Letteratura scientifica selezionata sul tema "M. P. Möller Organ Company"

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease that can not only cause systemic symptoms, such as fever and arthritis, but can also damage important organs, such as those of the central nervous system and the kidneys. Prevention of irreversible organ damage is important for better prognosis [1]. Additionally, the importance of maintaining the quality of life (QOL) of patients has recently been emphasized. However, only a few studies have examined the relationship between irreversible organ damage and patient QOL.Objectives:To assess the relationship between organ damage and QOL, and to survey which organs have more significant effects on QOL.Methods:We conducted a questionnaire-based survey of 183 patients with SLE at Kyoto University Hospital from September to December 2019. We used the SLICC/ACR Damage Index (SDI) to evaluate organ damage [2]. The following five scales were employed to evaluate QOL: the physical (PCS) and mental component summary (MCS) of the Medical Outcome Study (MOS) 36-Item Short-Form Health Survey version 2.0 (SF-36v2) [3], health (HRQOL) and non-health-related QOL (N-HRQOL) of LupusPRO [4], and SLE Symptom Checklist (SSC) [5].Results:Linear regression analysis showed significant correlation between the SDI score and all QOL scales except for N-HRQOL, suggesting negative effects of organ damage on QOL (Table 1). Next, we analysed whether there was a significant difference in the SF-36 score between those who were positive and negative for each SDI item (41 in total), using the Wilcoxon rank sum test. Muscle atrophy or weakness (p= 3.0×10-10), osteoporosis with fracture or vertebral collapse (p= 9.7×10-8), claudication (p= 7.4×10-5), and cognitive impairment or major psychosis (p= 9.9×10-5) significantly correlated (p< 1.2×10-3) with PCS, and scarring chronic alopecia (p= 3.4×10-4) with MCS (Table 2). In addition, the five SDI items significantly correlated with the remaining three QOL scales (HRQOL, N-HRQOL, and SSC;p< 0.05).Table 1.Relationship between the SDI score and QOLSF-36LupusPROSSCPCSMCSHRQOLN-HRQOLp-value<2.0×10-161.7×10-32.2×10-110.231.9×10-8Table 2.Relationship between each SDI item and the SF-36 score (p< 1.2×10-3SDI itemPCS scorep-valuePositive(Median (IQR))Negative(Median (IQR))Muscle atrophy/weakness33 (19-45)50 (43-54)3.0×10-10Osteoporosis with fracture/vertebral collapse24 (12-32)49 (38-54)9.7×10-8Claudication31 (19-35)49 (38-54)7.4×10-5Cognitive impairment/psychosis27 (17-33)49 (38-54)9.9×10-5SDI itemMCS scorep-valuePositive(Median (IQR))Negative(Median (IQR))Scarring chronic alopecia42 (29-51)49 (39-54)3.4×10-4Conclusion:We demonstrated that organ damage has negative effects on patient QOL, indicating the importance of preventing irreversible organ damage for maintaining QOL. Moreover, muscle atrophy/weakness, osteoporosis with fracture/vertebral collapse, claudication, cognitive impairment/major psychosis, and scarring chronic alopecia significantly correlated with QOL deterioration, suggesting that these items should be examined with special care in clinical practice.References:[1]Lopez R, et al. Rheumatology (Oxford). 2012; 51:491-498.[2]Gladman D, et al. Arthritis Rheum. 1996; 39:363-369.[3]Fukuhara S, et al. J Clin Epidemiol. 1998; 51:1037-1044.[4]Inoue M, et al. Lupus. 2017; 26:849-856.[5]Grootscholten C, et al. Qual Life Res. 2003; 12:635–644.Disclosure of Interests:Yudai Takase: None declared, Hiroshi Doi: None declared, Takeshi Iwasaki: None declared, Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Ryuta Inaba: None declared, Tomohiro Kozuki: None declared, Masashi Taniguchi: None declared, Yuya Tabuchi Paid instructor for: Astellas Pharma, GlaxoSmithKline, Mitsubishi Tanabe Pharma, and Nippon Shinyaku., Speakers bureau: AbbVie, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Shinyaku, and Novartis Pharma. (Outside the field of the present study.), Koji Kitagori: None declared, Syuji Akizuki: None declared, Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Ran Nakashima Grant/research support from: Takeda Pharmaceutical. (Outside the field of the present study.), Speakers bureau: Astellas Pharma, Medical & Biological Laboratories, AstraZeneca, and Boehringer Ingelheim. (Outside the field of the present study.), Hajime Yoshifuji Grant/research support from: Astellas Pharma. (Outside the field of the present study.), Speakers bureau: Chugai Pharmaceutical. (Outside the field of the present study.), Wataru Yamamoto: None declared, Masao Tanaka Grant/research support from: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical, and UCB Japan., Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Pfizer, Taisho Pharmaceutical, Takeda Pharmaceutical, and UCB Japan., Koichiro Ohmura Grant/research support from: Astellas Pharma, AYUMI Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Sanofi, and Takeda Pharmaceutical., Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma, AYUMI Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, and Sanofi.

