 required regimen change due to toxicities. VRD (20), VPomD (9) and VRMp (8) were the most commonly used alternative regimens in the case of toxicities. Following year 1 of maintenance, 96 patients (75%) started a second year of maintenance. VCD (30%) or RD (23%) were the most common regimens. 63(43%) patients completed 2 years of combination maintenance therapy. Grade III-V non-hematologic toxicities during the combined maintenance phase were infection (56%) and peripheral neuropathy (23%) and hematologic toxicities were thrombocytopenia (13%), neutropenia (12%) and anemia (8%). Conclusion According to our results, patients with high risk cytogenetics did not have an inferior PFS and OS. These results suggest that in newly diagnosed MM patients, upfront treatment using novel conditioning regimen and tandem ASCT followed by intensive maintenance therapy can result in a very high CR rates, particularly in patients with high risk cytogenetics. Infections and peripheral neuropathies were the most common non-hematologic toxicities during maintenance. Longer follow up will determine further impact of maintenance therapy. Disclosures No relevant conflicts of interest to declare.

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Rifkin, Robert M., Esprit Ma, Robyn Harrell, Yanyan Zhu, Edward Dow, Liviu Niculescu et Vijayveer Bonthapally. « Comparative Effectiveness Research on the Treatment Outcomes of Subcutaneous (SC) and Intravenous (IV) Bortezomib (BTZ) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) ». Blood 126, n^o 23 (3 décembre 2015) : 4506. http://dx.doi.org/10.1182/blood.v126.23.4506.4506.

