Journal articles on the topic 'Reeves Company'

Predicting customer churn has become the priority of every telecommunication service provider as the market is becoming more saturated and competitive. This paper presents a comparison of neural network learning algorithms for customer churn prediction. The data set used to train and test the neural network algorithms was provided by one of the leading telecommunication company in Malaysia. The Multilayer Perceptron (MLP) networks are trained using nine (9) types of learning algorithms, which are Levenberg Marquardt backpropagation (trainlm), BFGS Quasi-Newton backpropagation (trainbfg), Conjugate Gradient backpropagation with Fletcher-Reeves Updates (traincgf), Conjugate Gradient backpropagation with Polak-Ribiere Updates (traincgp), Conjugate Gradient backpropagation with Powell-Beale Restarts (traincgb), Scaled Conjugate Gradient backpropagation (trainscg), One Step Secant backpropagation (trainoss), Bayesian Regularization backpropagation (trainbr), and Resilient backpropagation (trainrp). The performance of the Neural Network is measured based on the prediction accuracy of the learning and testing phases. LM learning algorithm is found to be the optimum model of a neural network model consisting of fourteen input units, one hidden node and one output node. The best result of the experiment indicated that this model is able to produce the performance accuracy of 94.82%.

The work is aimed at solving a relevant for Ukraine and the world scientific and applied problem – the development of methods and means of constructing a psychophysical portrait of man to determine its stress resistance. For a number of professions, special methods of selecting personnel for special abilities are needed. Such abilities (qualities) include: health; motivation and will to act decisively, with the maximum effort of their physical, intellectual and psychological capabilities; physical training; level of mastery of technical means (or other means necessary in a critical situation); temperament; nature; emotional condition; accumulation of fatigue during the task and others. The article develops a method for classifying users according to the level of stress resistance on the basis of a modified auto-associative neural network using the Fletcher – Reeves algorithm. There are several ways to classify stress responses, but a more obvious study is to divide them into behavioral, intellectual, emotional and physiological manifestations of stress. The main signs of behavioral stress are psychomotor disorders (excessive muscle tension, winter breathing rhythm), lifestyle changes (changes in daily routine, sleep disturbances), occupational disorders (decreased productivity, increased fatigue), impaired social role functions, increased conflict, increasing aggression, etc.). In conditions of constant influence of stress factors on human consciousness, the decision can be ill-considered and made under the influence of emotions. To avoid such a situation in the workplace, the head of the company must monitor the condition of the operator. This human operator stress assessment system has been developed to predict human operator stress. The main task of the model is to predict based on the obtained parameters of the human condition (stress or not). Additional testing was added to increase the model’s performance based on input data on physical parameters, gender, age, height, and bad habits. The purpose of testing is to increase the accuracy of model prediction. Data from 92 respondents with 1180 records were selected for testing. Data set division: testing – 20 %, training / verification – 80%. The best results were achieved with the help of our own developed neural network based on Keras. Also in the paper the implementation of decision-making methods, the method of k-nearest neighbors and the modified auto-associative network was presented.

Abstract Background: Patients with relapsed or refractory (R/R) DLBCL generally have a poor prognosis, particularly if they are not candidates for autologous stem cell transplantation (ASCT) or experience relapse following approved CAR-T therapies. The UNITY-NHL study systematically explored the efficacy and tolerability of the PI3K-d/CK1-e inhibitor, umbralisib, alone (umbra), and in combination with the glycoengineered anti-CD20 monoclonal antibody ublituximab (U2), followed by a cohort treated with U2 plus bendamustine (U2+benda). Herein we report on the experience in a large cohort of patients with R/R DLBCL. Methods: This study explored a sequential combination design as described above. Eligible patients had histologically confirmed R/R DLBCL and were ineligible for ASCT, with no limit on number or type of prior treatment. Umbra was given orally at 800 mg once daily in 28-day cycles (C) until disease progression or unacceptable tolerability. Ublituximab was administered intravenously (IV) on Days 1, 8, and 15 of C1, on Day 1 of C2-6, and on Day 1 every 3C through C24. Benda was administered IV (90 mg/m 2) on Days 1/2 of C1-6. Cell of origin, NGS, and c-myc (FISH) were analyzed centrally. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee. Secondary endpoints included duration of response, progression-free survival, time to response, and safety. Results: 226 patients with DLBCL were enrolled as follows: umbra monotherapy (n=30), U2 (n=66), and U2+benda (n=130). The population demographics included the following features: median age was 72 years (range 32-95); 59% were male; 64% of patients had stage III or IV disease; 58% were refractory to their immediate prior therapy; and the median number of prior therapies was 2 (range 1-8). There were no substantive differences in these characteristics across cohorts. Median follow-up for the umbra, U2, and U2+benda arms was 51 months (range 47-61), 46 months (range 41-57), and 40 months (range 35-47), respectively. Overall and complete response rates for the umbra mono, U2, and U2+benda arms were 13.3% (CR 3.3%), 31.8% (CR 10.6%), and 43.1% (CR 16.9%), respectively. Results pertaining to secondary endpoints are listed in Table 1. Correlation of response to cell of origin and mutation/c-myc status is ongoing and will be available at the time of presentation. Adverse events (AEs) were similar across the cohorts, with the exception of hematologic AEs which were increased in patients receiving benda. The most common all-grade AEs by treatment arm (umbra, U2, and U2+benda, respectively) were diarrhea (47%; 41%; and 48%), nausea (40%; 45%; and 45%), fatigue (33%; 30%; and 41%) and neutropenia (3.3%; 18%; and 32%). All-grade AEs of special interest included non-infectious colitis (3.3%, 1.5%, and 2.3%) and pneumonitis (3%, 1.5%, and 1.5%) in umbra, U2 and U2+benda treated patients respectively. Grade 3/4 AEs were uncommon, with the only events >10% being limited to neutropenia (11% for U2; 27% for U2+benda), and anemia (17% for U2+benda). Conclusions: In the DLBCL cohort of UNITY-NHL, the U2+benda triplet regimen was active and well tolerated in patients with R/R DLBCL who were unsuitable for transplant or who had relapsed following ASCT. Umbra monotherapy and U2 were also well tolerated but resulted in lower ORR than in the U2+benda cohort. Figure 1 Figure 1. Disclosures Burke: X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Kura: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Verastem: Consultancy. Fonseca: Amgen: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Dava Oncology: Honoraria; Epizyme: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: 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; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Islas-Ohlmayer: Seagen Inc.: Research Funding. Reeves: Apollomics, Inc.: Research Funding; Tarveda Therapeutics: Research Funding; Ascentage Pharmaceuticals: Research Funding; Clovis Oncology: Research Funding; Arvinas: Research Funding; Pfizer: Research Funding; Ellipses: Research Funding; ImmunoGen: Research Funding; Karyopharm Therapeutics: Honoraria, Research Funding; Moderna: Research Funding; Thrive: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Astellas Pharma: Research Funding; IDEAYA Biosciences: Research Funding; Pharmacyclics: Research Funding; Loxo Oncology: Research Funding; AbbVie Inc.: Research Funding; Celgene: Research Funding; GSK: Research Funding; Jiangsu Hengrui Medicine Co.: Research Funding; Arcus Biosciences: Research Funding; Calithera: Research Funding; Amgen: Research Funding; Mirati Therapeutics, Inc.: Research Funding; Array BioPharma Inc.: Research Funding; Taiho Pharmaceutical: Research Funding; Boehringer Ingelheim: Research Funding; GI Therapeutics Inc.: Research Funding; Hutchison: Research Funding; MacroGenics: Research Funding; Ipsen: Research Funding; MedImmune, LLC.: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Janssen Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Co.: Research Funding, Speakers Bureau; Roche Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Arvinas: Research Funding; CytomX: Research Funding; Sermonix Pharmaceutical: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Evelo Biosciences: Research Funding. Wróbel: Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria; Janssen: Honoraria, Speakers Bureau. Pagel: Incyte/MorphoSys: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Nomocan: Consultancy; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Kymera: Consultancy, Current equity holder in publicly-traded company; Mundipharma: Consultancy. Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau.

The Alps in the oeuvre of Zygmunt KrasińskiWhen it comes to the scope of its topics and level of detail, the sketch “The Alps in the oeuvre of Zygmunt Krasiński” is a preliminary reconnaissance. Krasiński’s image of the Alps was influenced by his “educational” trip to Switzerland on which he went with his guardians in the autumn of 1829. The primeval and monumental nature of the Alpine landscape left an indelible mark on the psyche of the young Romantic poet. This can be seen in Krasiński’s letters to his father as well as discursive writings of the future author of Non-Divine Comedy. Of crucial importance in the exploration of the Alps by young Krasiński were his Alpine trips: first in the company of his tutor and English friend Henry Reeve and then in the company of Adam Mickiewicz and Edward Odyniec.

AbstractIn 1769, the East India Company decided to transform the Bengali silk industry, and introduced Piedmontese reeling technologies and spatially concentrated working practices into the area. Although Bengali raw silk reeled with the new methods never reached the standards of Piedmontese silks, the Company was able to produce huge quantities of low-quality raw silks, and to gain market share in London from the 1770s to the 1830s. By investigating the reasons behind this partial success, this article shows that some features of Piedmontese technologies had a crucial impact on peasants who specialized in the mulberry cultivation and the rearing of silkworms. The Company had to cope with resistance from some rural economic agents in late eighteenth- and early nineteenth-century Bengal, but other elements in local society were able to profit from the Company's interest in producing raw silk.

The article clarifies the concept of in-house interview as an interview of employees or job candidates, organized by the security service of a private company, identifies the types of in-house interview, clarifies the concept of confession. The two-stage model of inquest and some indicators of lying, which are used by the authors during the in-house interview, are described. The indicators correlating with lying in the course of service interview - the latent verbal aggression, lying strategies, presence of textual bridges and lacunas, separate elements of mimic and kinetic behavior are offered. The two-step model of Reed’s inquest, known as “Reed’s Nine Steps to Getting a Confession”; the approach of domestic psychologist L. B. Filonov, the authors’ approach to organizing the process of getting a confession within a service interview are partially described. The psychological mechanisms that make it possible to obtain previously unknown information during in-house interviews, which can be used in any kind of interviews and interrogations, are considered.

Controlled atmosphere (CA) preservation of perishable fruit and vegetables represents new opportunities for today's reefer operators. This technology affords the carrier an efficient and economical method of introducing and maintaining a low oxygen atmosphere that, when used in conjunction with temperature control, can significantly enhance the preservation of fruit and vegetables. Improved product quality, new markets, and reduced product losses are benefits realized through the use of hollow fiber membrane air separation technology. Seasonal products, which may be unavailable because of the transit time of shipping, are now a reality for operators utilizing this technology. High-value products such as fresh cut flowers, previously dedicated to air freight, may be a natural extension of the technology. The authors' company is a wholly owned subsidiary of The Dow Chemical Company. Generon supplies hollow fiber membrane systems for the on-site generation of gaseous nitrogen. In 1992 the company provided turnkey design and installation services of controlled atmosphere systems for three fully refrigerated containerships operated by the Great White Fleet. These ABS-classed vessels were the first of their type to fully utilize controlled atmosphere technology for the improved quality and reduction of perishable losses.

The Konkani Brahmin Babba Prabhu served the Dutch in Kerala as a merchant, broker and envoy for many years. Nevertheless, the Dutch were divided in their opinion of him. Rijcklof van Goens trusted him in 1663 as a competent merchant, but a year later Hustaert called him a roguish Brahmin. He was alternately praised and blamed, until in 1691, when Hendrik Adriaan van Reede visited Malabar as a commissioner, he was charged with several difficult tasks and was granted rather exceptional privileges. However, after Van Reede's departure pressure was put on him to repay his debts to the Company. Admittedly we can only trace the changing Dutch opinions of Babba and not his opinion of them. No sources other than the Dutch archives are available to us. But they contain a mass of factual information. From these we will reconstruct Babba's relations with the Dutch.

This paper reports the performance of four domestic houses at different locations in Bahrain, each have 7.8 kW of PV on the roof, and all panels are tilted at 12°, but the azimuth of the panels (orientation) in these houses varies slightly from south (±10°); depending on roof space availability and building surroundings. The data of year 2019 have been used because all these domestic houses were monitored, maintained, and cleaned by an assigned company from the government. The annual solar electricity generated was 11,329 kWh, 11,448 kWh, 10,978 kWh, and 9995 kWh for houses # 4, # 2, #1, and # 3, respectively. The annual Specific Yield (SY) obtained was 1468 kWh/kW, 1452 kWh/kW, 1407 kWh/kW and 1254 kWh/kW for houses # 2, #4, # 1, and # 3, respectively; this makes the daily average SY equals to 4.02 kWh/kW, 3.98 kWh/kW, 3.85 kWh/kW, and 3.43 kWh/kW, respectively. The average performance ratio (PR) of each PV system were found to range from 75.1% to 65.6%. The PV system performs better in house #4 due to its azimuth PV panels' angle (orientation) which is closest to the south direction. A polynomial equation is established, relating the month number (X) and the monthly average of monthly solar electricity generated as well as the monthly specific yield (Y). This work shows that installing a 7.8 kWp of PV on the roof of all residential building in Bahrain will reduce the total CO2 emission in Bahrain by 39.0% (4.637 tons) per year, saving 38,567 ft3 of natural gas. This is a step towards low-carbon building; in an attempt to make Bahrain a zero carbon by 2060.