Introduction: Selection of an appropriate donor is important for the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). In general, an HLA-matched related donor (M-RD) and an HLA-matched unrelated donor (M-UD) are considered to be the first and second preferred donors in allo-HCT. On the other hand, the most suitable alternative donor remains unclear, when M-RD and M-UD are unavailable. In addition, the information on a suitable donor selection for elderly patients are limited. We hypothesized that the patient age might change the donor selection priority in allo-HCT, because related donor age, organ function, or endurance against graft-versus-host disease or infection differ between younger and older patients. Therefore, we conducted a nationwide, large retrospective study to investigate the donor selection priority in allo-HCT, classified according to patient age. Methods: We analyzed 17848 adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome who underwent a first all-HCT between 2007 and 2017 in Japan. We compared the transplant outcomes among M-RD (n=4106), HLA 1-antigen-mismatched related donor (1MM-RD) (n=592), HLA 2,3-antigen-mismatched related donor (23MM-RD) (n=882), M-UD (n=3927), HLA 1-locus-mismatched unrelated donor (1MM-UD) (n=2474), and unrelated cord blood (U-CB) (n=5867), in the whole cohort and in subgroups of patients aged &lt;50 years (n=8572) and those aged ≥50 years (n=9275). All P-values were two sided, and P-values &lt;0.05 were considered statistically significant. Results: Results of multivariate analyses of overall survival (OS), non-relapse mortality (NRM) and relapse are summarized in Table 1. For all patients, 1MM-RD, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS and NRM (hazard ratio [HR] 1.26, p&lt;0.001 and HR 1.93, p&lt;0.001 for 1MM-RD; HR 1.46, p&lt;0.001 and HR 2.15, p&lt;0.001 for 23MM-RD; HR 1.12, p=0.0032 and HR 1.68, p&lt;0.001 for 1MM-UD; and HR 1.19, p&lt;0.001 and HR 1.70, p&lt;0.001 for U-CB) compared to M-RD. On the other hand, there was no significant difference in OS between the M-RD and M-UD groups (HR 0.94, p=0.093), although NRM in the M-UD was inferior to that in the M-RD group (HR 1.27, p&lt;0.001). The risk of relapse in the 1MM-RD, 23MMRD, M-UD, 1MM-UD, and U-CB groups were significantly lower than that in the M-RD group. An interaction test revealed that the effect of M-UD on OS and NRM differed between the patient age &lt;50 years and ≥50 years (HR 0.88, p=0.055 and HR 0.78, p=0.019). Next, we compared transplant outcomes among these donor source within subgroups of patients grouped according to patient age. For the patients aged &lt;50 years, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS (HR 1.46, p&lt;0.001, HR 1.18, p&lt;0.001 and HR 1.20, p&lt;0.001), and 1MM-RD tended to be an adverse factor for OS (HR 1.19, p=0.052). On the other hand, OS in the M-UD group was comparable to that in the M-RD group (HR 1.02, p=0.72). For the patients aged ≥50 years, 1MM-RD, 23MMRD, and U-CB were independent significant adverse factors for OS (HR 1.29, p=0.0013, HR 1.42, p&lt;0.001 and HR 1.17, p&lt;0.001). 1MM-UD was not a significant adverse factor for OS (HR 1.07, p=0.18). Conversely, OS in the M-UD group was superior to that in the M-RD group (HR 0.89, p=0.012). In addition, we classified the M-UD group according to donor age (M-UD-Y, donor age &lt;50 years; M-UD-O, donor age ≥50 years). For the patients aged ≥50 years, OS in the M-UD-Y group was superior to that in the M-RD group (HR 0.86, p=0.035), although there was no significant difference in OS between the M-UD-O and M-RD groups (HR 1.08, p=0.70). However, for the patients aged &lt;50 years, OS in the both M-UD-Y and M-UD-O groups were comparable to those in the M-RD group (HR 1.02, p=0.73 and HR 1.04, p=0.82). The probabilities of adjusted OS at 3 years for the patients aged &lt;50 years and aged ≥50 years were 63.6% and 41.6% in the M-RD group, 58.4% and 38.8% in the 1MM-RD group, 52.3% and 30.4% in the 23MM-RD group, 63.6% and 46.8% in the M-UD group, 58.9% and 42.3% in the 1MM-UD group, and 60.1% and 40.3% in the U-CB group (Figure 1). Conclusions: Donor selection priority in all-HCT might be different according to patient age. In particular, young M-UD might be the first preferred donor for patients aged 50 years or older. We should reconsider donor selection priority in allo-HCT based on patient and donor age. Disclosures Kanda: Takeda: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Bristol-Meyers Squib: Honoraria; JCR Pharmaceuticals: Honoraria; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Kimura:JSPS KAKENHI: Research Funding. Ozawa:Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria. Kanda:Pfizer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Otsuka: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Taisho-Toyama: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Takara-bio: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding.

Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

Abstract Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose ("mini")-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT. Methods: Patients &lt;70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power. Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P&lt;0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P&lt;0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P&lt;0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P&lt;0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06). Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Background:Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease, characterized by autoimmune inflammatory microvascular damage with progressive loss of capillaries, fibrosis and ischemia of skin and internal organs. (1) Nailfold videocapillaroscopy (NVC) is a safe toll for early diagnosis of SSc, it identify morphological changes of vessel that are predictive for clinical disease progression and organ involvement.(2) About clinical complication the loss of bone mass and body composition abnormalities, particularly muscle mass and strength loss (sarcopenia), are recognized in advanced disease.(3)Objectives:To evaluated in SSc patients, the body composition and the bone status according to the microvascular condition, assessed and scored by nailfold videocapillaroscopy (NVC, “Early”,”Active”,”Late” patterns).Methods:Body composition and bone mineral density (BMD) were assessed by DEXA in 35 female SSc patients classified according to the 2013 EULAR/ACR criteria and 32 sex-matched healthy subjects. Clinical, laboratory, body composition and bone parameters were analysed according to the different NVC patterns. Means were compared by the Student’s t test or one way analysis of variance; medians were compared by the Kruskall Wallis test; and frequencies by the chi square test.Results:Higher prevalence of vertebral (26.4%vs 9.3%) and femoral (32.3% vs 9.3%) osteoporosis (OP) was found in SSc. Particularly SSc patients with “Late” NVC pattern showed a significantly higher prevalence of vertebral (p=0.018) and femoral OP (p=0.016). Regional assessment of bone mass (BM) in 7 different body areas showed a significant lower BMD only at the total spine (P=0.008) and femoral neck (p=0.027) in advanced microvascular damage. Patients with “Late” NVC pattern showed lower whole body lean mass (LM) compared to “Early” and “Active” NVC patterns, particularly at upper limbs. To note, in all body sites, BMD correlate with LM and BMC according to NVC pattern severity.Conclusion:SSc patients with most severe microvascular damage show a significantly altered body composition and bone status suggesting a strong link between microvascular failure and associated muscle/bone sufference.References:[1]Cutolo M et al. Expert Rev Clin Immunol 2019; 15(7):753-64[2]Cutolo M et al. Clin Rheumatol 2019; 38(9):2293-7[3]Corallo C et al. Rheumatol Int 2019;39(10):1767-75.Disclosure of Interests:Sabrina Paolino: None declared, Emanuele Gotelli: None declared, Andrea Casabella: None declared, Francesco Cattelan: None declared, Carlotta Schenone: None declared, Massimo Patanè: None declared, Greta Pacini: None declared, Carmen Pizzorni: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

Abstract Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP &gt; 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p&lt;0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) can be an aggressive, often deadly disease without any approved treatments. Current available treatments for EBV + PTLD may include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). However, the long-term consequences of CHOP are poorly understood in immunocompromised transplant patients with cancer who may have different outcomes than immunocompetent cancer patients. This study reviewed and described the evidence for the long-term consequences associated with components of CHOP in transplant