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Abstract Background BTZ is approved for the treatment of MM via either SC or IV administration. The observed non-inferior efficacy (overall response rate after 4 cycles) and tolerability with SC administration of BTZ as reported in relapsed/refractory MM (Moreau et al Lancet Oncol 2011) has the potential to impact treatment outcomes in the clinical setting. However, there is a paucity of comparative effectiveness data on SC vs IV BTZ as initial therapy in MM in clinical practice. The main objective of this study was therefore to evaluate the treatment outcomes in NDMM pts who received SC vs IV BTZ in the US community oncology setting. Methods NDMM pts aged ≥18 yrs who received BTZ-based treatment within the McKesson Specialty Health/US Oncology Network between Jan 1 and Dec 31, 2012, and had ≥2 MM-related visits and ≥6 mos' follow-up through Jul 2014, were evaluated. Data were collected via the iKnowMed electronic health records database and supplemented with medical chart reviews. Cohorts stratified by route of administration were matched 2:1 as the Moreau study, and by age, gender, practice region, and performance status. Chi-square analysis (categorical variables), t-tests/non-parametric Mann-Whitney tests (continuous variables), and Kaplan-Meier methodology were employed. Univariate and multivariate Cox models adjusted for clinically relevant covariates were used for associations between cumulative BTZ dose and treatment outcomes. Results 372 NDMM pts who received BTZ were included; 248 received SC and 124 IV BTZ. Similar baseline demographics and clinical characteristics were observed in the SC and IV groups (Table 1). Median BTZ treatment duration was 4.4 and 4.1 mos in the SC and IV groups, respectively (p = 0.21). Among pts receiving SC and IV BTZ, 10% and 13% had dose reductions in the first 16 wks (p = 0.41) and the median time to dose reduction was 49 d in both groups. While observed median relative dose intensities were similar between the SC and IV groups (1.0 [range 0.67-1.2] vs 1.0 [0.5-1.3]; p = 0.89), a higher median cumulative BTZ dose of 25.8 mg/m2 (1.3-208.6) was observed in SC pts, vs 22.9 mg/m2 (1.3-105.9) in IV pts (p = 0.08). When dichotomized by median cumulative BTZ dose (24.7 mg/m2), a numerically greater proportion of SC pts vs IV pts received the higher dose (52% vs 48%, p = 0.38). Higher cumulative dose was associated with longer PFS and better response rate at cycle 4 (12 wks) in multivariate analyses (Table 2). Treatment outcomes were comparable between SC and IV BTZ; 2-yr overall survival (OS) was 81% vs 78% (Fig 1); 2-yr progression-free survival (PFS) was 75% vs 70% (Fig 2). In 204 response-evaluable pts (of 372 in the overall population with a median follow up of 19.1 mos [range 0.1-30.1] in SC pts and 20.8 mos [0.3-30.8] in IV pts), complete response/very good partial response rate was 16% vs 22%. Documented rates of adverse events in the SC vs IV BTZ groups were 34% vs 28% neuropathy (p = 0.27), 13% vs 10% thrombocytopenia (p = 0.57), 10% vs 5% neutropenia (p = 0.09), and 25% vs 24% anemia (p = 0.87). Conclusions The observed non-inferior treatment outcomes between SC and IV BTZ in NDMM pts are consistent with findings from the phase 3 relapsed/refractory MM trial. In addition, SC vs IV BTZ was associated with a trend towards higher cumulative dose, which was associated with improved response rate and PFS. These findings support extended therapy for higher cumulative dosage and better treatment outcomes as demonstrated in a prior phase 3 clinical trial (Benboubker et al NEJM 2014). Table 1. NDMM Pt Baseline Demographics and Clinical Characteristics BTZ SC (N = 248) BTZ IV (N = 124) p value Median age at diagnosis, yrs (range) 66 (32-90+) 68 (36-88) 0.87 Age at diagnosis ≥65 yrs, % 57 60 0.55 Male % 56 56 1.00 IgG / IgA / light chain / other or unknown MM, % 53 / 21 / 22 / 4 41 / 30 / 23 / 6 0.28 Pts with available ISS stage I / II / III disease, % n = 145 22 / 43 / 34 n = 64 17 / 33 / 50 0.12 Peripheral neuropathy, % 4.4 3.2 0.78 Table 2. Regression analyses (RA) for association with cumulative BTZ dose, high vs low (> or < 24.7 mg/m2) Univariate analysis Multivariate analysis OR (95% CI) p value OR (95% CI) p value Objective response* at cycle 4 1.67 (0.86, 3.24) 0.13 2.20 (1.01, 4.80) 0.047 HR (95% CI) HR (95% CI) PFS† 0.41 (0.27, 0.62) <0.0001 0.34 (0.22, 0.54) <0.0001 *Logistic RA †Cox RA Disclosures Rifkin: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ma:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Harrell:McKesson Specialty Health: Employment. Zhu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dow:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda: Equity Ownership. Niculescu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bonthapally:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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Moreau, Philippe, Asher Chanan-Khan, Andrew W. Roberts, Amit B. Agarwal, Thierry Facon, Shaji Kumar, Cyrille Touzeau et al. « Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma : Phase 1b Results ». Blood 126, n^o 23 (3 décembre 2015) : 3038. http://dx.doi.org/10.1182/blood.v126.23.3038.3038.