Abstract Introduction: Excessive accumulation of iron is caused by a variety of conditions, including hereditary hemochromatosis and transfusional hemosiderosis. If untreated, iron overload can lead to damage in those organs where iron accumulates. Therefore, accurate and reproducible evaluation of body iron stores is needed to guide diagnosis, grading, and treatment monitoring of iron overload. While serum ferritin is the simplest means to assess body iron, it is also an acute phase reactant and therefore is not a reliable biomarker of body iron. Liver iron concentration (LIC) is directly and linearly related to total body iron stores. As such, LIC is widely recognized as a useful surrogate biomarker for the evaluation of iron overload. Liver biopsy is limited by its invasive nature and is contraindicated in many patients (eg. thrombocytopenia) due to bleeding risk. Magnetic resonance imaging (MRI) is a standard of care tool to measure LIC. Arguably the most practical method is R2* MRI due to its speed and ease of use, but the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Therefore, we evaluated the reproducibility and calibration of R2*-based LIC measurement via a single-breath-hold, confounder-corrected R2*-MRI at both 1.5T and 3T, through a multi-center, multi-vendor study. Methods: Four centers (University of Wisconsin-Madison, University of Texas-Southwestern, Johns Hopkins University, and Stanford University) using MRI scanners of different vendors (GE, Philips, and Siemens) participated in this HIPAA-compliant IRB-approved prospective cross-sectional study. This study recruited subjects with known or suspected iron overload from a variety of etiologies, including hereditary hemochromatosis, transfusional hemosiderosis (due to non-malignant or malignant conditions), and chronic liver disease. Subjects with were recruited for same day multiecho gradient-echo MRI for R2* mapping at both 1.5T and 3T (UW, UTSW, Stanford: 3.0T; JHU: 2.89T). R2* maps were reconstructed from the raw multiecho images and analyzed at a single center. Spin-echo MRI were also performed at 1.5T according to a standardized protocol (FerriScan, Resonance Health, Australia) and processed by a commercial algorithm to obtain FDA-approved reference standard LIC estimates. R2*-vs.-LIC calibrations were generated across centers and field strengths using linear regression and compared using F-tests. A predicted 2.89T calibration was interpolated from the 1.5T and 3.0T calibrations, and compared to the measured (JHU) calibration. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic accuracy of R2* MRI for detection of clinically relevant LIC thresholds. Results: A total of 200 subjects were recruited and successfully scanned for this study. We confirmed a linear relationship between R2* and LIC. All calibrations within the same field strength (see Figure 1) were highly reproducible showing no statistically significant center-specific differences (F > 3.0461). Pooled calibrations for 1.5T, 2.89T, and 3.0T were generated. At either field strength and for each of the LIC thresholds under consideration (1.8, 3.2, 7.0, 15.0 mg/g), estimated areas under the ROC curve (AUCs) of 0.98 or higher were observed. Discussion and Conclusions: In conclusion, confounder-corrected R2* MRI enables accurate and reproducible quantification of liver iron overload, over clinically relevant ranges of LIC. The data generated in this study provide the necessary calibrations for broad dissemination of R2*-based LIC quantification. Figure 1 Figure 1. Disclosures Hernando: Calimetrix: Current holder of individual stocks in a privately-held company. Pedrosa: Merck: Honoraria; Bayer Healthcare: Honoraria; Health Tech International: Current holder of stock options in a privately-held company. Vasanawala: HeartVista: Current holder of individual stocks in a privately-held company; InkSpace: Current holder of individual stocks in a privately-held company; Arterys: Current holder of individual stocks in a privately-held company. Reeder: Bayer: Research Funding; Pfizer: Research Funding; Calimetrix, LLC: Current holder of individual stocks in a privately-held company; Reveal Pharmaceuticals: Current holder of individual stocks in a privately-held company; Elucent Medical: Current holder of individual stocks in a privately-held company; Cellectar Biosciences: Current holder of individual stocks in a privately-held company; HeartVista: Current holder of individual stocks in a privately-held company.

Abstract Introduction: DARA is approved across lines of therapy for multiple myeloma, including in combination with standard-of-care regimens for NDMM. The CXCR4 receptor antagonist plerixafor is used in conjunction with granulocyte colony-stimulating factor (G-CSF) to increase stem cell mobilization for autologous stem cell transplant (ASCT) and can be given by upfront decision or as a rescue strategy. The phase 2 randomized GRIFFIN study (NCT02874742) evaluates frontline DARA in combination with lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible NDMM. In the primary analysis, more pts undergoing stem cell mobilization/collection in the D-RVd group received plerixafor compared with the RVd group (69.5% [66/95] vs 56.3% [45/80]) (Voorhees PM, et al. Blood. 2020). The phase 2 MASTER study (NCT03224507) evaluates DARA plus carfilzomib, lenalidomide, and dexamethasone (D-KRd) in transplant-eligible NDMM (Costa LJ, et al. EHA Library. 2020). Here, we present a summary of stem cell mobilization, collection yields, and ASCT data following frontline DARA-based induction therapy in GRIFFIN and MASTER. Methods: Eligible pts had NDMM and were candidates for ASCT. In GRIFFIN, pts were randomized 1:1 to receive D-RVd or RVd. Pts received 4 induction cycles (21 days) of lenalidomide (R; 25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (d; 40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4). After Cycle 4, pts underwent stem cell mobilization with G-CSF ± plerixafor, per institutional standards; if unsuccessful, chemo mobilization was permitted. Pts then received ASCT and subsequently 2 consolidation cycles (21 days) of D-RVd or RVd followed by maintenance therapy with R ± DARA. In the single-arm MASTER study, pts received 4 D-KRd induction cycles, ASCT, and 0, 4 or 8 D-KRd consolidation cycles followed by maintenance therapy with R, based upon achievement of minimal residual disease-negativity. In each 28-day cycle, all pts received carfilzomib (20/56 mg/m 2 IV QW), R (25 mg PO on Days 1-21), d (40 mg PO or IV QW), and DARA (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). Mobilization was with G-CSF ± plerixafor as per institutional standards. Results: In GRIFFIN, among 207 (D-RVd, n=104; RVd, n=103) randomized pts, 91.3% (n=95) of D-RVd pts and 77.7% (n=80) of RVd pts underwent stem cell mobilization; of those mobilized, 98.9% (n=94) and 97.5% (n=78) underwent ASCT, respectively. In MASTER, 123 D-KRd pts enrolled and at last follow-up, 91.1% (n=112) underwent stem cell mobilization; of those mobilized, 98.2% (n=110) completed ASCT. In GRIFFIN, 46.3% (n=81) of mobilized pts received plerixafor upfront (D-RVd, 51.6%, n=49; RVd, 40.0%, n=32), and 18.3% (n=32 pts) received rescue plerixafor (D-RVd, 20.0%, n=19; RVd, 16.3%, n=13). In MASTER, 70.5% (n=79) D-KRd pts received upfront plerixafor and 25.9% (n=29) received rescue plerixafor. Median CD34 + cell yield was 8.3 × 10 6/kg for D-RVd and 9.4 ×10 6/kg for RVd in GRIFFIN, 6.0 ×10 6/kg for D-KRd in MASTER, and was numerically higher for pts who received upfront plerixafor. Median days for stem cell collection was 1 for pts receiving RVd and 2 for those receiving D-RVd or D-KRd. Median transplanted CD34 + cell count was 4.2 ×10 6/kg for D-RVd and 4.8 ×10 6/kg for RVd in GRIFFIN, and 3.2 ×10 6/kg for D-KRd in MASTER. In GRIFFIN, 93.7% of D-RVd pts and 98.8% of RVd pts reached the minimum institutional CD34 + threshold to perform a single ASCT, which was comparable to results in MASTER (95.5% of D-KRd pts) after first mobilization attempt; 85.3% of D-RVd pts, 92.5% of RVd pts, and 79.5% of D-KRd pts collected 2 times the minimum threshold of stem cells. Additional data by upfront and rescue plerixafor strategies are shown in the Table. Conclusion: The addition of DARA to proteasome inhibitor/immunomodulatory drug/dexamethasone-based induction therapy has a modest impact on stem cell mobilization, with a lower yield of stem cells and higher median number of days required for collection. Nonetheless, pts were able to undergo transplantation, and most pts collected sufficient stem cells for 2 transplants. Pts who received plerixafor by an upfront decision had numerically higher stem cell yields than pts who received plerixafor by a rescue strategy. An upfront plerixafor strategy for pts receiving DARA-based quadruplet induction therapy should be considered with allowance for additional days of apheresis as needed. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Costa: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kaufman: BMS: Consultancy, Research Funding; Fortis Therapeutics: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Tecnofarma SAS, AbbVie: Honoraria; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding. Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy; GlaxoSmithKline: Consultancy. Reeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Rodriguez: Karyopharm: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: 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, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: Sutro Biopharma: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; CareDx: Consultancy; Sanofi: Consultancy; Kite: Consultancy; Poseida: Research Funding; Amgen: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; GSK: Consultancy; Precision Biosciences: Research Funding; Teneobio: Research Funding; Oncopeptides: Consultancy; Nektar: Research Funding; Karyopharm: Consultancy. Bumma: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Holstein: Oncopeptides: 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; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Shain: Novartis Pharmaceuticals Corporation: Consultancy; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, 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; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cowan: Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Harpoon: Research Funding; GSK: Consultancy; Secura Bio: Consultancy; BMS: Research Funding; Nektar: Research Funding. Dholaria: Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding; Janssen: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Voorhees: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Abstract Introduction: DARA is approved for NDMM and previously treated MM. In the primary analysis of the phase 2 GRIFFIN trial (NCT02874742) in autologous stem cell transplant (ASCT)-eligible NDMM pts (median follow-up, 13.5 mo), DARA plus RVd (D-RVd) improved the rate of stringent complete response (sCR) by the end of post-ASCT consolidation versus RVd (42.4% vs 32.0%, 1-sided P=0.068) (Voorhees PM, et al. Blood. 2020). With longer follow-up (median, 27.4 mo), responses deepened and were improved for D-RVd versus RVd (sCR rate: 63.6% vs 47.4%, 2-sided P=0.0253), as did the MRD-negativity (10 -5) rate (62.5% vs 27.2%, P<0.0001) (Kaufman JL, et al. Blood. 2020). Here, we present updated efficacy and safety results after 24 months of maintenance therapy or treatment discontinuation (median follow-up, 38.6 mo). Methods: Pts with NDMM eligible for high-dose therapy (HDT) and ASCT were randomized 1:1 to receive RVd or D-RVd, stratified by ISS disease stage (I, II, or III) and creatinine clearance (30-50 or >50 mL/min). Pts received 4 RVd or D-RVd induction cycles, HDT, ASCT, 2 RVd or D-RVd consolidation cycles, and maintenance with lenalidomide (R) alone or with DARA (D-R) for 24 months. During induction and consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycle 10+) ± DARA (16 mg/kg IV) Q8W (or Q4W per pt decision after protocol amendment 2) until disease progression or up to 24 months. The primary endpoint was sCR rate by the end of post-ASCT consolidation (tested at 1-sided α of 0.10). Responses were assessed per IMWG criteria by a validated computer algorithm. Key secondary endpoints included progression-free survival (PFS) and MRD negativity assessed by NGS at the minimum sensitivity threshold of 10 -5, at suspected complete response or better (≥CR), at the end of induction and consolidation, and after 12 and 24 months of maintenance, regardless of response. Secondary analyses were evaluated using 2-sided α of 0.05, not adjusted for multiplicity. Results: In total, 207 pts were randomized (D-RVd, n=104; RVd, n=103); baseline characteristics were well balanced. After 24 months of D-R or R maintenance therapy, the rate of sCR favored D-RVd versus RVd in the response-evaluable population (66.0% [66/100] vs 47.4% [46/97], 2-sided P=0.0096; Figure). In the intent-to-treat (ITT) population, MRD-negativity (10 -5) rates also remained higher for D-RVd versus RVd (64.4% [67/104] vs 30.1% [31/103], P<0.0001), as well as among pts who achieved ≥CR (78.0% [64/82] vs 47.5% [28/59], P=0.0003). Similarly, MRD-negativity (10 -6) rates favored D-RVd versus RVd in the ITT population (35.6% vs 14.6%, P=0.0007; Figure), as well as among pts who achieved ≥CR (42.7% vs 22.0%, P=0.0121). The rate of sustained MRD negativity (10 -5) lasting ≥12 months in the ITT population was >3-fold higher for D-RVd versus RVd (44.2% vs 12.6%, P<0.0001). With 38.6 months follow-up, median PFS was not reached in either arm but trended towards favoring D-RVd versus RVd (hazard ratio, 0.46; 95% CI, 0.21-1.01; Figure). The estimated 36-month PFS rate was 88.9% for D-RVd and 81.2% for RVd. In total, 14 pts died (D-RVd, n=7; RVd, n=7), 9 from progressive disease (D-RVd, n=5; RVd, n=4). No new safety concerns were observed with extended follow-up. In total, 86.9% (86/99) of D-RVd pts and 79.4% (81/102) of RVd pts developed grade 3/4 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 46.5% of D-RVd pts and 52.0% of RVd pts. TEAEs led to discontinuation of study treatment at the same rate (D-RVd, 34.3%; RVd, 34.3%). One pt in each group died due to TEAEs, neither related to study treatment. Conclusion: After 24 months of maintenance therapy, the addition of DARA to RVd induction and consolidation in conjunction with ASCT, followed by DARA plus R maintenance, continued to demonstrate deep and durable responses in pts with transplant-eligible NDMM, including sCR and MRD-negativity (10 -5 and 10 -6) rates. While this study was not powered for PFS, there is a positive trend towards improved PFS in the D-RVd group. No new safety concerns were observed with longer follow-up. These results support the use of D-RVd induction/consolidation and D-R maintenance in transplant-eligible NDMM pts. Figure 1 Figure 1. Disclosures Kaufman: Sutro, Takeda: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Amgen: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Janssen: Honoraria; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Heidelberg Pharma: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Sborov: Sanofi: Consultancy; SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Reeves: Bristol-Myers Squibb: Speakers Bureau; Incyte Corporation: Honoraria; Takeda: Honoraria; Pharma Essentia: Consultancy, Honoraria. Rodriguez: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria. Chari: Oncopeptides: 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, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: GSK: Consultancy; Nektar: Research Funding; Kite: Consultancy; CareDx: Consultancy; CSL Behring: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Poseida: Research Funding; Karyopharm: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Oncopeptides: Consultancy; Teneobio: Research Funding; Sanofi: Consultancy; Precision Biosciences: Research Funding; Sutro Biopharma: Research Funding; Amgen: Consultancy. Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holstein: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowiak: Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Shain: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Genzyme: Consultancy, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy. Cowan: BMS: Research Funding; Secura Bio: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Richardson: Sanofi: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Voorhees: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Abstract Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the phase 2 GRIFFIN trial (NCT02874742) in pts with transplant-eligible NDMM (median follow-up, 13.5 mo), D-RVd improved the rate of stringent complete response (sCR) by the end of post-autologous stem cell transplant (ASCT) consolidation versus RVd (42.4% vs 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P=0.068) (Voorhees PM, et al. Blood. 2020). With longer follow-up (median, 27.4 mo) after 12 months of maintenance therapy, sCR rates deepened for D-RVd versus RVd (63.6% vs 47.4%, 2-sided P=0.0253), as did the rate of minimal residual disease (MRD; 10 -5) negativity (62.5% vs 27.2%, P<0.0001) (Kaufman JL, et al. Blood. 2020). Here, we present an analysis among clinically relevant subgroups (age ≥65 years, International Staging System [ISS] stage III disease, and high cytogenetic risk [del17p, t(4;14), or t(14;16) abnormalities]) after 24 months of maintenance therapy (median follow-up, 38.6 mo). Methods: Eligible pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. Pts received 4 RVd or D-RVd induction cycles, high dose therapy, ASCT, 2 RVd or D-RVd consolidation cycles, and maintenance with lenalidomide (R) alone or with DARA (D-R) for 24 months. During induction and consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), bortezomib (1.3 mg/m 2 SC on Days 1, 4, 8, and 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W, or Q4W per pt decision after Amendment 2) until disease progression or up to 24 months. The primary endpoint was sCR rate by the end of post-ASCT consolidation. Responses were assessed per International Myeloma Working Group criteria by a validated computer algorithm. Additional endpoints included progression-free survival (PFS) and MRD-negativity (10 -5) rate by next-generation sequencing. Results: In total, 207 pts were randomized (D-RVd, n=104; RVd, n=103); each group had a similar number of pts with age ≥65 years (n=28; n=28), ISS stage III disease (n=14; n=14), or high cytogenetic risk (n=16; n=14). Among response-evaluable pts, the rate of sCR after 24 months of maintenance therapy was numerically higher for D-RVd versus RVd among pts ≥65 years (63.0% vs 40.7%, OR, 2.47, 95% CI, 0.83-7.39), but similar for D-RVd and RVd pts with ISS stage III disease (57.1% vs 61.5%, OR, 0.83, 95% CI, 0.18-3.88) and high cytogenetic risk (43.8% vs 38.5%, OR, 1.24, 95% CI, 0.28-5.53; Figure). MRD-negativity (10 -5) rates favored D-RVd versus RVd across all subgroups: ≥65 years (67.9% vs 17.9%), ISS stage III disease (71.4% vs 35.7%), and high cytogenetic risk (43.8% vs 28.6%; Figure). With 38.6 months median follow-up, median PFS was not reached (NR) for pts ≥65 years in either treatment group (6 pts progressed: D-RVd, n=1; RVd, n=5). Among pts with ISS stage III disease, median PFS was NR for D-RVd and 33.1 months for RVd (7 pts progressed: D-RVd, n=1; RVd, n=6). Among pts with high cytogenetic risk, median PFS was NR for D-RVd and 36.1 months for RVd (10 pts progressed: D-RVd, n=5; RVd, n=5; Figure). In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd pts and 77.8% of RVd pts; the most common (≥20%) were neutropenia (37.0%; 29.6%) and lymphopenia (25.9%; 11.1%). Serious TEAEs occurred in 55.6% and 40.7% of pts, respectively. TEAEs led to study treatment discontinuation in 33.3% of D-RVd pts and 25.9% of RVd pts. One death due to a TEAE (unrelated to study treatment) occurred in a D-RVd pt ≥65 years of age. Conclusion: Subgroup analyses of pts in GRIFFIN show that the addition of DARA to RVd induction/consolidation and R maintenance, in conjunction with ASCT, may benefit clinically relevant subgroups. sCR rates were improved for D-RVd versus RVd in pts ≥65 years but not in pts with ISS stage III disease or high cytogenetic risk. Improved MRD-negativity rates were observed for D-RVd in all subgroups. Although immature and with limited pt numbers, PFS results also trended towards favoring D-RVd in these subgroups. Among pts ≥65 years, TEAEs and serious TEAEs were numerically higher for D-RVd. These results support the use of DARA in transplant-eligible NDMM pts among high-risk subgroups, although larger studies are needed. Figure 1 Figure 1. Disclosures Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman: Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Janssen: Honoraria; Novartis: Research Funding; Heidelberg Pharma: Research Funding; Incyte, celgene: Consultancy; BMS: Consultancy, Research Funding; Amgen: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Fortis Therapeutics: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Sborov: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy; Sanofi: Consultancy. Reeves: Pharma Essentia: Consultancy, Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Incyte Corporation: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Chari: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium/Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Costa: Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding. Shah: Janssen: Research Funding; Nektar: Research Funding; Kite: Consultancy; Karyopharm: Consultancy; Indapta Therapeutics: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; Amgen: Consultancy; CareDx: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding. Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holstein: Oncopeptides: 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; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak: Celgene: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wildes: Carevive: Consultancy; Seattle Genetics: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Shain: Sanofi Genzyme: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy; GlaxoSmithLine, LLC: 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; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cowan: BMS: Research Funding; Secura Bio: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Cortoos: Janssen: Current Employment, Current equity holder in publicly-traded company. Patel: Janssen: Current Employment. Bartlett: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Lin: Janssen: Current Employment. Voorhees: Amgen: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Regeneron: Consultancy; AstraZeneca: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