recipients. Methods: Potential long-term consequences of the components of CHOP were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n&gt;100, observation study n&gt;100, case series n&gt;20). Relevant studies that met the criteria were extracted and synthesized; of these, studies were selected if they evaluated patients who received any type of transplantation as part of their primary cancer treatment. Results: A total of 7 studies met the pre-specified selection criteria, all of which evaluated patients with hematopoietic stem cell transplantation (HCT) and none assessed solid organ transplant (SOT). None of the studies focused specifically on the CHOP regimen or EBV + PTLD. Long-term consequences of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment reported in these HCT studies included: hormone deficiencies and infertility (n=4 studies), osteonecrosis (n=2), and health status and quality of life (QoL; n=1). Results from three studies suggested that cancer survivors who received alkylating agents experienced hormone deficiencies and those with a HCT had a high risk. One quantified this by showing that, compared with cancer survivors without a history of HCT (CS), cancer survivors with a history of HCT (CS-HCT) and a history of total body irradiation had significantly impaired follicle stimulating hormone (40.42 vs 9.39 mIU/ml, P&lt;0.001), Estradiol (15.09 vs 25.13 pg/ml, P=0.04), Inhibin B (10.61 vs 32.92 pg/ml, P=0.003), anti-Müllerian hormone (0.01 vs 1.28 ng/ml, P&lt;0.001), antral follicle count (0.71 vs 17.78, P&lt;0.001) and ovarian volume (1.82 vs 8.21 ml, P&lt;0.001). In one study on the risk of osteonecrosis, the CS-HCT group had a significantly increased risk of developing osteonecrosis compared to the CS group treated with chemotherapy (6.8% vs 1.4%, respectively); cumulative incidence of osteonecrosis was 3.8% in the CS group for a steroid dose &gt;5,835 mg/m 2 and 23.8% in the CS-HCT group for a post-transplant steroid dose &gt;2,055 mg/m 2; and patients developed symptomatic osteonecrosis within a median of 2.4 years in the CS group with chemotherapy and 0.9 years after the first transplant in the CS-HCT group. A second study showed the rate ratio (RR) of osteonecrosis compared with a sibling comparison group was highest among the CS-HCT for acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia (RR = 26.9, 66.5, and 93.1, respectively; P&lt;0.001 for all). One study reported that childhood acute leukemia survivors treated with HCT with preparative regimen with either busulfan-cyclophosphamide or total body irradiation/cyclophosphamide had a significantly lower QoL short-form (SF)-36 mental and physical composite scores in both treatment groups compared with norms. Conclusions: Since only a small number of studies (7) of long-term consequences in transplant recipients were identified and none were seen in patients with EBV + PTLD or in SOT recipients, more research is needed to evaluate adverse consequences of CHOP or its components in EBV + PTLD, especially in SOT patients where no studies were found. Results from this review suggest that immunocompromised HCT recipients who were cancer survivors are significantly more impaired by long-term consequences (hormone deficiencies and infertility, osteonecrosis, and QoL) of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment compared with other cancer survivors without HCT. Disclosures Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

Abstract Introduction: Light chain (AL) amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils into organs leading to organ dysfunction and death. The analysis at 6 and 12 months of the ANDROMEDA study (NCT03201965) showed that the addition of subcutaneous (SC) daratumumab to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Based on these findings daratumumab with VCd (D-VCd) was approved for newly diagnosed AL amyloidosis in January 2021 in the US and June 2021 in the EU. Here, we present data from the analysis at 18 months of the ANDROMEDA study. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study including patients with newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, estimated glomerular filtration rate ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to D-VCd or VCd for 6 28-day cycles. Bortezomib (1.3 mg/m 2), cyclophosphamide (300 mg/m 2 up to 500 mg per week), and dexamethasone (20-40 mg) were administered weekly. SC daratumumab (1800 mg co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 to 6. Patients in the D-VCd arm received only SC daratumumab after cycle 6, every 4 weeks (up to a total of 24 cycles from first dose). The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of free light chain (FLC) levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if involved FLC was lower than the upper limit of normal. Secondary endpoints included major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, overall survival (OS), and safety. Results: A total of 388 patients were randomized to receive D-VCd (N=195) or VCd alone (N=193). At the May 2021 clinical cutoff, the median duration of treatment for D-VCd and VCd arms was 21.3 and 5.3 months, respectively. In the D-VCd arm, 149 patients (77.2%) received daratumumab monotherapy after completing 6 cycles of D-VCd; of those, 17 (11.4%) were still receiving treatment. The rates of deep hematological responses favored the D-VCd treatment arm (Table). At a median follow-up of 25.8 months, the rate of hematologic CR was significantly higher in the D-VCd arm vs the VCd arm (59.5% vs 19.2%; odds ratio [95% confidence interval (CI)], 6.03 [3.80-9.58]; P&lt;0.0001). Similarly, more patients achieved a very good partial response or better (≥VGPR) (D-VCd vs VCd, 79.0% vs 50.3%; odds ratio [95% CI], 3.74 [2.39-5.86]; P&lt;0.0001). Among patients who responded, the median time from randomization to ≥VGPR was shorter in the D-VCd arm (0.56 months) vs the VCd arm (0.82 months). Comparable to the cardiac response analysis at 6 months (D-VCd vs VCd, 42% vs 22%), greater cardiac response rates were achieved with D-VCd compared with VCd at 18 months (53% vs 24%). Similarly, renal response rates remained superior with D-VCd vs VCd alone at 18 months (58% vs 26% compared with 6 months [54% vs 27%]). A total of 79 deaths occurred (D-VCd, N=34; VCd, N=45). In the D-VCd arm, only 1 additional grade 3/4 treatment-emergent adverse event occurred over 18 months vs 12 months (119 [61.7%] vs 118 [61.1%] patients) and no additional infusion-related reactions were reported. OS will be analyzed and major organ deterioration PFS will be updated after approximately 200 events have occurred. Conclusions: These results demonstrate the sustained clinical benefits of D-VCd vs VCd in terms of hematologic and organ responses with longer follow-up, although it should be noted that many patients in the D-VCd arm received daratumumab monotherapy following 6 cycles of D-VCd, while patients in the VCd group stopped study treatment. Nevertheless, the study continues to support the use of D-VCd over VCd alone in patients with newly diagnosed AL amyloidosis. Following its recent approval, D-VCd represents a new SOC for patients with AL amyloidosis. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Caelum: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Janssen: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy. Wechalekar: Amgen: Research Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria; Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy. Jaccard: Pfizer: Honoraria; Abbvie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Janssen: Consultancy, Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Lee: Karyopharm: Consultancy; Celgene: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Genentech: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy, Research Funding; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Regeneron: Research Funding. Sanchorawala: Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Proclara: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Suzuki: Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Cibeira: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: 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; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Libby: Genentech: Research Funding; BMS: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding. Valent: Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau. Hungria: Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel ; Abbvie: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig: Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Akcea: Speakers Bureau; Takeda: Speakers Bureau; Onocopeptides: Speakers Bureau. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Qin: Janssen: Current Employment. Khaled: Jazz: Honoraria; Astellas: Honoraria; Alexion: Honoraria, Speakers Bureau; Omeros: Honoraria; Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company.