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Abstract Background: The anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Bortezomib (BTZ) can inhibit MCL-1 activity by stabilizing the MCL-1 antagonist, NOXA. Venetoclax is an orally bioavailable, highly selective BCL-2 inhibitor, which enhances BTZ efficacy in MM xenograft models. This Phase 1 study evaluates venetoclax with BTZ and dexamethasone (Dex) in patients (pts) with relapsed/refractory MM. Methods: Objectives include safety, pharmacokinetics, preliminary efficacy and maximum therapeutic dose of venetoclax with BTZ and Dex. A fixed dose of venetoclax ranging from 50 to 800 mg PO daily, according to dose cohort assignment, was given in combination in cycles (C) 1-11 and alone in C12 and beyond. Dose escalation decisions were made using the continual reassessment method. Pts received BTZ (1.3 mg/m2 SC, days [D] 1, 4, 8, 11) and Dex (20 mg PO, D1, 2, 4, 5, 8, 9, 11, 12) in cycles (C)1-8 (21D), then BTZ + Dex (D1, 8, 15, 22) in C9-11 (35D). Results: Forty-one pts were enrolled as of June 15, 2015 (pts in each cohort: 50 mg, n=3; 100 mg, n=5; 200 mg, n=6; 300 mg, n=7; 400 mg, n=6; 500 mg, n=7; 600 mg, n=5; 800 mg, n=2). Median age was 65 (38-79); 15/26 F/M. 14 were ISS stage I, 11 stage II, 11 stage III, 5 missing. Median (range) number of prior lines of therapy was 5 (1-15). Thirty-five pts had received prior BTZ (10 refractory), 34 prior lenalidomide (22 refractory); 29 had undergone stem cell transplantation. Based on FISH analysis, 5 pts had MM with t(11;14); 3 with t(4;14), 20 with del 17p, and 10 with del 13q. Treatment-emergent AEs occurring in ≥20% of pts were constipation (37%), diarrhea (37%), thrombocytopenia (32%), asthenia (29%), insomnia (29%), anemia (27%), peripheral neuropathy (27%), dyspnea (24%), peripheral edema (22%), and nausea (20%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (20%), and anemia (17%). SAEs occurred in 18 pts; SAEs in ≥2 pts were cardiac failure, embolism, pyrexia, respiratory failure, sepsis, thrombocytopenia (n=2 each, no SAEs were venetoclax-related). Twenty-nine pts have discontinued treatment: 23 due to PD, 2 due to AEs [adenocarcinoma; cardiac and respiratory decompensation attributed to Dex (DLT at 300 mg)], and 4 withdrew consent. Three deaths occurred (all due to PD). No TLS occurred. In preliminary PK analyses (n=41), dose-normalized venetoclax exposure when given with BTZ+Dex was similar when compared to venetoclax monotherapy in MM as well as CLL and NHL pts. Forty of 41 pts were evaluable for efficacy. All responses occurred in BTZ sensitive or naïve pts. Median (range) duration or response was 5.9 (0-14.1) months in all pts, 8.5 (2.3-11.4) months in BTZ naïve pts, and 4.7 (0-14.1) months in BTZ-sensitive pts. Conclusions: Venetoclax with BTZ and Dex has an acceptable safety profile in heavily pretreated MM pts; no new safety signals were identified compared to other venetoclax studies. These early data suggest the combination of proteasome and BCL-2 inhibition resulted in anti-tumor activity. Responses were observed only in pts naïve or sensitive to prior BTZ (ORR = 100% and 58%, respectively) and occurred in all dose cohorts. The study is currently enrolling pts in the 1000 mg dose escalation cohort. Figure 1. Figure 1. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Agarwal:Amgen, Millennium: Consultancy; Celgene, Onyx: Speakers Bureau; AbbVie: Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Touzeau:AbbVie: Research Funding. Darden:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; AbbVie: Research Funding.

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Richardson, Paul G., Rachid Baz, Luhua Wang, Andrzej J. Jakubowiak, Deborah Berg, Guohui Liu, Neeraj Gupta, Alessandra Di Bacco, Ai-Min Hui et Sagar Lonial. « Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM) : Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study ». Blood 118, n^o 21 (18 novembre 2011) : 301. http://dx.doi.org/10.1182/blood.v118.21.301.301.