Abstract Background: The current standard of care for eligible newly diagnosed multiple myeloma (MM) patients is induction therapy with novel agents followed by high dose chemotherapy and autologous stem cell transplant (ASCT). The International Myeloma Working Group proposed the Revised International Staging System (R-ISS) based on the presence of adverse chromosomal abnormalities (CA) detected by FISH (t(4;14), t(14;16) or del17p), in combination with ISS and LDH at diagnosis. However, there are a limited number of studies that have validated this risk model in the transplant and novel agents setting. Aims: To determine whether R-ISS is an appropriate risk-model for estimating overall survival (OS) and progression free survival (PFS) for transplant-eligible MM patients. Patients and Methods: We retrospectively studied a cohort of 519 MM patients who received novel drugs in the induction and subsequently underwent ASCT at Mayo Clinic Arizona from 2005 to 2014. In all, 95 patients met the inclusion criteria: comprising complete data at diagnosis (ISS, serum LDH level, and CA by FISH). The primary endpoint was OS from SCT and the secondary end point was PFS from ASCT. R-ISS groups were defined as described by Palumbo et al. J Clin Oncol. 2015; 33(26):2863-2869. Results: There were 50 (52.6%) men and 45 (47.4%) women who underwent ASCT in this period, with a median age at the time of transplant of 66-years-old (range, 36-78). There were 27 patients (28.4%) with high-risk CA: 12 patients (12.6%) with del17p; 11 patients (11.6%) with t(4;14); and 6 (6%) with t(14;16). In addition, 8 patients (8.5%) had high LDH levels and 9 patients (9.5%) presented with renal impairment at diagnosis. The patients were staged at diagnosis according to the three R-ISS groups: 44 patients (46.3%) had stage I, 26 (27.4%) had stage II, and 25 (26.3%) had stage III. CyBorD was the preferred induction regimen which was received by 42 patients (44%). There were 14 patients (15%) who received at least 2 lines of induction. All patients were in at least partial response (PR) at the moment of transplant: 32 in complete response (CR), 32 in very good partial response (VGPR) and the remaining 31 in PR. The response achieved at day +100 after ASCT improved, with 54 patients (57%) in CR, and only 18 patients (19%) in PR. After a median follow-up of 61 months (range, 14-135), median OS from SCT was 108 months (95% CI: 85 - 132 months) and the median PFS was 45.4 months (95% CI: 31.1 - 53.8 months) in the whole series.MM patients with R-ISS III had a significantly shorter median OS compared to patients with R-ISS II or R-ISS I (32.1 months vs. 94.7 months vs. not reached, respectively, P<0.0001) (Figure). No statistically significant differences in baseline characteristics were identified among these groups to explain the differences in OS observed. PFS among these groups was not statistically significant, only showing a trend towards shorter PFS in R-ISS III compared with either R-ISS I or II: median 22.1 months vs. 35.7 months, respectively, (P=0.2). Renal impairment at diagnosis, IgA subtype, ≥ 2 lines of induction treatment, and less than CR achieved at day +100 after ASCT were also associated with significantly inferior OS. Multivariate analysis selected R-ISS as an independent predictor for OS (HR: 2.3, 95% CI: 1.1-4.8; P=0.03), as well as ≥ 2 lines before ASCT. CR at day +100 after ASCT was the most important independent factor for predicting PFS (HR: 0.4; 95% CI: 0.2-0.6; P<0.001). Conclusion: R-ISS assessed at diagnosis was an independent predictor for OS after ASCT in our series, with median OS for the different R-ISS groups comparable to those reported by Palumbo et al. in their subgroup of younger patients. Thus, this study lends further support for the R-ISS as a reliable prognostic tool for estimating OS in transplant-eligible MM patients. In addition, new treatment approaches are needed for the high-risk patients (R-ISS III) with a median OS of 2.5 years. Figure Figure. Disclosures Reeder: Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Mikhael:Abbvie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Stewart:celgene: Consultancy. Fonseca:Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Bayer: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Novartis: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms.

Abstract Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi: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. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 &lt;6 months). While these primary induction failure (PIF) and early relapse (ER) pts are treated collectively with late relapse (LR) pts (CR1 &gt;6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts. Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 &lt; 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death. Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, &lt;5% bone marrow blast) was 42.1% (16/38; 7 CR, 4 CRh, 4 CRi, and 1 MLFS), with 68.8% (11/16) subsequently undergoing stem cell transplant. PIF pts showed a CRR of 45.8% (11/24; 5 CR, 3 CRh, and 3 CRi); CRR for ER pts was 35.7% (5/14; 2 CR, 1 CRh, 1CRi and 1 MLFS). Median time to first response was 1 cycle (range: 1-3 cycles). Sixty-nine percent (11/16) of responders normalized PB counts while on FLZ. Transfusion independence was achieved in 35.7% (10/28) of pts for whom data were available. Preliminary, median duration of response (mDOR) was 3.1 months (range 0.4-30.0 months) with many pts (29%, 11/38) still ongoing. With a median follow up time of 10.8 months, median overall survival (mOS) was 4.5 months (95% confidence interval [CI]: 2.9, 8.8). In pts that responded (CRR) the mOS was 7.7 months (95% confidence interval [CI]: 2.9, NA). Overall 6 and 12-month survival rates are 41 % (22.1%, 59.0%) and 24 % (6.1%, 42.5%), respectively. Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956] 1 Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020. Disclosures Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy:Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano:Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt:Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Takeda: Research Funding; OBI: Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Mark Veniaminovich Karminskyi (1930–1995) is a composer who, already during his lifetime, was appreciated by his contemporaries as the brightest figure in musical art, in particular, musical theater. Well-known in the country and his native Kharkiv, he was also the constant reader of the Kharkiv ‘K. Stanislavskyi’ Music and Theater Library for many years, taking part in many events that took place within its walls. An excellent lecturer and interlocutor, benevolent and affable person, he found an attentive audience and ardent admirers of his musical talent among the library’s readers and stuff. Perhaps, this is why M. Karminskyi chose the Library as the main curator of his archive. What is better than studying the artist’s personal archive to give an idea of his personality, creative methods and worldview? Even a cursory glance at the collection of documents classified on the shelves of the archive, illustrating particular biographical episodes, helps the researcher to form a holistic impression of the artist’s creative personality, as well as to orient, if necessary, for further more depth studying of his heritage. The purpose of this article is a brief review of the general content of the archival fund of M. V. Karminskyi, with the materials of which the author had the honor to conduct research and bibliographic work, as of a documentary sources base for future research of the composer’s work and the history of the musical culture of Kharkiv in 1950–2000 years. Statement of the main positions of the publication. The composer began to transfer his archive to the library during his lifetime: he arranged folders with manuscripts, gave explanations about the time of writing and purpose of individual works. It was this archive that was the first to get into the library as a full-fledged array of documents about the life of a creative person. The condition for its transfer was the possibility of unimpeded viewing of the archive and its copying for the purpose of training and concert performance of the composer’s works. The full description of M. Karminskyi’s archive was completed in 1996, but the fund was supplemented several times thanks to new materials that came to the archival collection after its formation. It contains a variety of documents, including musical manuscripts, newspaper clippings, photographic documents, sound recordings on various media, posters, booklets, programs, manuscripts by other authors related to the activities of the composer. Thus, for the theater – opera, drama – the composer has been actively working since a young age. He wrote music for performances of Kharkiv theaters – Puppet Theater, Young Audience Theater, Ukrainian Drama Theater named after Taras Shevchenko, Jewish Theater, even for student amateur theaters. Four operas by M. Karminskyi, among them – “Ten days that shook the world”, “Irkutsk story” – were successfully staged in many theaters in Ukraine, Russia, the Czech Republic and Germany. Particular attention was drawn to the opera “Ten Days That Shook the World” based on John Reed’s book about the events in Petrograd in 1917, which was published as the separate piano reduction and received a large number of reviews in periodicals. The typewritten copies of reviews by famous Ukrainian musicologists K. Heivandova and I. Zolotovytska have been preserved in the archive. The collection of the archive also includes the published piano score of the opera “Irkutsk story”, the known “Waltz” from which served as a call sign of the Kharkiv Regional Radio for many years. One of the most interesting manuscripts of the archive is the music for the unfinished ballet “Rembrandt” on the libretto by V. Dubrovskyi. The musical “Robin Hood”, which was performed not only in Kharkiv, but also in Moscow, brought the composer national fame. The sound recording of the Moscow play was distributed thanks to the release of gramophone records created with the participation of stars of Soviet stage – the singers Joseph Kobzon, Lev Leshchenko, Valentina Tolkunova and the famous actor Eugene Leonov. The popularity of this musical was phenomenal; excerpts from it were performed even in children’s music schools, as evidenced by the archival documents. During the composer’s life and after his death, his vocal and choral works, works for various instruments were mostly published. The array of these musical editions and manuscripts of M. Karminskyi is arranged in the archive by musical genres. These are piano pieces and other instrumental works, among them is one of the most popular opuses of the composer – “Jewish Prayer” for solo violin (the first performer – Honored Artist of Ukraine Hryhoriy Kuperman). Number a large of publications about the life and career of M. Karminskyi published in books and periodicals are collected, among them are K. Heivandova’s book (1981) “Mark Karminskyi”, the brief collection of memoirs about the composer (compiler – H. Hansburg, 2000) and the congregation of booklets of various festivals and competitions, for example, the booklets of the International Music Festival “Kharkiv Assemblies”, in which the composer has participated since the day of their founding. The booklet of the M. Karminskyi Choral Music Festival testifies to a unique phenomenon in the musical life of the city: never before or since has such a large-scale event dedicated to the work of a single person taken place attracting so many choirs from all Ukraine. A separate array of documents is the photo archive, which includes 136 portraits, photos from various events; 41 of them were donated by a famous Kharkiv photographer Yu. L. Shcherbinin. The audio-video archive of M. V. Karminskyi consists of records of his works, released by the company “Melody”: staging of performances “Robin Hood”, “There are musketeers!” (based on the play by M. Svetlov “20 years later”), various songs, video and tape cassettes with recordings of concerts. Other interesting documents have been preserved, for example, a typewritten script for the Kharkiv TV program about M. Karminskyi with his own participation or the library form, which can be used to trace his preferences as a reader. M. Karminskyi also compiled reviews of publications on the performance of his works and short bibliographic descriptions of their print editions. Conclusions. M. Karminskyi’s personal archive founded by him own in Kharkiv ‘K. S. Stanislavskyi’ Music and Theater Library has been functioning as an independent library fund since 1996 and today it is an unique comprehensive ordered collection, which is freely available and stores documents of various types: music publications and manuscripts, newspaper and magazine fragments, announces, photos, sound and video documents. M. Karminskyi’s archival fund is used as a documentary source for scientific researches (the Candidate’s dissertations of art critics Yu. Ivanova (2001) and E. Kushchova (2004) were defended using the materials of the archive) and as a basic congregation of works by the composer for their performance. The use of digital technologies is part of the necessary modern perspective of the fund’s development, the value of which as a primary source of historical and cultural information only grows over time.

Sommaire La Loi du Salaire minimum de Québec, n'est pas, quant aux employeurs dont les travaux et entreprises relèvent de la juridiction fédérale, ultra vires des pouvoirs de la Législature du Québec en tant que le droit de fixer des salaires minimums est concerné. Cette loi, ainsi que son Ordonnance No. 4, s'appliquent à ces employeurs et à leurs employés quant aux salaires minimums qu'elles fixent pour les travaux effectués dans les limites territoriales du Québec et aux prélèvements sur les salaires décrétés par elles. Commission du Salaire minimum v. The Bell Telephone Company of Canada Limited; Cour supérieure de Québec, l'hon. juge Roger Brassard; No. 518-029 — Montréal, 22 novembre 1962; 1963 C.S. pp. 433-453; René Reeves, c.r., pour la demanderesse; P.C. Venne, c.r., Fiset et Robitaille, pour la défenderesse. — Cette cause est en appel, No 8066 (Montréal).