Abstract Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. The combination of the proteasome inhibitor (PI) Bortezomib, an alkylator (Cyclophosphamide or Melphalan) and Dexamethasone (Dex) /Prednisone is a widely used first-line therapy. Most patients achieve a rapid response within the first two cycles. The lack of a deep response to the bortezomib-based therapy predicts an inferior outcome, a poor response to newer PIs and limited therapeutic options. Different studies highlighted the role of the PD1/PDL1 pathway in myeloma immune escape and progression. The expression of PDL1 by myeloma cells is higher in relapsed or refractory disease and on minimal residual disease cells. At least one preclinical study showed that the binding of PD1 to PDL1 expressed by the myeloma cells leads to a reverse signal that induces resistance to bortezomib and melphalan. Also, Bortezomib is known to enhance anti-myeloma immune response by different mechanisms, including stimulating myeloma cell apoptosis, sensitizing myeloma cells to natural killer cell mediated killing and enhancing antigen presentation by dendritic cells. This suggests a mutual potentiation between Pembrolizumab and Cyclophosphamide, Bortezomib and Dex (CyBorD). An early immune-based intervention is likely more beneficial. With time and disease progression, the host is more immune-compromised and the disease is more refractory with redundant escape mechanisms. The benefits of early intervention are carefully weighed against the potential risks and other available therapeutic options. The adaptive design of this CMRG-006 trial is meant to select the population with the highest need for treatment improvement while still in the early phase of therapy. We expect the combination of Pembrolizumab and CyBorD to be more effective and well tolerated. Design and Methods: Phase 2A, pilot study. Non-transplant eligible newly diagnosed myeloma patients (NTE-NDMM) will start their standard nine cycles of CyBorD (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycle). Patients not having primary disease progression and achieving less than Very Good Partial Response (VGPR) after 2 cycles will be screened for this study during cycle 3. Eligible patients will receive Pembrolizumab 200 mg IV every 3 weeks starting with day 1 of cycle 4 (P-CyBorD). After completion of cycle nine of CyBorD, Pembrolizumab will be administered as a single agent for up to total of 35 doses. The objectives are to evaluate the efficacy and tolerability of P-CyBorD. The key inclusion criteria are having a NTE-NDMM with a measurable disease; no primary progressive disease and not achieving VGPR after two cycles of CyBorD; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-PD1 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and AL amyloidosis. S ample Size: A maximum of 20 patients will be enrolled to ensure 16 or more patients evaluable for response. Patients with less than VGPR after two cycles of CyBorD have ≤20% probability to achieve ≥VGPR after cycle 9. With the addition of Pembrolizumab, a minimal clinically important difference (MCID) of 10% would be meaningful, and a 50% response rate (≥VGPR) in 16 evaluable patients will be statistically significant. This study is currently recruiting. Clinicaltrials.gov #: NCT04258683. Disclosures Kotb: Amgen: Honoraria; BMS: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Othman: Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Reece: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; GSK: Honoraria.