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Abstract Abstract 301 Background: The investigational agent MLN9708 is the first oral proteasome inhibitor (PI) to enter clinical investigation in MM pts. MLN9708 has shown antitumor activity in solid tumor and hematologic malignancy xenograft models, including in vivo models of MM. The primary objectives of this study (NCT00932698) were to determine safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral MLN9708 in pts with relapsed and/or refractory MM. Secondary objectives included evaluation of response rate and characterization of pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (20S proteasome inhibition in blood). Methods: Pts aged ≥18 years with measurable disease and no grade ≥2 peripheral neuropathy (PN) were eligible. For the dose-escalation phase (3+3 design), pts required ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. Pts could have received other PIs. At the MTD, pts were enrolled to four expansion cohorts: relapsed and refractory cohort (progressive disease [PD] on therapy or <60 days after last dose of most recent prior therapy), bortezomib-relapsed cohort (relapsed after previous bortezomib but not refractory), PI-naïve cohort (relapsed after ≥1 therapy, including thalidomide or lenalidomide and corticosteroids), and prior carfilzomib cohort (last dose of carfilzomib 21–60 days prior to first dose of MLN9708). MLN9708 was administered orally on days 1, 4, 8, and 11 of 21-day cycles. Adverse events (AEs) were graded per NCI-CTCAE v3.0. Response was assessed per modified EBMT/IMWG uniform criteria. Blood samples were obtained at multiple time points on days 1 and 11, cycle 1, for PK and pharmacodynamic analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: As of June 29 2011, 53 pts have been enrolled (53% male). Median age was 66 years (range 50–86), median time since initial MM diagnosis was 4.6 years (range 1.1–24.3), and median number of prior therapies was 4 (range 1–28); 55% of pts had received stem cell transplant, 92%, 80%, 56%, and 4% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively, and 47% were refractory to last therapy, including 28% who were bortezomib-refractory. During dose escalation, 27 pts received MLN9708 0.24–2.23 mg/m2; the MTD was determined as 2.0 mg/m2. To date, 32 pts have been enrolled to the expansion cohorts (including 6 from the dose-escalation phase): 17, 11, and 4 to the relapsed and refractory, bortezomib-relapsed, and PI-naïve cohorts, respectively. Overall, pts have received a median of 3 cycles (range 1–17), with 6 (11%) receiving ≥12 cycles. At data cut-off, 58% of pts had discontinued, mainly due to PD (36%). Safety profiles appeared similar between dose-escalation and expansion cohorts. Overall, 87% of pts experienced drug-related AEs, the most common being fatigue (45%), thrombocytopenia (30%), nausea (26%), diarrhea (25%), vomiting, and rash (each 23%). Only four (8%) pts had drug-related PN (three grade 1, one grade 2); all had grade 1 PN (n=3) or paresthesias (n=1) at baseline. Overall, 58% had grade ≥3 AEs, 21% had dose reductions, and 6% discontinued due to AEs (thrombocytopenia, arthralgia, hypoxia). Two pts died on study due to PD and a cardiac disorder, considered unrelated. To date, of 36 evaluable pts, six have achieved minimal response or better, including two with partial responses (in the 1.2 and 2.23 mg/m2 cohorts), with duration of disease control of up to 11.3 months; all 6 pts remain in response. Another 22 pts have achieved stable disease, which also proved durable with stabilization for up to 9.9 months. MLN9708 was rapidly absorbed with MLN2238 Tmax of 0.5–1.25 hours and terminal half-life of approximately 4–5 days after multiple MLN9708 dosing. MLN2238 plasma exposure appeared to increase proportionally with increasing MLN9708 dose from 0.8–2.23 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that single-agent MLN9708 may result in clinical activity in heavily pretreated relapsed and/or refractory MM pts, including durable disease control, and is generally well tolerated, with infrequent PN. Updated information for all cohorts, plus data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708, will be presented. Disclosures: Richardson: Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Baz:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Orthobiotech: Research Funding. Wang:Millennium Pharmaceuticals, Inc.: Research Funding. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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Kumar, Shaji, William I. Bensinger, Craig B. Reeder, Todd M. Zimmerman, James R. Berenson, Deborah Berg, Guohui Liu et al. « Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma : Results From a Phase 1 Dose-Escalation Study ». Blood 118, n^o 21 (18 novembre 2011) : 816. http://dx.doi.org/10.1182/blood.v118.21.816.816.