Oncor Electric Delivery Company, LLC (Oncor) is planning to construct the Owl Hills—Tunstill 138-kV Transmission Line Route in Culberson, Reeves and Loving Counties, Texas. Oncor contracted with Halff Associates, Inc. to conduct an intensive pedestrian survey of 18.5 miles of new 138-kV transmission line on private property. The survey was conducted January 20-24, 2020 and a total of 102 shovel tests were excavated in areas where buried archeological deposits where expected, and two 15-meter (32.8-foot) transects underwent pedestrian survey within the 70-foot (21.3-meter) wide survey corridor, which measures approximately 157 acres. Three archeological sites (41RV208, 41RV209 and 41RV213) were identified and recorded during the archeological survey. Site 41RV208 is a prehistoric occupation containing a surface deposit of 12 lithic debitage, 6 flake tools, 6 cores, 2 groundstone fragments and 40 fire cracked rocks (FCR). The site is situated on a gravelly and deflated upland that forms the western rim of the Pecos River valley. Site 41RV209 consists of a prehistoric occupation containing a surface deposit of 12 FCR, 6 lithic debitage, 3 flake tools, 2 cores, 1 uniface, and 1 biface. This site is situated on the heavily eroded west bank of Salt Creek and has been disturbed by construction activities associated with an adjacent pipeline corridor. Site 41RV213 is an abandoned section of the Atchison, Topeka & Santa Fe (ATSF) Railway that parallels U.S. Highway 285 to the east. The section of railroad in the surveyed area has undergone extensive disturbance and consists of a narrow linear piling of fill, railroad gravels and non-descript metal debris. It is Halff’s recommendation that sites 41RV208, 41RV209 and 41RV213 are ineligible for National Register of Historic Places consideration in the surveyed area and no further cultural resources investigations are warranted for the project. While shovel testing within the lower terraces of the Pecos River valley floor resulted in negative findings, most of the shovel tests in this area did not encounter restrictive deposits soil or geologic deposits that antedate the Holocene. Therefore, the installation of the transmission line poles located along the lower alluvial terraces of the Pecos River was recommended for archeological monitoring. Halff recommends that construction of the remainder of the proposed transmission line route be allowed to proceed and that no additional archaeological investigations are recommended outside of the monitoring area. However, if the proposed transmission line route alignment changes, additional archeological survey may be necessary. In addition, should any cultural resources be discovered during the construction or maintenance activities associated with the project, work in the immediate area shall cease and the Texas Historical Commission be notified of the discovery.

Abstract We use newly linked tax records to show that the large responses of UK company owner-managers to personal taxes are due to intertemporal income shifting and not to reductions in real business activity. Around half of this shifting is short-term and helps prevent volatile incomes being taxed more heavily under progressive personal taxes. The remainder reects systemic profit retention over long periods to take advantage of lower tax rates, including preferential treatment of capital gains. We find no evidence that this tax-induced retention increases business investment. It does, however, substantially reduce the tax revenue raised from high income business owners.

This paper presents an overview of SpaceX which is a private limited United States aerospace maker/producer and space transportation service provider company which was founded by Elon Reeve Musk in 2002. The main goal of SpaceX is to reduce the cost of space transportation and in the end enable the colonization of fourth planet in our solar system that is Mars. Since its inception, SpaceX has achieved many significant milestones in space exploration. One of the most notable achievements of SpaceX was the development of reusable rockets and spacecraft, which has greatly reduced the cost of space transportation. SpaceX has also successfully launched and landed multiple rockets, including the Falcon 9 and Falcon Heavy. These rockets have been used to launch satellites into orbit, resupply the International Space Station, and deliver payloads to deep space. In addition, SpaceX has also developed the Crew Dragon spacecraft, which has successfully transported astronauts to and from the ISS that is International Space Station. Looking towards the future, SpaceX has many ambitious plans for space exploration. The company plans to launch the Starship spacecraft, which is designed for deep space missions and has the potential to transport humans to Mars. SpaceX also aims to establish a permanent human presence on Mars within the next decade. Keywords: SpaceX, Elon Musk, Artificial Intelligence, Falcon, Rocket, and many.

A multi-billion dollar chemical company (DupontCanada) developed, over twenty years, a unique leadership philosophy and practice that was instrumental in the company’s remarkable improvement and great financial and societal success. The beliefs that are fundamental to this Developmental Leadership model are: values are the foundation of leadership; everyone can learn to lead; leaders develop role model leading competence through learning certain skills, character attributes and purposeful behaviours; the work of leaders in organizations is developing high performance work systems dedicated to achieving sustainable growth; and learning to be a better leader is a life-long endeavor. A leadership course for engineering students based on this was developed by the former CEO and Chairman of the company (first author David Colcleugh), an engineer by training, and has been offered to undergraduate and post-graduate engineering students at the University of Toronto since 2007. At first the course was offered as a combined undergraduate-graduate course. In 2011 it was decided to offer separate coursesfor graduate students and undergraduate students. Atextbook, Everyone a Leader, was prepared (byColceugh) and beginning in 2012 was used, in manuscript form, in both courses. The textbook provided the curriculum and instructional framework that permitted a second instructor to lead the course –(second author Doug Reeve). The Developmental Leadership Model serves as a framework for instruction so long as the instructor’s own leadership experience is well integrated into course discussions. The course hasnow been offered eight times.The motivation for the course arises from the belief that engineering students should, in addition to having strong scientific and technical capabilities and being self-motivated to contribute, should be well prepared emotionally, socially, and ethically to accept challenges and should be to committed to develop non-technical as well as technical competencies.

Justin Hurd, a regional manager for Marten Transport, Ltd. (Marten), hung up the phone feeling frustrated following a call with his Division VP. The mandate he received was simple--improve operational efficiencies and reduce operational costs. Justin saw his company do amazing things. He saw the company thrive by delivering loads quickly, efficiently and accurately to its customers. They always maintained a good work ethic and honest business practices, even in the face of high stress and publicity. He even saw his company make leaps and bounds in how much technology they utilized, from GPS tracking to data analytics. However, as he considered his current challenges, he realized that finding and using the data to drive performance improvements was not going to be easy. Justin considered Marten a unique trucking company that stood apart from its competitors. But right now he needed to find the information on where Marten could improve. He contacted Marten’s Vice President of IT, Randy Baier to see what performance data was already collected. Randy informed him that by utilizing telematics to include ID Systems and StarTrak devices, Marten could monitor reefer settings and performance as well as trailer positions to uncover possible trailer abuse or operating inefficiencies. The data collected so far, identified clear inefficiencies, and indicated possible abuse by warehouse operators at Marten’s expense. The challenge any firm faced with a big data problem was determining how they would convert relevant data into useful information. Because of the exponential rate at which data was produced, companies must practice ingenuity by proposing specific operations, and focusing their data gathering efforts on what they needed and what they could use. Marten’s data gathering initiative had produced a wealth of information related to these issues, but how could this data be transformed into useful, actionable metrics that could reduce these inefficiencies and protect Marten’s bottom line? Was more data needed? If so, what kind of data and how should it be collected? Were there other technological control measures that could be applied by Marten to mitigate the impacts of their current issues? Surely other leading transport companies were facing similar issues. Perhaps there were existing solutions being implemented, but would they work for Marten? Justin Hurd was confident the answers were in the vast amount of data collected, but how could he best use that data to meet his cost reduction and performance improvement mandate?

Purpose: In this study, we compared clinically relevant biochemical properties of each chelator for pH, osmolarity, and calcium chelation potential. Methods: In total, 0.2 M K2EDTA and K3EDTA (BD vacutainer tubes by Becton, Dickinson and Company) and Na2EDTA (Sigma Aldrich) solutions were made. The pH of each solution was measured (Mettler Toledo pH meter), and the theoretical osmolarity was calculated. Next, we determined the calcium chelation potential of each EDTA salt by titrating it with 10 μmol of calcium hydroxyapatite or CaCl2 containing Patton–Reeder colorimetric indicator. Statistical significance was analyzed using analysis of variance. Results: The 0.2 M solutions of Na2EDTA, K2EDTA, and K3EDTA have pH values of 4.43, 5.71, and 9.191 and theoretical osmolarities of 600, 600, and 800 mOsm/L, respectively. Calcium chelation ability was similar among all 3 solutions: 0.94 to 0.98 mol of EDTA was needed to fully chelate 1 mol calcium ions of CaCl2 (P = 0.296), 0.100 to 0.108 mol of EDTA for 1 mol calcium ions of the hydroxyapatite aqueous suspension (P = 0.296), and 0.992 to 0.996 mol for 1 mol calcium ions of hydroxyapatite in acidic solution (P = 0.178). Compared with the clinical standard of 3% (30 mg/mL) Na2EDTA, approximately 3.3% (33 mg/mL) K2EDTA and 3.6% (36 mg/mL) K3EDTA are needed to chelate an equivalent amount of calcium. Conclusions: In this article, we provide clinically relevant biochemical properties of 2 alternatives to Na2EDTA and demonstrate comparable calcium chelation ability among all 3 solutions. In situations where sterile sources of Na2EDTA are unavailable, potassium EDTA may provide a convenient and equally effective method of treatment for band keratopathy.