Background: Blockade of PD-1/PD-L1 pathways enhances anti-leukemic responses in pre-clinical studies. PD1 inhibition alone had limited clinical activity in AML. CLTA4 inhibition demonstrated encouraging single-agent CR's in postASCT patients (pts), especially for extra-medullary (EMD) relapses (Davis M et al, NEJM 2016). AZA+Nivo up-regulated CTLA4 on bone marrow (BM) CD8 cells in both responders (R) and non-responders (NR) on treatment (Daver N, et al, Cancer Discovery 2019), suggesting a triplet of AZA+Nivo+Ipi may abrogate PD-1 mediated resistance. Methods: Pts were eligible for the AZA+Nivo (cohort 1, n=59) if they had R/R AML, ECOG ≤ 2, and adequate organ function. This cohort has completed enrollment. A cohort of AZA+Nivo+Ipi was opened (cohort 2), with the same eligibility criteria. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule and found to be safe in a lead-in dose cohort. Results: Cohort 1 (59 R/R AML) pts were treated with Aza+Nivo (Daver et al., Cancer Discovery 2019). CR/CRi and OS were superior to contemporary historic HMA-based clinical trial controls at MDACC (Table 1). Pts with low pretherapy BM blasts (&lt;20% BM blasts) and early salvage (salvage 1) had encouraging median (med) OS 11 months (mos), indicating progressive T-cell exhaustion with multiple relapses. Importantly, on 40-parametric CYTOF assessment, Rs to AZA+Nivo had a higher frequency of pre-therapy BMA CD3+ and CD8+ cells compared with NRs (optimal CD3+ cutoff 13.2%: ORR 56% versus 23%), suggesting pre-existing BM T-cell infiltration may be a pre-requisite of response to PD1 based therapies, as PD1 inhibitors have limited ability to mobilize peripheral T-cells (Fig 1A). The pre-therapy BM CD4 polyfunctional strength index (PSI) defined as percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines, assessed by single cell cytokine analysis was dramatically different between Rs and NRs (P=0.03). Single-cell RNA-seq on 113,394 BM cells collected longitudinally from 8 pts (3R, 2 stable disease (SD), 3NR) demonstrated that deletion 7/7q, LSC signature enrichment, and activated metabolic/oxidative pathways, were associated with resistance to AZA+Nivo (Abbas H et al, ASH 2020). Importantly, AZA+Nivo induced novel and expanded T cell clonotypes, almost exclusively in Rs. Cohort 2 (36 R/R AML) pts were treated with Aza+Nivo+Ipi, with med age 67 years (25-83), secondary AML (50%), ELN unfavorable cytogenetics (67%), TP53 (36%), med salvage 2 (range, 1-3), and prior HMA based therapies in 67%. All 36 pts are evaluable. Per ELN 2017, CR/CRi was noted in 7 (19%) and PR in 1 (3%). Five (14%) pts had durable stable disease (SD) (defined as absence of CR, CRi, PR; with SD on treatment for ≥6 months), and 23 (64%) were NRs (Table 1). Interestingly, 4 pts with EMD were enrolled and 3 had CR/PR [med DOR 8 (5-13) mos]. The 4- and 8-week mortalities were 0 and 6%, respectively. Grade 3/4 immune toxicities noted in 8 pts (19%), including rash, pneumonitis, colitis, pyrexia. One pt required ICU stay, but no deaths attributed to immune toxicity. Other grade ≥2 toxicities were as expected for R/R AML population and were mostly infections/febrile neutropenia. Converse to AZA+Nivo, on CYTOF, R did not have a higher frequency of pre-therapy BM CD8+ infiltration, but did have progressive BM CD8+ infiltration on therapy, compared with NRs, demonstrating that Ipi (unlike Nivo) may be able to mobilize peripheral T-cells to the BM (Fig 1B). Expansion of a cluster of antigen experienced CD8+ T cells was associated with response (Fig 1B). In all salvage the med OS with Aza+Ipi+Nivo versus Aza+Nivo versus contemporary HMA-controls in R/R AML, were 7.6, 5.9, and 4.6 mos, respectively (P=0.01) (Fig 1C). The 1-year OS in R/R AML pts with AZA+Nivo+Ipi was 25%. The med OS with Aza+Ipi+Nivo was comparable to med OS 6-8 mos reported with HMA+VEN salvage in numerous studies. Conclusion: The OS with Aza+Nivo+Ipi was modestly improved over AZA+Nivo and HMA-controls in R/R AML. Single-cell cytokine profiling and single-cell RNA-seq from Aza+Nivo showed striking pre- and on-treatment differences among R and NR not only in T-cell fitness and clonality, but also in the tumor microenvironment. Ipi may be uniquely able to mobilize peripheral T-cell to BM and EMD. This underappreciated immune diversity suggests a critical need for biomarker-based trials (as we are doing with molecular therapies) for immunotherapies in AML. Disclosures Daver: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Merck: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Sanofi: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding. DiNardo:AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy. Borthakur:Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding. Allison:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAB: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Cyclacel: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Sharma:Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab and Ipilimumab based combinations for AML, will be discussed. These agents do not have an on label indication for AML at this time.