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Abstract Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in >20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.

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Alsina, Melissa, Suzanne Trudel, Marcy Vallone, Christopher Molineaux, Lori Kunkel et Andre Goy. « Phase 1 Single Agent Antitumor Activity of Twice Weekly Consecutive Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies. » Blood 110, n^o 11 (16 novembre 2007) : 411. http://dx.doi.org/10.1182/blood.v110.11.411.411.

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Abstract Carfilzomib (CFZ) is a structurally- and mechanistically-novel proteasome inhibitor of peptide epoxyketone class that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. CFZ is similar to bortezomib (BTZ,Velcade®), in that it is a potent inhibitor of the proteasome chymotrypsin-like activity, but unlike BTZ, CFZ has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Preclinical human tumor xenograft models indicated that consecutive day (D1, D2) dosing resulting in 48 hours of proteasome suppression was superior to split dosing (D1, D4). This phase 1 sequential dose escalation trial tested twice weekly consecutive day dosing (48 hour proteasome inhibition) with carfilzomib. Carfilzomib was administered as an IVP on a 28 day cycle (D1, 2, 8, 9, 15 and 16 with 12 days rest) at doses from 1.2 mg/m2 to 27 mg/m2. Patients with Multiple myeloma (MM), non-Hodgkin’s Lymphoma (NHL) that included mantle cell lymphoma (MCL), Hodgkin’s disease (HD), or Waldenström’s macroglobulinemia (WM) were eligible if they had relapsed after at least 2 prior therapies. A total of 37 subjects have been treated. The minimal effective dose (MED) was 15 mg/m2, and maximum (80%) proteasome inhibition was achieved in peripheral blood and mononuclear cells at this dose. Five objective responses have occurred in 16 patients (13 MM, 3 MCL) enrolled at ≥ the MED: 4 MM partial response (PR), 1 MM minimal responses (MR). The responses have been durable (134 to 392 days) and occurred in patients who had failed bortezomib, immunomodulatory agents and stem cell transplant. Six additional patients have had stable disease (SD): 2 MM, 1 T NHL, 2 MCL, 1 B NHL. Dose limiting toxicity reported at 27 mg/m2 included a hypoxic event and Grade 2 thrombocytopenia increasing to Grade 4. A reversible Grade 2 creatinine D2 was reported in 3/5 MM patients treated at 27 mg/m2 and was associated with a rapid decline in M-protein without evidence of tumor lysis syndrome and the event did not occur on rechallenge. Cyclic thrombocytopenia was rapidly reversible and painful peripheral neuropathy was not reported. This study demonstrates that consecutive CFZ dosing leading to sustained proteasome inhibition is well tolerated on a weekly basis. The selectivity of epoxyketone class of proteasome inhibitors may provide a wide therapeutic index. Patients have remained on therapy for over a year, and furthermore, antitumor responses in heavily pretreated MM patients suggest non-cross resistant activity. Phase 2 trials in relapse and refractory MM and relapse solid tumors are proceeding with this schedule.

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Di Liberto, Maurizio, Xiangao Huang, Rediet Zewdu, Francesco Parlati, Monette Aujay, Ruben Niesvizky et Selina Chen-Kiang. « Selective inhibition of CDK4/CDK6 sensitizes bone marrow myeloma cells for killing by proteasome inhibitors carfilzomib and PR-047 through cell cycle-dependent expression of pro-apoptotic Noxa and Bim. » Blood 114, n^o 22 (20 novembre 2009) : 2854. http://dx.doi.org/10.1182/blood.v114.22.2854.2854.