Photo by Marek Studzinski on Unsplash ABSTRACT Payment models directly impact the way patients experience care. Historically, payment model innovations have been examined mostly from economic, organizational, and public health lenses. Financial incentives exist in all healthcare systems, whether a socialized, private or public insurance, or single payer system. This article examines the alignment of current predominant payment models of fee-for-service, capitation, and value-based payments with patient care ethics. The volume-based incentive of fee-for-service is misaligned with patient care, while capitation is a relatively neutral and highly modifiable model. Value-based payments offer a unique benefit in improving patient agency and have a larger benefit of cost control. However, no model adequately addresses health disparities, and a larger consideration for justice is needed by payment model designers when considering incentives. In consideration of related values, bioethics must expand the discourse around patient care ethics to cover patient interactions with the health system and market forces outside the clinical context. INTRODUCTION Healthcare payment models have always been controversial. Discussions about healthcare payment models broadly include economic, ethical, and medical realms. The “simple” act of one party paying for health care creates interactions between the payer, the provider, and the patient. Payments are based on an agreed-upon price between the paying party and the provider. While in most industries, at the level of retail delivery, the direct customer pays for the item received, in healthcare, the system is more complex. Deciding what metrics to base healthcare prices on has become arduous. Whether organizations should charge a patient for healthcare in nations where it is considered a human right is a subject of debate. This ethical debate over providing care is combined with the theoretical framework of how to price and pay for healthcare. This paper examines the ethics of various approaches to paying for care. Outside of the controversial notion of patients financing their care, existing payment models always involve some entity other than the patient paying for the bulk of the care – whether in a socialized system, single payer, or public or private insurance system. In these systems, an implicit financial incentive to provide care based on payment criteria arises.[1] Depending on the nature of the payment, the financial incentive may align with, be neutral toward, or misalign with a patient’s best interest and goals of care. These payments create market forces in capitalistic or single payer healthcare models and drive organizational behavior in nationalized models.[2] We can see the organizational and marketplace adaptations to predominant volume-based payment models in the United States in the form of shorter visits, unnecessary care or increased volume of care, and medical determination of which care is provided based on coverage. Fee-for-service has incentivized higher patient volume over quality time with patients, leading to 10- to 25-minute patient visits.[3] Payments based on any metric implicitly direct patient care by moving provider action toward the metric the payment is based on, regardless of intent or conscious effort.[4] For example, when the paying body financially rewards hospitals for shorter inpatient stays, then the average length of stay will decrease.[5] Payment for care has numerous, widespread effects on how patients experience care and even the quality of care they receive, creating ethical and economic issues. Oddly, from a strictly financial perspective, patients are secondary consumers of their care in most healthcare systems. With this, providers have a financial responsibility to the paying body to act within the bounds of payment incentives (specifically, the paying body, such as an insurance company, is assured that the patient gets the care that is paid for based usually on pre-agreed terms) and an ethical and duty-based responsibility to the patient for patient care. As an example of misaligned interests, there is a clear financial incentive to deny prior authorization for a medication that is an expensive yet otherwise appropriate alternative for a patient’s condition. This could result in equal treatment, perhaps a generic version even, or an alternative that the provider and patient would not have chosen otherwise. It could result in the patient being deprived of a choice. l. Patient Care Ethics and Payment Using the four principles of bioethics, the tenets of ethics for patient care, the payment systems have clear effects on patient autonomy and agency, and may conflict with beneficence, non-maleficence, and justice.[6]The tension that providers experience in navigating payers while fulfilling their patient responsibility causes ethical dilemmas. Volume-based reimbursement schemes prioritize efficiency, regardless of these major bioethical principles. To truly evaluate a payment model, we need not vaguely consider the supposed moral intentions of a model – we need to evaluate the theoretical incentive design as it pertains to the tenets of bioethics. I propose a novel model for viewing incentives with a bioethical framework. The motivation for viewing how the system design for payment models use incentives under a bioethical lens is summarized below. a. Payments, by nature, create active and passive organizational incentives. b. Incentives affect organizational and provider behavior, regardless of intent. c. Changed behavior in response to a financial incentive directly and implicitly impacts the tenets of bioethics. d. For payment models to be considered ethical, they must align organizational incentives with patient care goals and ethics. The argument that incentives should not exist in healthcare because they foster competition and, therefore, cause disparities is acknowledged.[7] However, the argument against incentives ignores the reality of healthcare, especially in the United States, where the most progressive recommendations still retain a paying agency. Therefore, the focus in this paper concerns the existing payment models. The alignment of predominant payment models—including fee-for-service, capitation or mixed models, and value-based payments —with patient care ethics is difficult. This paper argues that the value-based payment model is the most appropriately aligned model when considering health disparities, the Rawlsian difference principle, and distributive justice. ll. Payment Models and Patient Care Ethics Alignment Payment models are highly varied. As it currently stands, the most widely used model globally is fee-for-service, a volume-based model in which insurance companies pay physicians and organizations for performed actions based on evaluations such as relative value units. Relative value units consider physician work, practice expense, service rendered, and professional liability.[8] Later models, like capitation, were enacted to control costs. Simply put, purely capitated payments consist of flat-term payments for patient care that do not change based on services rendered.[9] Within the past decade, value-based payments, which pay physicians based on patient value, as defined by outcomes divided by costs, became popular.[10] There are other approaches to paying for patient care, such as health savings accounts or direct primary care (patients directly pay physicians without insurance).[11] While these are assuredly interesting areas of study, the financial incentives mimic fee-for-service, in which physicians and organizations receive payments based on direct services rendered and will not be discussed further in this article. lll. Fee-For-Service Fee-for-service is the main payment model worldwide.[12] It has played a large role in shaping the structural nature of healthcare, particularly in the United States.[13] Fee-for-service, although declining, is still pervasive in the US health system and has created market forces that indirectly affect the geographic distribution of care, with an obvious volume-based market force.[14] Even with the advent of alternative payment models, fee-for-service remains the primary mode of physician compensation by percentage in primary care in the US.[15] Fee-for-service’s financial and organizational incentives are based on the number of patients seen and services rendered. The World Health Organization stated in its 2010 Health System Financing report that this model likely leads to care overprovision, inefficiency, and upwardly spiraling costs.[16] The pervasive volume-based incentive in fee-for-service misaligns with patient care goals as patient care is not its primary goal. This rudimentary payment system attempts to finance health care as if it were any other good or industry. But more care is not necessarily better care, and fee-for-service leads to higher patient bills, higher system costs, and largely inefficient and unnecessary treatment schemes.[17] Tummalapalli, et al. found that capitated models had lower visit frequency and fewer interventional actions with no difference in outcomes compared to fee-for-service models. Care overprovision—in services rendered—and upwardly spiraling costs are not in the best interest of patients, violating beneficence at the population level. The misalignment of incentives is at the root of the problem. As a rudimentary payment system, fee-for-service does not have patient care in mind, nor has beneficence as its goal. To evaluate fee-for-service from its own goals, the question here should not center around whether this model is in the best interest of patients. Instead, it should focus on the principle of non-maleficence. Can we truly say that upwardly spiraling healthcare costs do not harm patients? In the US, fee-for-service has largely negative social effects on burdens in minority populations, enhancing disparity.[18] The system is arguably unjust, violating the principle of justice. Disadvantaged groups bear a disproportionally large brunt of the deleterious effects of fee-for-service.[19] With the wastefulness, the inefficiency, the failure to align with patient goals, and the injustice, it becomes clear that fee-for-service does not align with patient care ethics because of organizational and financial incentives. lV. Capitation and Mixed Payment Models Pure capitation is a less common model than fee-for-service. The maximum effectiveness of this model is generally achieved with some combination of fee-for-service or value-based payment modifiers.[20] Both in principle and practice, capping payments for a term or service period inherently controls costs by setting a payment “cap.” From a theoretical perspective, the issue here is clear – there are minimal incentives in pure capitation to provide more care. In some cases, this can lead to care underprovision.[21] This neglect is a problem: whether intended, there are generally fewer visits and interventional approaches to care in pure capitation models.[22] Some view the care under-provision as a disservice to patients. However, the true practice of capitation is rarely without some combined incentive model for organizations or physician salary.[23] Adding fee-for-service incentives to capitation balances these issues while maintaining a discordant theoretical incentive compared to patient care. Value-based modifiers add a more aligned incentive for reasons described in the following section. The overall nature of capitation is not inherently aligned or misaligned with patient care, given that it is a highly moldable model, and therefore is neutral regarding its alignment with patient care ethics. V. Value-Based Payments Since their inception, value-based payments have become a widespread and popular payment model internationally.[24] The payment revolves around value, defined as patient outcomes divided by costs. The assumption in adopting such a model is that outcomes and costs can be readily measured, which is a challenge in implementing this model. However, aligning payments with patient value has spurred the adoption of more accurate cost accounting systems and the innovation of patient-reported outcome measures. While the full details of cost accounting are beyond the scope of this paper, Robert Kaplan is a proponent of using time-driven activity-based costing, an essential component in calculating value and an empirically more accurate accounting method than the other predominant forms in healthcare and fee-for-service payments.[25] While this is an accomplishment, perhaps the more ethically interesting innovation in value-based payments comes from measuring patient outcomes. These generally take form in two ways: objective measures and patient-reported measures. The objective measures include ideally controllable disease factors, such as hospital admissions or disease exacerbations in patients living with chronic obstructive pulmonary disease.[26] Such measures align payment incentives with quality and results, an important aspect of patient care but not an absolute placeholder for ethical measures. One of the largest critiques of value-based payments has always been that value cannot simply be measured with empirical data but must account for patient values.[27] The solution to such a critique is patient-reported outcome measures (PROMs), which factor patient values and lifestyle into the empirical payment calculation.[28] A study by Groeneveld et al. showed that PROMs were useful in evaluating the progression of stroke patients at several different time intervals.[29] Bernstein showed that PROMs give insight into the sociodemographic factors a patient may be experiencing, which can guide targeted interventions.[30] To providers, these may not sound like innovative clinical tools, but they resemble the everyday scoring systems and social work consultations seen in patient care. PROMs are an attempt to formally incorporate such items directly to payment. Value-based payments directly incentivize innovation, use of accurate costs and the consideration of patient values. However, there are valid critiques. This payment model has the potential to prioritize care for those who are healthy and more likely to achieve favorable outcomes. Adjustment for important social factors could worsen outcomes and undermine the model’s propensity to drive value for all patients.[31] Comparatively, value-based payments still incentivize a market force that is more in line with patient care ethics when contrasted with the other predominant forms of payment. This payment model has the theoretical advantage of spurring competitive forces to work toward a goal-like value while outcomes consider patient priorities and costs to be more accurate. From an ethical standpoint, the ideal value-based payment model addresses beneficence toward patients with some (but comparatively less) potential for harm and worsening of disparities. Safeguards can protect patients in this realm. Another main ethical advantage of value-based payments is that they add more patient marketplace agency by allowing patient desires and priorities to play a direct role in the payment process. This is a unique benefit that value-based payments have over fee-for-service and pure capitation, where the latter models are simply modicums for payment, not modicums for patient agency. Based on these comparative ethics, the value-based payment models are the most aligned payment model with patient care ethics but require safeguards. Vl. Limitations of Payment Models in Addressing Disparities and Distributive Justice The aforementioned payment models continually miss opportunities to explicitly incentivize care for underserved and at-risk populations. Studies have explicitly shown how fee-for-service can worsen care for minority groups. The greatest difference in care is seen in the chronically ill, the poor, and those with high burdens based on the social determinants of health.[32] While value-based payments have been touted as a potential route to incentivize care for these populations, comparative studies show that those of lower socioeconomic status experienced no benefit when using a value-based modifier.[33] Other scholars have pointed out that these payment models are both slower to roll out in low-resource areas and are more likely to have the unintended consequence of leading to lower funding in these areas.[34] Therefore, the disparity may be a lack of access to the model rather than a reflection of its capabilities. These valid critiques of worsening health disparities under all existing payment models show that such models are not a silver bullet for the health system and that they do not address other crucial issues in medicine, like equity. However, this is not to say that payment models cannot address social disadvantages and disparities. Value-based payments more ethically align payment-related incentives and spur more innovation. To this end, innovation must take place with consideration for distributive justice. The Rawlsian difference principle, or the notion that any systemic approach must maximize the improvement of the least advantaged groups, is essential when discussing payment models.[35] As it currently stands, value-based payments may incentivize procedural justice or a more just and equitable process once patients are in the healthcare system. Yet, none of them ensure a just distribution of care to those of low socioeconomic status. Future models must work towards incentivizing principles of distributive justice. While there have been many attempts to modify payments, those who design payment models clearly tend not to leverage financial benefits to help patients of low socioeconomic status. By leaving those least well-off in society out of the consideration, payment model designers contribute to systemic disparities, regardless of intent. All future designers of payment models must do more to improve incentive designs to work for these patients, not against them. Vll. How Should We Ethically View Incentive Design? The public and those in charge of medical policy must realize the importance of market forces beyond efficiency. Payment incentives should align with patient well-being, autonomy, access to care for underserved populations, and market efficiency. While some of these factors will be more pertinent than others depending on which health system is under discussion, we need ethical principles for patients on a system level that prioritize the patient's interaction with the health system outside of purely clinical scenarios. CONCLUSION Payment models remain a powerful tool for any health system that pays providers or organizations. The simple act of payment creates both direct and indirect financial incentives. These incentives create market forces that affect how patients experience their care, directly impacting autonomy, beneficence, non-maleficence, and justice. As it currently stands, the predominant payment model of fee-for-service does not align with patient care ethics. While follow-up models to fee-for-service, such as capitation, aimed to simply control costs, neither explicitly intended to give patients marketplace agency or improve patient care ethics. The overall alignment of capitation and patient care ethics remained relatively neutral. Newer innovations such as value-based payments have a much stronger stated purpose of aligning payment with positive outcomes and lower costs, where outcomes have patient-defined criteria and costs are more accurate. Value-based payments create a comparatively more aligned model than fee-for-service or capitation. Yet no payment model fully addresses the tenet of justice, and the Rawlsian difference principle must be employed here to ensure that those of lowest socioeconomic status or the most disadvantaged are not worse off than before the implementation of a new payment model. As a system, healthcare should strive for the best possible outcomes for all patients, necessitating an integrated approach to social factors. - [1] Porter M. What is Value in Healthcare? N Engl J Med. 2010;363(26):2477-2482. [2] Kontopantelis E, Reeves D, Valderas JM, Campbell S, Doran T. Recorded quality of primary care for patients with diabetes in England before and after the introduction of a financial incentive scheme: A longitudinal observational study. BMJ Qual Saf. 2013;22(1):53-64. doi:10.1136/bmjqs-2012-001033 [3] Linzer M, Bitton A, Tu SP, Plews-Ogan M, Horowitz KR, Schwartz MD. The End of the 15–20 Minute Primary Care Visit. J Gen Intern Med. 2015;30(11):1584-1586. doi:10.1007/s11606-015-3341-3 [4] Gupta R, Gupta S. The effect of explicit financial incentives on physician behavior. Arch Intern Med. 2002;162(5):612-613. doi:10.1001/archinte.162.5.612; Rosenthal M. How will paying for performance affect patient care? AMA Ethics. 2006;8(3):162-165. [5] Wang Y, Ding Y, Park E, Hunte G. Do Financial Incentives Change Length-of-stay Performance in Emergency Departments? A Retrospective Study of the Pay-for-performance Program in Metro Vancouver. Acad Emerg Med. 2019;26(8):856-866. doi:10.1111/ACEM.13635 [6] Beauchamp T, Childress J. Principles of Biomedical Ethics. 8th ed. Oxford University Press; 2019. [7] Groenewoud AS, Westert GP, Kremer JAM. Value based competition in health care’s ethical drawbacks and the need for a values-driven approach. BMC Health Serv Res. 2019;19(1):1-6. doi:10.1186/s12913-019-4081-6 [8] Katz S, Melmed G. How relative value units undervalue the cognitive physician visit: A focus on inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12(4):240-244.; Cattel D, Eijkenaar F. Value-Based Provider Payment Initiatives Combining Global Payments With Explicit Quality Incentives: A Systematic Review. Medical Care Research and Review. 2020;77(6):511-537. doi:10.1177/1077558719856775 [9] Tummalapalli SL, Estrella MM, Jannat-Khah DP, Keyhani S, Ibrahim S. Capitated versus fee-for-service reimbursement and quality of care for chronic disease: a US cross-sectional analysis. BMC Health Serv Res. 2022;22(1):1-12. doi:10.1186/s12913-021-07313-3; Emanuel EJ, Mostashari F, Navathe AS. Designing a Successful Primary Care Physician Capitation Model. JAMA - Journal of the American Medical Association. 2021;325(20):2043-2044. doi:10.1001/jama.2021.5133 [10] Porter M. 2477-2482. [11] Kofman M. HSAs: A Great Tax Shelter for Wealthy, Healthy People but Little Help to the Uninsured, Underinsured, And People with Medical Needs. AMA Ethics. 2005;7(7):522-524.; Eskew PM, Klink K. Direct primary care: Practice distribution and cost across the nation. Journal of the American Board of Family Medicine. 2015;28(6):793-801. doi:10.3122/jabfm.2015.06.140337 [12] Cattel D, Eijkenaar F. 511-537 [13] Linzer M, Bitton A, Tu SP, Plews-Ogan M, Horowitz KR, Schwartz MD. 1584-1586. [14] Lurie N. The role of market forces in US health care. New England Journal of Medicine. 2020;383(15):1401-1404. [15] Reid RO, Tom AK, Ross RM, Duffy EL, Damberg CL. Physician Compensation Arrangements and Financial Performance Incentives in US Health Systems. JAMA Health Forum. 2022;3(1):e214634. doi:10.1001/jamahealthforum.2021.4634 [16] WHO. Health System Financing Country Profile. 2013. [17] Tummalapalli SL, Estrella MM, Jannat-Khah DP, Keyhani S, Ibrahim S. 1-12. [18] Hudson D, Sacks T, Irani K, Asher A. The price of the ticket: Health costs of upward mobility among African Americans. Int J Environ Res Public Health. 2020;17(4):1-18. doi:10.3390/ijerph17041179 [19] Ibid. [20] Tummalapalli SL, Estrella MM, Jannat-Khah DP, Keyhani S, Ibrahim S. 1-12.; Emanuel EJ, Mostashari F, Navathe AS. 2043-2044; Brosig-Koch J, Hennig-Schmidt H, Kairies N, Wiesen D. How to improve patient care? An analysis of capitation, fee-for-service, and mixed payment schemes for physicians. RUHR Economic Papers. Published online 2013:1-36. doi:10.1080/00185860009596559 [21] Emanuel EJ, Mostashari F, Navathe AS. 2043-2044; Brosig-Koch J, Hennig-Schmidt H, Kairies N, Wiesen D. 1-36. [22] Ibid. [23] Emanuel EJ, Mostashari F, Navathe AS. 2043-2044.; Reid RO, Tom AK, Ross RM, Duffy EL, Damberg CL. e214634. [24] Porter M. 2477-2482.; Teisberg E, Wallace S, O’Hara S. Defining and Implementing Value-Based Health Care: A Strategic Framework. Academic Medicine. 2020;95(5):682-685. doi:10.1097/ACM.0000000000003122 [25] Kaplan RS, Anderson SR. Time-Driven Activity-Based Costing Robert S. Kaplan and Steven R. Anderson November 2003. Harv Bus Rev. 2003;82(November):131-138.; Akhavan S, Ward L, Bozic KJ. Time-driven Activity-based Costing More Accurately Reflects Costs in Arthroplasty Surgery. Clin Orthop Relat Res. 2016;474(1):8-15. doi:10.1007/s11999-015-4214-0 [26] Shah T, Press VG, Huisingh-Scheetz M, White SR. COPD Readmissions: Addressing COPD in the Era of Value-based Health Care. Chest. 2016;150(4):916-926. doi:10.1016/j.chest.2016.05.002 [27] Lynn J, McKethan A, Jha AK. Value-based payments require valuing what matters to patients. JAMA - Journal of the American Medical Association. 2015;314(14):1445-1446. doi:10.1001/jama.2015.8909 [28] Groeneveld IF, Goossens PH, van Meijeren-Pont W. Value-Based Stroke Rehabilitation: Feasibility and Results of Patient-Reported Outcome Measures in the First Year After Stroke. Journal of Stroke and Cerebrovascular Diseases. 2019;28(2):499-512. doi:10.1016/j.jstrokecerebrovasdis.2018.10.033; Bernstein DN, Mayo K, Baumhauer JF, Dasilva C, Fear K, Houck JR. Do Patient Sociodemographic Factors Impact the PROMIS Scores Meeting the Patient-Acceptable Symptom State at the Initial Point of Care in Orthopaedic Foot and Ankle Patients? Clin Orthop Relat Res. 2019;477(11):2555-2565. doi:10.1097/CORR.0000000000000866 [29] Groeneveld IF, Goossens PH, van Meijeren-Pont W, et al. 499-512. [30] Bernstein DN, Mayo K, Baumhauer JF, Dasilva C, Fear K, Houck JR. 2555-2565 [31] Tran L. Social Risk Adjustment in Health Care Performance Measures. JAMA Netw Open. 2020;3(6). doi: doi:10.1001/jamanetworkopen.2020.8020 [32] Webster NJ. Medicare and Racial Disparities in Health: Fee-for-Service versus Managed Care. Vol 28. Elsevier; 2010. doi:10.1108/S0275-4959(2010)0000028005 [33] Roberts ET, Zaslavsky AM, Mcwilliams JM. The value-based payment modifier: Program outcomes and implications for disparities. Ann Intern Med. 2018;168(4):255-265. doi:10.7326/M17-1740 [34] Bazzoli GJ, Thompson MP, Waters TM. Medicare Payment Penalties and Safety Net Hospital Profitability: Minimal Impact on These Vulnerable Hospitals. Health Serv Res. 2018;53(5):3495-3506. doi:10.1111/1475-6773.12833 [35] Ekmekci PE, Arda B. Enhancing John Rawls’s Theory of Justice to Cover Health and Social Determinants of Health. Acta Bioeth. 2015;21(2):227-236. doi:10.4067/S1726-569X2015000200009

IntroductionThe 2009 American film Trash Humpers, directed by Harmony Korine, was released at a time when the hipster had become a ubiquitous concept, entering into the common vernacular of numerous cultures throughout the world, and gaining significant press, social media and academic attention (see Žižek; Arsel and Thompson; Greif et al.; Stahl; Ouellette; Reeve; Schiermer; Maly and Varis). Trash Humpers emerged soon after the 2008 Global Financial Crisis triggered Occupy movements in numerous cities, aided by social media platforms, reported on by blogs such as Gawker, and stylized by multi-national youth-subculture brands such as Vice, American Apparel, Urban Outfitters and a plethora of localised variants.Korine’s film, which is made to resemble found VHS footage of old-aged vandals, epitomises the ironic, retro stylizations and “counterculture-meets-kitsch” aesthetics so familiar to hipster culture. As a creative stereotype from 1940s and ‘50s jazz and beatnik subcultures, the hipster re-emerged in the twenty-first century as a negative embodiment of alternative culture in the age of the Internet. As well as plumbing the recent past for things not yet incorporated into contemporary marketing mechanisms, the hipster also signifies the blurring of irony and authenticity. Such “outsiderness as insiderness” postures can be regarded as a continuation of the marginality-from-the-centre logic of cool capitalism that emerged after World War Two. Particularly between 2007 and 2015, the post-postmodern concept of the hipster was a resonant cultural trope in Western and non-Western cultures alike, coinciding with the normalisation of the new digital terrain and the establishment of mobile social media as an integral aspect of many people’s daily lives. While Korine’s 79-minute feature could be thought of as following in the schlocky footsteps of the likes of Rob Zombie’s The Devil’s Rejects (2006), it is decidedly more arthouse, and more attuned to the influence of contemporary alternative media brands and independent film history alike – as if the love child of Jack Smith’s Flaming Creatures (1963) and Vice Video, the latter having been labelled as “devil-may-care hipsterism” (Carr). Upon release, Trash Humpers was described by Gene McHugh as “a mildly hip take on Jackass”; by Mike D’Angelo as “an empty hipster pose”; and by Aaron Hillis as either “the work of an insincere hipster or an eccentric provocateur”. Lacking any semblance of a conventional plot, Trash Humpers essentially revolves around four elderly-looking protagonists – three men and a woman – who document themselves with a low-quality video camera as they go about behaving badly in the suburbs of Nashville, Tennessee, where Korine still lives. They cackle eerily to themselves as they try to stave off boredom, masturbating frantically on rubbish bins, defecating and drinking alcohol in public, fellating foliage, smashing televisions, playing ten-pin bowling, lighting firecrackers and telling gay “hate” jokes to camera with no punchlines. In one purposefully undramatic scene half-way through the film, the humpers are shown in the aftermath of an attack on a man wearing a French maid’s outfit; he lies dead in a pool of blood on their kitchen floor with a hammer at his feet. The humpers are consummate “bad” performers in every sense of the term, and they are joined by a range of other, apparently lower-class, misfits with whom they stage tap dance routines and repetitively sing nursery-rhyme-styled raps such as: “make it, make it, don’t break it; make it, make it, don’t fake it; make it, make it, don’t take it”, which acts as a surrogate theme song for the film. Korine sometimes depicts his main characters on crutches or in a wheelchair, and a baby doll is never too far away from the action, as a silent and Surrealist witness to their weird, sinister and sometimes very funny exploits. The film cuts from scene to scene as if edited on a video recorder, utilising in-house VHS titling sequences, audio glitches and video static to create the sense that one is engaging voyeuristically with a found video document rather than a scripted movie. Mainstream AlternativesAs a viewer of Trash Humpers, one has to try hard to suspend disbelief if one is to see the humpers as genuine geriatric peeping Toms rather than as hipsters in old-man masks trying to be rebellious. However, as Korine’s earlier films such as Gummo (1997) attest, he clearly delights in blurring the line between failure and transcendence, or, in this case, between pretentious art-school bravado and authentic redneck ennui. As noted in a review by Jeannette Catsoulis, writing for the New York Times: “Much of this is just so much juvenile posturing, but every so often the screen freezes into something approximating beauty: a blurry, spaced-out, yellow-green landscape, as alien as an ancient photograph”. Korine has made a career out of generating this wavering uncertainty in his work, polarising audiences with a mix of critical, cinema-verité styles and cynical exploitations. His work has consistently revelled in ethical ambiguities, creating environments where teenagers take Ritalin for kicks, kill cats, wage war with their families and engage in acts of sexual deviancy – all of which are depicted with a photographer’s eye for the uncanny.The elusive and contradictory aspects of Korine’s work – at once ugly and beautiful, abstract and commercial, pessimistic and nostalgic – are evident not just in films such as Gummo, Julien Donkey Boy (1999) and Mister Lonely (2007) but also in his screenplay for Kids (1995), his performance-like appearances on The Tonight Show with David Letterman (1993-2015) and in publications such as A Crackup at the Race Riots (1998) and Pass the Bitch Chicken (2001). As well as these outputs, Korine is also a painter who is represented by Gagosian Gallery – one of the world’s leading art galleries – and he has directed numerous music videos, documentaries and commercials throughout his career. More than just update of the traditional figure of the auteur, Korine, instead, resembles a contemporary media artist whose avant-garde and grotesque treatments of Americana permeate almost everything he does. Korine wrote the screenplay for Kids when he was just 19, and subsequently built his reputation on the paradoxical mainstreaming of alternative culture in the 1990s. This is exemplified by the establishment of music and film genres such “alternative” and “independent”; the popularity of the slacker ethos attributed to Generation X; the increased visibility of alternative press zines; the birth of grunge in fashion and music; and the coining of “cool hunting” – a bottom-up market research phenomenon that aimed to discover new trends in urban subcultures for the purpose of mass marketing. Key to “alternative culture”, and its related categories such as “indie” and “arthouse”, is the idea of evoking artistic authenticity while covertly maintaining a parasitic relationship with the mainstream. As Holly Kruse notes in her account of the indie music scenes of the 1990s, which gained tremendous popularity in the wake of grunge bands such as Nirvana: without dominant, mainstream musics against which to react, independent music cannot be independent. Its existence depends upon dominant music structures and practices against which to define itself. Indie music has therefore been continually engaged in an economic and ideological struggle in which its ‘outsider’ status is re-examined, re-defined, and re-articulated to sets of musical practices. (Kruse 149)Alternative culture follows a similar, highly contentious, logic, appearing as a nebulous, authentic and artistic “other” whose exponents risk being entirely defined by the mainstream markets they profess to oppose. Kids was directed by the artist cum indie-director Larry Clark, who discovered Korine riding his skateboard with a group of friends in New York’s Washington Square in the early 1990s, before commissioning him to write a script. The then subcultural community of skating – which gained prominence in the 1990s amidst the increased visibility of “alternative sports” – provides an important backdrop to the film, which documents a group of disaffected New York teenagers at a time of the Aids crisis in America. Korine has been active in promoting the DIY ethos, creativity and anti-authoritarian branding of skate culture since this time – an industry that, in its attempts to maintain a non-mainstream profile while also being highly branded, has become emblematic of the category of “alternative culture”. Korine has undertaken commercial projects with an array skate-wear brands, but he is particularly associated with Supreme, a so-called “guerrilla fashion” label originating in 1994 that credits Clark and other 1990s indie darlings, and Korine cohorts, Chloë Sevigny and Terry Richardson, as former models and collaborators (Williams). The company is well known for its designer skateboard decks, its collaborations with prominent contemporary visual artists, its hip-hop branding and “inscrutable” web videos. It is also well known for its limited runs of new clothing lines, which help to stoke demand through one-offs – blending street-wear accessibility with the restricted-market and anti-authoritarian sensibility of avant-garde art.Of course, “alternative culture” poses a notorious conundrum for analysis, involving highly subjective demarcations of “mainstream” from “subversive” culture, not to mention “genuine subversion” from mere “corporate alternatives”. As Pierre Bourdieu has argued, the roots of alternative culture lie in the Western tradition of the avant-garde and the “aesthetic gaze” that developed in the nineteenth century (Field 36). In analysing the modernist notion of advanced cultural practice – where art is presented as an alternative to bourgeois academic taste and to the common realm of cultural commodities – Bourdieu proposed a distinction between two types of “fields”, or logics of cultural production. Alternative culture follows what Bourdieu called “the field of restricted production”, which adheres to “art for art’s sake” ideals, where audiences are targeted as if like-minded peers (Field 50). In contrast, the “field of large-scale production” reflects the commercial imperatives of mainstream culture, in which goods are produced for the general public at large. The latter field of large-scale production tends to service pre-established markets, operating in response to public demand. Furthermore, whereas success in the field of restricted production is often indirect, and latent – involving artists who create niche markets without making any concessions to those markets – success in the field of large-scale production is typically more immediate and quantifiable (Field 39). Here we can see that central to the branding of “alternative culture” is the perceived refusal to conform to popular taste and the logic of capitalism more generally is. As Supreme founder James Jebbia stated about his brand in a rare interview: “The less known the better” (Williams). On this, Bourdieu states that, in the field of restricted production, the fundamental principles of all ordinary economies are inversed to create a “loser wins” scenario (Field 39). Profit and cultural esteem become detrimental attributes in this context, potentially tainting the integrity and marginalisation on which alternative products depend. As one ironic hipster t-shirt puts it: “Nothing is any good if other people like it” (Diesel Sweeties).Trash HipstersIn abandoning linear narrative for rough assemblages of vignettes – or “moments” – recorded with an unsteady handheld camera, Trash Humpers positions itself in ironic opposition to mainstream filmmaking, refusing the narrative arcs and unwritten rules of Hollywood film, save for its opening and closing credits. Given Korine’s much publicized appreciation of cinema pioneers, we can understand Trash Humpers as paying homage to independent and DIY film history, including Jack Smith’s Flaming Creatures, William Eggleston’s Stranded in Canton (1973), Andy Warhol’s and Paul Morrissey’s Lonesome Cowboys (1967) and Trash (1970), and John Waters’s Pink Flamingos (1972), all of which jubilantly embraced the “bad” aesthetic of home movies. Posed as fantasized substitutions for mainstream movie-making, such works were also underwritten by the legitimacy of camp as a form of counter-culture critique, blurring parody and documentary to give voice to an array of non-mainstream and counter-cultural identities. The employment of camp in postmodern culture became known not merely as an aesthetic subversion of cultural mores but also as “a gesture of self-legitimation” (Derrida 290), its “failed seriousness” regarded as a critical response to the specific historical problem of being a “culturally over-saturated” subject (Sontag 288).The significant difference between Korine’s film and those of his 1970s-era forbears is precisely the attention he pays to the formal aspects of his medium, revelling in analogue editing glitches to the point of fetishism, in some cases lasting as long as the scenes themselves. Consciously working out-of-step with the media of his day, Trash Humpers in imbued with nostalgia from its very beginning. Whereas Smith, Eggleston, Warhol, Morrissey and Waters blurred fantasy and documentary in ways that raised the social and political identities of their subjects, Korine seems much more interested in “trash” as an aesthetic trope. In following this interest, he rightfully pays homage to the tropes of queer cinema, however, he conveniently leaves behind their underlying commentaries about (hetero-) normative culture. A sequence where the trash humpers visit a whorehouse and amuse themselves by smoking cigars and slapping the ample bottoms of prostitutes in G-strings confirms the heterosexual tenor of the film, which is reiterated throughout by numerous deadpan gay jokes and slurs.Trash Humpers can be understood precisely in terms of Korine’s desire to maintain the aesthetic imperatives of alternative culture, where formal experimentation and the subverting of mainstream genres can provide a certain amount of freedom from explicated meaning, and, in particular, from socio-political commentary. Bourdieu rightly points out how the pleasures of the aesthetic gaze often manifest themselves curiously as form of “deferred pleasure” (353) or “pleasure without enjoyment” (495), which corresponds to Immanuel Kant’s notion of the disinterested nature of aesthetic judgement. Aesthetic dispositions posed in the negative – as in the avant-garde artists who mined primitive and ugly cultural stereotypes – typically use as reference points “facile” or “vulgar” (393) working-class tropes that refer negatively to sensuous pleasure as their major criterion of judgment. For Bourdieu, the pleasures provided by the aesthetic gaze in such instances are not sensual pleasures so much as the pleasures of social distinction – signifying the author’s distance from taste as a form of gratification. Here, it is easy to see how the orgiastic central characters in Trash Humpers might be employed by Korine for a similar end-result. As noted by Jeremiah Kipp in a review of the film: “You don't ‘like’ a movie like Trash Humpers, but I’m very happy such films exist”. Propelled by aesthetic, rather than by social, questions of value, those that “get” the obscure works of alternative culture have a tendency to legitimize them on the basis of the high-degree of formal analysis skills they require. For Bourdieu, this obscures the fact that one’s aesthetic “‘eye’ is a product of history reproduced by education” – a privileged mode of looking, estranged from those unfamiliar with the internal logic of decoding presupposed by the very notion of “aesthetic enjoyment” (2).The rhetorical priority of alternative culture is, in Bourdieu’s terms, the “autonomous” perfection of the form rather than the “heteronomous” attempt to monopolise on it (Field 40). However, such distinctions are, in actuality, more nuanced than Bourdieu sometimes assumed. This is especially true in the context of global digital culture, which makes explicit how the same cultural signs can have vastly different meanings and motivations across different social contexts. This has arguably resulted in the destabilisation of prescriptive analyses of cultural taste, and has contributed to recent “post-critical” advances, in which academics such as Bruno Latour and Rita Felski advocate for cultural analyses and practices that promote relationality and attachment rather than suspicious (critical) dispositions towards marginal and popular subjects alike. Latour’s call for a move away from the “sledge hammer” of critique applies as much to cultural practice as it does to written analysis. Rather than maintaining hierarchical oppositions between authentic versus inauthentic taste, Latour understands culture – and the material world more generally – as having agency alongside, and with, that of the social world.Hipsters with No AlternativeIf, as Karl Spracklen suggests, alternativism is thought of “as a political project of resistance to capitalism, with communicative oppositionality as its defining feature” (254), it is clear that there has been a progressive waning in