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Abstract Abstract 2854 Poster Board II-830 Targeting the cell cycle in combination with cytotoxic killing is a rational approach to cancer therapy. Progression in multiple myeloma (MM) stems from both loss of apoptotic control in the bone marrow (BM) microenvironment and dysregulation of the cyclindependent kinases (CDK)4 and CDK6, which precedes uncontrolled proliferation of myeloma cells in vivo in particular during relapse. This reinforces the critical importance of targeting CDK4/CDK6 in MM. Through selective and reversible inhibition of CDK4/CDK6 with PD 0332991, the only known CDK4/6-specific inhibitor, we have recently developed a novel strategy to sensitize primary myeloma cells for cytotoxic killing by diverse cytotoxic drugs. These include carfilzomib (PR-171), an irreversible selective inhibitor of the chymotrypsin-like activity of the proteasome, and PR-047, an orally bioavailable analog of carfilzomib. We showed that induction of prolonged early G1 arrest following inhibition of CDK4/CDK6 markedly enhances cytotoxic killing of primary BM myeloma cells by either carfilzomib or PR-047 despite protection by BM stromal cells. The enhancement of cytotoxic killing is further augmented during synchronous S phase entry upon removal of PD 0332991 subsequent to induction of prolonged G1 arrest in myeloma cell lines. In both cases, the enhancement in carfilzomib (or PR-047) mediated killing is not associated with cell cycle regulation of the proteasome activity. It is caspase-dependent, requiring only a brief (one hour) exposure to the proteasome inhibitor at concentrations as low as 30 nM. This killing is mediated by synergistic and rapid induction of mitochondrial membrane depolarization and activation of downstream caspase-9. Further, it is apparently initiated by cell cycle-dependent expression of the pro-apoptotic BH3-only proteins, which neutralize the anti-apoptotic Bcl-2 family proteins upstream of mitochondrial depolarization. Bim is upregulated during early G1 arrest to neutralize the anti-apoptotic MCL-1 and Bcl-2. By contrast, Noxa is silenced in G1 but dramatically upregulated in S phase, in particular when combined with carfilzomib. Importantly, targeting CDK4/CDK6 with PD 0332991 in combination with either carfilzomib or PR-047 leads to complete eradication of myeloma cells ex vivo, in contrast to the combination of PD 0332991 with other proteasome inhibitors. Selective inhibition of CDK4/CDK6 in combination with carfilzomib (or PR-047), therefore, not only halts tumor cell proliferation but also potently induces synergistic killing that is likely to profoundly inhibit cell cycle reentry and self-renewal in MM. PD 0332991 is a small molecule with bio-availability and proven tumor suppressing activity in both human myeloma xenograft and immunocompetent mouse myeloma models. It is well tolerated in humans as indicated by the ongoing Phase I/II clinical trials in myeloma and previous phase I trials in mantle cell lymphoma and solid tumors. Evidence from Phase 2 trials of carfilzomib indicates that it is also well tolerated, in fact, the peripheral neuropathy that is commonly observed with the proteasome inhibitor bortezomib appears to be less severe and possibly less frequent. Mechanism-based targeting of CDK4/6 in combination with selective proteasome inhibitors, like carfilzomib and PR-047, thus represents a new and promising therapeutic strategy for multiple myeloma and potentially other hematopoietic malignancies. Disclosures: Off Label Use: PD 0332991 is going to be used as a CDK4/6-specific inhibitor. Parlati:Proteolix, Inc.: Employment, Equity Ownership. Aujay:Proteolix, Inc.: Employment, Equity Ownership. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.

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Voorhees, Peter M., Flora Mulkey, Hani Hassoun, Claudia E. Paba-Prada, Yvonne A. Efebera, Eva Hoke, Guadalupe Aquino, Destin Carlisle, Vera Suman et Paul G. Richardson. « Alliance A061202. a Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib Versus Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Refractory to Lenalidomide and Proteasome Inhibitor Based Therapy : Phase I Results ». Blood 126, n^o 23 (3 décembre 2015) : 375. http://dx.doi.org/10.1182/blood.v126.23.375.375.

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Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

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