relevance of the category of “alternative culture” in the age of the Internet, which coincides with the triumph of so-called “neoliberal individualism” (258). To this end, Korine has lost some of his artistic credibility over the course of the 2000s. If viewed negatively, icons of 1990s alternative culture such as Korine can be seen as merely exploiting Dada-like techniques of mimetic exacerbation and symbolic détournement for the purpose of alternative, “arty” branding rather than pertaining to a counter-hegemonic cultural movement (Foster 31). It is within this context of heightened scepticism surrounding alternative culture that the hipster stereotype emerged in cultures throughout the world, as if a contested symbol of the aesthetic gaze in an era of neoliberal identity politics. Whatever the psychological motivations underpinning one’s use of the term, to call someone a hipster is typically to point out that their distinctive alternative or “arty” status appears overstated; their creative decisions considered as if a type of bathos. For detractors of alternative cultural producers such as Korine, he is trying too hard to be different, using the stylised codes of “alternative” to conceal what is essentially his cultural and political immaturity. The hipster – who is rarely ever self-identified – re-emerged in the 2000s to operate as a scapegoat for inauthentic markers of alternative culture, associated with men and women who appear to embrace Realpolitik, sincerity and authentic expressions of identity while remaining tethered to irony, autonomous aesthetics and self-design. Perhaps the real irony of the hipster is the pervasiveness of irony in contemporary culture. R. J Magill Jnr. has argued that “a certain cultural bitterness legitimated through trenchant disbelief” (xi) has come to define the dominant mode of political engagement in many societies since the early 2000s, in response to mass digital information, twenty-four-hour news cycles, and the climate of suspicion produced by information about terrorism threats. He analyses the prominence of political irony in American TV shows including The Daily Show with Jon Stewart, The Simpsons, South Park, The Chappelle Show and The Colbert Report but he also notes its pervasiveness as a twenty-first-century worldview – a distancing that “paradoxically and secretly preserves the ideals of sincerity, honesty and authenticity by momentarily belying its own appearance” (x). Crucially, then, the utterance “hipster” has come to signify instances when irony and aesthetic distance are perceived to have been taken too far, generating the most disdain from those for whom irony, aesthetic discernment and cultural connoisseurship still provide much-needed moments of disconnection from capitalist cultures drowning in commercial hyperbole and grave news hype. Korine himself has acknowledged that Spring Breakers (2013) – his follow-up feature film to Trash Humpers – was created in response to the notion that “alternative culture”, once a legitimate challenge to mainstream taste, had lost its oppositional power with the decentralization of digital culture. He states that he made Spring Breakers at a moment “when there’s no such thing as high or low, it’s all been exploded. There is no underground or above-ground, there’s nothing that’s alternative. We’re at a point of post-everything, so it’s all about finding the spirit inside, and the logic, and making your own connections” (Hawker). In this context, we can understand Trash Humpers as the last of the Korine films to be branded with the authenticity of alternative culture. In Spring Breakers Korine moved from the gritty low-fi sensibility of his previous films and adopted a more digital, light-filled and pastel-coloured palette. Focussing more conventionally on plot than ever before, Spring Breakers follows four college girls who hold up a restaurant in order to fund their spring break vacation. Critic Michael Chaiken noted that the film marks a shift in Korine’s career, from the alternative stylings of the pre-Internet generation to “the cultural heirs [of] the doomed protagonists of Kids: nineties babies, who grew up with the Internet, whose sensibilities have been shaped by the sweeping technological changes that have taken place in the interval between the Clinton and Obama eras” (33).By the end of the 2000s, an entire generation came of age having not experienced a time when the obscure films, music or art of the past took more effort to track down. Having been a key participant in the branding of alternative culture, Korine is in a good position to recall a different, pre-YouTube time – when cultural discernment was still caught up in the authenticity of artistic identity, and when one’s cultural tastes could still operate with a certain amount of freedom from sociological scrutiny. Such ideas seem a long way away from today’s cultural environments, which have been shaped not only by digital media’s promotion of cultural interconnection and mass information, but also by social media’s emphasis on mobilization and ethical awareness. ConclusionI should reiterate here that is not Korine’s lack of seriousness, or irony, alone that marks Trash Humpers as a response to the scepticism surrounding alternative culture symbolised by the figure of the hipster. It is, rather, that Korine’s mock-documentary about juvenile geriatrics works too hard to obscure its implicit social commentary, appearing driven to condemn contemporary capitalism’s exploitations of youthfulness only to divert such “uncool” critical commentaries through unsubtle formal distractions, visual poetics and “bad boy” avant-garde signifiers of authenticity. Before being bludgeoned to death, the unnamed man in the French maid’s outfit recites a poem on a bridge amidst a barrage of fire crackers let off by a nearby humper in a wheelchair. Although easily overlooked, it could, in fact, be a pivotal scene in the film. Spoken with mock high-art pretentions, the final lines of the poem are: So what? Why, I ask, why? Why castigate these creatures whose angelic features are bumping and grinding on trash? Are they not spawned by our greed? Are they not our true seed? Are they not what we’ve bought for our cash? We’ve created this lot, of the ooze and the rot, deliberately and unabashed. Whose orgiastic elation and one mission in creation is to savagely fornicate TRASH!Here, the character’s warning of capitalist overabundance is drowned out by the (aesthetic) shocks of the fire crackers, just as the stereotypical hipster’s ethical ideals are drowned out by their aesthetic excess. The scene also functions as a metaphor for the humpers themselves, whose elderly masks – embodiments of nostalgia – temporarily suspend their real socio-political identities for the sake of role-play. It is in this sense that Trash Humpers is too enamoured with its own artifices – including its anonymous “boys club” mentality – to suggest anything other than the aesthetic distance that has come to mark the failings of the “alternative culture” category. In such instances, alternative taste appears as a rhetorical posture, with Korine asking us to gawk knowingly at the hedonistic and destructive pleasures pursued by the humpers while factoring in, and accepting, our likely disapproval.ReferencesArsel, Zeynep, and Craig J. Thompson. “Demythologizing Consumption Practices: How Consumers Protect Their Field-Dependent Identity Investments from Devaluing Marketplace Myths.” Journal of Consumer Research 37.5 (2011): 791-806.Bourdieu, Pierre. 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Introduction This paper offers a survey of familiar popular music performers and songwriters who reference coffee in their work. It examines three areas of discourse: the psychoactive effects of caffeine, coffee and courtship rituals, and the politics of coffee consumption. I claim that coffee carries a cultural and musicological significance comparable to that of the chemical stimulants and consumer goods more readily associated with popular music. Songs about coffee may not be as potent as those featuring drugs and alcohol (Primack; Schapiro), or as common as those referencing commodities like clothes and cars (Englis; McCracken), but they do feature across a wide range of genres, some of which enjoy archetypal associations with this beverage. m.o.m.m.y. Needs c.o.f.f.e.e.: The Psychoactive Effect of Coffee The act of performing and listening to popular music involves psychological elements comparable to the overwhelming sensory experience of drug taking: altered perceptions, repetitive grooves, improvisation, self-expression, and psychological empathy—such as that between musician and audience (Curry). Most popular music genres are, as a result, culturally and sociologically identified with the consumption of at least one mind-altering substance (Lyttle; Primack; Schapiro). While the analysis of lyrics referring to this theme has hitherto focused on illegal drugs and alcoholic beverages (Cooper), coffee and its psychoactive ingredient caffeine have been almost entirely overlooked (Summer). The most recent study of drugs in popular music, for example, defined substance use as “tobacco, alcohol, marijuana, cocaine and other stimulants, heroin and other opiates, hallucinogens, inhalants, prescription drugs, over-the-counter drugs, and nonspecific substances” (Primack 172), thereby ignoring a chemical stimulant consumed by 90 per cent of adult Americans every day (Lovett). The wide availability of coffee and the comparatively mild effect of caffeine means that its consumption rarely causes harm. One researcher has described it as a ubiquitous and unobtrusive “generalised public activity […] ‘invisible’ to analysts seeking distinctive social events” (Cooper 92). Coffee may provide only a relatively mild “buzz”—but it is now accepted that caffeine is an addictive substance (Juliano) and, due to its universal legality, coffee is also the world’s most extensively traded and enthusiastically consumed psychoactive consumer product (Juliano 1). The musical genre of jazz has a longstanding relationship with marijuana and narcotics (Curry; Singer; Tolson; Winick). Unsurprisingly, given its Round Midnight connotations, jazz standards also celebrate the restorative impact of coffee. Exemplary compositions include Burke/Webster’s insomniac torch song Black Coffee, which provided hits for Sarah Vaughan (1949), Ella Fitzgerald (1953), and Peggy Lee (1960); and Frank Sinatra’s recordings of Hilliard/Dick’s The Coffee Song (1946, 1960), which satirised the coffee surplus in Brazil at a time when this nation enjoyed a near monopoly on production. Sinatra joked that this ubiquitous drink was that country’s only means of liquid refreshment, in a refrain that has since become a headline writer’s phrasal template: “There’s an Awful Lot of Coffee in Vietnam,” “An Awful Lot of Coffee in the Bin,” and “There’s an Awful Lot of Taxes in Brazil.” Ethnographer Aaron Fox has shown how country music gives expression to the lived social experience of blue-collar and agrarian workers (Real 29). Coffee’s role in energising working class America (Cooper) is featured in such recordings as Dolly Parton’s Nine To Five (1980), which describes her morning routine using a memorable “kitchen/cup of ambition” rhyme, and Don't Forget the Coffee Billy Joe (1973) by Tom T. Hall which laments the hardship of unemployment, hunger, cold, and lack of healthcare. Country music’s “tired truck driver” is the most enduring blue-collar trope celebrating coffee’s analeptic powers. Versions include Truck Drivin' Man by Buck Owens (1964), host of the country TV show Hee Haw and pioneer of the Bakersfield sound, and Driving My Life Away from pop-country crossover star Eddie Rabbitt (1980). Both feature characteristically gendered stereotypes of male truck drivers pushing on through the night with the help of a truck stop waitress who has fuelled them with caffeine. Johnny Cash’s A Cup of Coffee (1966), recorded at the nadir of his addiction to pills and alcohol, has an incoherent improvised lyric on this subject; while Jerry Reed even prescribed amphetamines to keep drivers awake in Caffein [sic], Nicotine, Benzedrine (And Wish Me Luck) (1980). Doye O’Dell’s Diesel Smoke, Dangerous Curves (1952) is the archetypal “truck drivin’ country” song and the most exciting track of its type. It subsequently became a hit for the doyen of the subgenre, Red Simpson (1966). An exhausted driver, having spent the night with a woman whose name he cannot now recall, is fighting fatigue and wrestling his hot-rod low-loader around hairpin mountain curves in an attempt to rendezvous with a pretty truck stop waitress. The song’s palpable energy comes from its frenetic guitar picking and the danger implicit in trailing a heavy load downhill while falling asleep at the wheel. Tommy Faile’s Phantom 309, a hit for Red Sovine (1967) that was later covered by Tom Waits (Big Joe and the Phantom 309, 1975), elevates the “tired truck driver” narrative to gothic literary form. Reflecting country music’s moral code of citizenship and its culture of performative storytelling (Fox, Real 23), it tells of a drenched and exhausted young hitchhiker picked up by Big Joe—the driver of a handsome eighteen-wheeler. On arriving at a truck stop, Joe drops the traveller off, giving him money for a restorative coffee. The diner falls silent as the hitchhiker orders up his “cup of mud”. Big Joe, it transpires, is a phantom trucker. After running off the road to avoid a school bus, his distinctive ghost rig now only reappears to rescue stranded travellers. Punk rock, a genre closely associated with recreational amphetamines (McNeil 76, 87), also features a number of caffeine-as-stimulant songs. Californian punk band, Descendents, identified caffeine as their drug of choice in two 1996 releases, Coffee Mug and Kids on Coffee. These songs describe chugging the drink with much the same relish and energy that others might pull at the neck of a beer bottle, and vividly compare the effects of the drug to the intense rush of speed. The host of “New Music News” (a segment of MTV’s 120 Minutes) references this correlation in 1986 while introducing the band’s video—in which they literally bounce off the walls: “You know, while everybody is cracking down on crack, what about that most respectable of toxic substances or stimulants, the good old cup of coffee? That is the preferred high, actually, of California’s own Descendents—it is also the subject of their brand new video” (“New Music News”). Descendents’s Sessions EP (1997) featured an overflowing cup of coffee on the sleeve, while punk’s caffeine-as-amphetamine trope is also promulgated by Hellbender (Caffeinated 1996), Lagwagon (Mr. Coffee 1997), and Regatta 69 (Addicted to Coffee 2005). Coffee in the Morning and Kisses in the Night: Coffee and Courtship Coffee as romantic metaphor in song corroborates the findings of early researchers who examined courtship rituals in popular music. Donald Horton’s 1957 study found that hit songs codified the socially constructed self-image and limited life expectations of young people during the 1950s by depicting conservative, idealised, and traditional relationship scenarios. He summarised these as initial courtship, honeymoon period, uncertainty, and parting (570-4). Eleven years after this landmark analysis, James Carey replicated Horton’s method. His results revealed that pop lyrics had become more realistic and less bound by convention during the 1960s. They incorporated a wider variety of discourse including the temporariness of romantic commitment, the importance of individual autonomy in relationships, more liberal attitudes, and increasingly unconventional courtship behaviours (725). Socially conservative coffee songs include Coffee in the Morning and Kisses in the Night by The Boswell Sisters (1933) in which the protagonist swears fidelity to her partner on condition that this desire is expressed strictly in the appropriate social context of marriage. It encapsulates the restrictions Horton identified on courtship discourse in popular song prior to the arrival of rock and roll. The Henderson/DeSylva/Brown composition You're the Cream in My Coffee, recorded by Annette Hanshaw (1928) and by Nat King Cole (1946), also celebrates the social ideal of monogamous devotion. The persistence of such idealised traditional themes continued into the 1960s. American pop singer Don Cherry had a hit with Then You Can Tell Me Goodbye (1962) that used coffee as a metaphor for undying and everlasting love. Otis Redding’s version of Butler/Thomas/Walker’s Cigarettes and Coffee (1966)—arguably soul music’s exemplary romantic coffee song—carries a similar message as a couple proclaim their devotion in a late night conversation over coffee. Like much of the Stax catalogue, Cigarettes and Coffee, has a distinctly “down home” feel and timbre. The lovers are simply content with each other; they don’t need “cream” or “sugar.” Horton found 1950s blues and R&B lyrics much more sexually explicit than pop songs (567). Dawson (1994) subsequently characterised black popular music as a distinct public sphere, and Squires (2002) argued that it displayed elements of what she defined as “enclave” and “counterpublic” traits. Lawson (2010) has argued that marginalised and/or subversive blues artists offered a form of countercultural resistance against prevailing social norms. Indeed, several blues and R&B coffee songs disregard established courtship ideals and associate the product with non-normative and even transgressive relationship circumstances—including infidelity, divorce, and domestic violence. Lightnin’ Hopkins’s Coffee Blues (1950) references child neglect and spousal abuse, while the narrative of Muddy Waters’s scorching Iodine in my Coffee (1952) tells of an attempted poisoning by his Waters’s partner. In 40 Cups of Coffee (1953) Ella Mae Morse is waiting for her husband to return home, fuelling her anger and anxiety with caffeine. This song does eventually comply with traditional courtship ideals: when her lover eventually returns home at five in the morning, he is greeted with a relieved kiss. In Keep That Coffee Hot (1955), Scatman Crothers supplies a counterpoint to Morse’s late-night-abandonment narrative, asking his partner to keep his favourite drink warm during his adulterous absence. Brook Benton’s Another Cup of Coffee (1964) expresses acute feelings of regret and loneliness after a failed relationship. More obliquely, in Coffee Blues (1966) Mississippi John Hurt sings affectionately about his favourite brand, a “lovin’ spoonful” of Maxwell House. In this, he bequeathed the moniker of folk-rock band The Lovin’ Spoonful, whose hits included Do You Believe in Magic (1965) and Summer in the City (1966). However, an alternative reading of Hurt’s lyric suggests that this particular phrase is a metaphorical device proclaiming the author’s sexual potency. Hurt’s “lovin’ spoonful” may actually be a portion of his seminal emission. In the 1950s, Horton identified country as particularly “doleful” (570), and coffee provides a common metaphor for failed romance in a genre dominated by “metanarratives of loss and desire” (Fox, Jukebox 54). Claude Gray’s I'll Have Another Cup of Coffee (Then I’ll Go) (1961) tells of a protagonist delivering child support payments according to his divorce lawyer’s instructions. The couple share late night coffee as their children sleep through the conversation. This song was subsequently recorded by seventeen-year-old Bob Marley (One Cup of Coffee, 1962) under the pseudonym Bobby Martell, a decade prior to his breakthrough as an international reggae star. Marley’s youngest son Damian has also performed the track while, interestingly in the context of this discussion, his older sibling Rohan co-founded Marley Coffee, an organic farm in the Jamaican Blue Mountains. Following Carey’s demonstration of mainstream pop’s increasingly realistic depiction of courtship behaviours during the 1960s, songwriters continued to draw on coffee as a metaphor for failed romance. In Carly Simon’s You’re So Vain (1972), she dreams of clouds in her coffee while contemplating an ostentatious ex-lover. Squeeze’s Black Coffee In Bed (1982) uses a coffee stain metaphor to describe the end of what appears to be yet another dead-end relationship for the protagonist. Sarah Harmer’s Coffee Stain (1998) expands on this device by reworking the familiar “lipstick on your collar” trope, while Sexsmith & Kerr’s duet Raindrops in my Coffee (2005) superimposes teardrops in coffee and raindrops on the pavement with compelling effect. Kate Bush’s Coffee Homeground (1978) provides the most extreme narrative of relationship breakdown: the true story of Cora Henrietta Crippin’s poisoning. Researchers who replicated Horton’s and Carey’s methodology in the late 1970s (Bridges; Denisoff) were surprised to find their results dominated by traditional courtship ideals. The new liberal values unearthed by Carey in the late 1960s simply failed to materialise in subsequent decades. In this context, it is interesting to observe how romantic coffee songs in contemporary soul and jazz continue to disavow the post-1960s trend towards realistic social narratives, adopting instead a conspicuously consumerist outlook accompanied by smooth musical timbres. This phenomenon possibly betrays the influence of contemporary coffee advertising. From the 1980s, television commercials have sought to establish coffee as a desirable high end product, enjoyed by bohemian lovers in a conspicuously up-market environment (Werder). All Saints’s Black Coffee (2000) and Lebrado’s Coffee (2006) identify strongly with the culture industry’s image of coffee as a luxurious beverage whose consumption signifies prominent social status. All Saints’s promotional video is set in a opulent location (although its visuals emphasise the lyric’s romantic disharmony), while Natalie Cole’s Coffee Time (2008) might have been itself written as a commercial. Busting Up a Starbucks: The Politics of Coffee Politics and coffee meet most palpably at the coffee shop. This conjunction has a well-documented history beginning with the establishment of coffee houses in Europe and the birth of the public sphere (Habermas; Love; Pincus). The first popular songs to reference coffee shops include Jaybird Coleman’s Coffee Grinder Blues (1930), which boasts of skills that precede the contemporary notion of a barista by four decades; and Let's Have Another Cup of Coffee (1932) from Irving Berlin’s depression-era musical Face The Music, where the protagonists decide to stay in a restaurant drinking coffee and eating pie until the economy improves. Coffee in a Cardboard Cup (1971) from the Broadway musical 70 Girls 70 is an unambiguous condemnation of consumerism, however, it was written, recorded and produced a generation before Starbucks’ aggressive expansion and rapid dominance of the coffee house market during the 1990s. The growth of this company caused significant criticism and protest against what seemed to be a ruthless homogenising force that sought to overwhelm local competition (Holt; Thomson). In response, Starbucks has sought to be defined as a more responsive and interactive brand that encourages “glocalisation” (de Larios; Thompson). Koller, however, has characterised glocalisation as the manipulative fabrication of an “imagined community”—whose heterogeneity is in fact maintained by the aesthetics and purchasing choices of consumers who make distinctive and conscious anti-brand statements (114). Neat Capitalism is a more useful concept here, one that intercedes between corporate ideology and postmodern cultural logic, where such notions as community relations and customer satisfaction are deliberately and perhaps somewhat cynically conflated with the goal of profit maximisation (Rojek). As the world’s largest chain of coffee houses with over 19,400 stores in March 2012 (Loxcel), Starbucks is an exemplar of this phenomenon. Their apparent commitment to environmental stewardship, community relations, and ethical sourcing is outlined in the company’s annual “Global Responsibility Report” (Vimac). It is also demonstrated in their engagement with charitable and environmental non-governmental organisations such as Fairtrade and Co-operative for Assistance and Relief Everywhere (CARE). By emphasising this, Starbucks are able to interpellate (that is, “call forth”, “summon”, or “hail” in Althusserian terms) those consumers who value environmental protection, social justice and ethical business practices (Rojek 117). Bob Dylan and Sheryl Crow provide interesting case studies of the persuasive cultural influence evoked by Neat Capitalism. Dylan’s 1962 song Talkin’ New York satirised his formative experiences as an impoverished performer in Greenwich Village’s coffee houses. In 1995, however, his decision to distribute the Bob Dylan: Live At The Gaslight 1962 CD exclusively via Starbucks generated significant media controversy. Prominent commentators expressed their disapproval (Wilson Harris) and HMV Canada withdrew Dylan’s product from their shelves (Lynskey). Despite this, the success of this and other projects resulted in the launch of Starbucks’s in-house record company, Hear Music, which released entirely new recordings from major artists such as Ray Charles, Paul McCartney, Joni Mitchell, Carly Simon and Elvis Costello—although the company has recently announced a restructuring of their involvement in this venture (O’Neil). Sheryl Crow disparaged her former life as a waitress in Coffee Shop (1995), a song recorded for her second album. “Yes, I was a waitress. I was a waitress not so long ago; then I won a Grammy” she affirmed in a YouTube clip of a live performance from the same year. More recently, however, Crow has become an avowed self-proclaimed “Starbucks groupie” (Tickle), releasing an Artist’s Choice (2003) compilation album exclusively via Hear Music and performing at the company’s 2010 Annual Shareholders’s Meeting. Songs voicing more unequivocal dissatisfaction with Starbucks’s particular variant of Neat Capitalism include Busting Up a Starbucks (Mike Doughty, 2005), and Starbucks Takes All My Money (KJ-52, 2008). The most successful of these is undoubtedly Ron Sexsmith’s Jazz at the Bookstore (2006). Sexsmith bemoans the irony of intense original blues artists such as Leadbelly being drowned out by the cacophony of coffee grinding machines while customers queue up to purchase expensive coffees whose names they can’t pronounce. In this, he juxtaposes the progressive patina of corporate culture against the circumstances of African-American labour conditions in the deep South, the shocking incongruity of which eventually cause the old bluesman to turn in his grave. Fredric Jameson may have good reason to lament the depthless a-historical pastiche of postmodern popular culture, but this is no “nostalgia film”: Sexsmith articulates an artfully framed set of subtle, sensitive, and carefully contextualised observations. Songs about coffee also intersect with politics via lyrics that play on the mid-brown colour of the beverage, by employing it as a metaphor for the sociological meta-narratives of acculturation and assimilation. First popularised in Israel Zangwill’s 1905 stage play, The Melting Pot, this term is more commonly associated with Americanisation rather than miscegenation in the United States—a nuanced distinction that British band Blue Mink failed to grasp with their memorable invocation of “coffee-coloured people” in Melting Pot (1969). Re-titled in the US as People Are Together (Mickey Murray, 1970) the song was considered too extreme for mainstream radio airplay (Thompson). Ike and Tina Turner’s Black Coffee (1972) provided a more accomplished articulation of coffee as a signifier of racial identity; first by associating it with the history of slavery and the post-Civil Rights discourse of African-American autonomy, then by celebrating its role as an energising force for African-American workers seeking economic self-determination. Anyone familiar with the re-casting of black popular music in an industry dominated by Caucasian interests and aesthetics (Cashmore; Garofalo) will be unsurprised to find British super-group Humble Pie’s (1973) version of this song more recognisable. Conclusion Coffee-flavoured popular songs celebrate the stimulant effects of caffeine, provide metaphors for courtship rituals, and offer critiques of Neat Capitalism. Harold Love and Guthrie Ramsey have each argued (from different perspectives) that the cultural micro-narratives of small social groups allow us to identify important “ethnographic truths” (Ramsey 22). Aesthetically satisfying and intellectually stimulating coffee songs are found where these micro-narratives intersect with the ethnographic truths of coffee culture. 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The story of Barbie is a tapestry woven with threads of cultural significance, societal shifts, and corporate narratives. It’s a tale that encapsulates the evolution of American post-war capitalism, mirroring the changing tides of social norms, aspirations, and identities. Barbie’s journey from Germany to Los Angeles, along the way becoming a global icon, is a testament to the power of Ruth Handler’s vision and Barbie’s marketing. Barbie embodies and reflects the rise of mass consumption and the early days of television advertising, where one doll could become a household name and shape the dreams of children worldwide. The controversies and criticisms surrounding Barbie – from promoting a ‘thin ideal’ to perpetuating gender and racial stereotypes – highlight the complexities of representation in popular culture. Yet, Barbie’s enduring message, “You can be anything”, continues to inspire and empower, even as it evolves to embrace a more inclusive and diverse portrayals of power, beauty, and potential. Barbie’s story is not just about a doll; it’s about the aspirations she represents, the societal changes she’s witnessed, and the ongoing conversation about her impact on gender roles, body image, and consumer culture. It’s a narrative that continues to unfold, as Barbie adapts to the times and remains a symbol of possibility. Barbie: A Popular Culture Icon “It is impossible to conceive of the toy industry as being anything other than dependent on a popular culture which shapes and structures the meanings carried by toys” (Fleming 40). The relationship between toys and popular culture is symbiotic. While popular culture influences the creation of toys, toys also contribute to the spread and longevity of cultural icons and narratives. Today, one of the most influential, popular, and contested toys of the twentieth century is Mattel’s Barbie doll. Her launch at the New York Toy Fair on 9 March 1959 by Mattel co-founder Ruth Handler was a game-changer in the toy industry. Her adult appearance, symbolised by her fashionable swimsuit and ponytail, was a bold move by Mattel. Despite the doubts from the toy industry which thought nobody would want to play with a doll that had breasts (Tamkin) and Mattel’s skepticism of its commercial success (Westenhouser 14), Barbie was a success, selling over 350,000 units in her first year, and she quickly became an iconic figure, paving the way for other male and female adult dolls. For the first time in mid-century America, Barbie meant children could play with a doll that looked like a woman, not a little girl or a baby. In a 1965 interview, Ruth Handler argued that American girls needed a doll with a “teen-age figure and a lot of glorious, imaginative, high-fashion clothes” (cited in Giacomin and Lubinski 3). In a 1993 interview, Handler said it was “important that Barbie allowed play situations that little girls could project themselves into … to imagine, pretend and to fantasize”. Hence Ruth Handler’s Barbie could be an “avatar for girls to project their dreams onto” (Southwell). Barbie hit the market with a “sassy ponytail, heavy eyeliner, a healthy dose of side-eye and a distinctly adult body” (Blackmore). Her arched eyebrows were matched with a coy sideways glance reflecting her sexual origins (Thong). Mattel did not reveal that Ruth Handler’s Barbie was inspired by a German novelty men’s toy, Bild Lilli, which Handler had purchased on a European holiday in 1955. Mattel fought several lawsuits and eventually secured the rights to Bild Lilli in 1964, which required the German maker of the Bild Lilli doll to not make her again. Barbie dolls, both blonde and brunette, changed little until 1967, when Mattel launch the ‘new’ Barbie doll which is the foundation for today’s Stereotypical Barbie. The same size as the original, thanks to Mattel engineer Jack Ryan she could twist and turn at the waist. Her facial features were softened, she had ‘real’ eyelashes’ and took on an ‘outdoor look’. The new 1967 version of Barbie originally retailed for US$3.00. Mattel, assuming consumers may not want to buy a new Barbie when they already had one, offered buyers the new Barbie at US$1.50 if they traded in their old 1950s Barbie. The television advertising campaign for the new Barbie featured Maureen McMormick (who would go on to play Marcia Brady in the TV series The Brady Bunch from 1969 to 1974). The original #1 Barbie today sells for over US$25,000 (Reinhard). The most expensive Barbie sold to date was a Stefano Canturi-designed Barbie that sold in 2010 for US$302,500 at Christies in New York (Clarendon). Barbie has been described as “the most successful doll in history”, “the most popular toy in history”, the “empress of fashion dolls” (Rogers 86), the “most famous doll in the world” (Ferorelli), the biggest-selling fashion doll in history (Green and Gellene), and is one if the world’s “most commercially successful toys” (Fleming 41). Barbie is both “idealistic and materialistic” and characterises an “American fantasy” (Tamkin). More so, she is a popular culture icon and “a unique indicator of women’s history” (Vander Bent). The inclusion of Barbie in America’s twentieth-century Time Capsule “cemented her status as a true American icon” (Ford), as did Andy Warhol when he iconised Barbie in his 1968 painting of her (Moore). During the 1950s and 1960s, Barbie’s name was licenced to over 100 companies; while a strategic move that expanded Barbie’s brand presence, it also provided Mattel with substantial royalty payments for decades. This approach helped solidify Barbie’s status as a cultural icon and enabled her to become a lucrative asset for Mattel (Rogers). Sixty-five years later, Barbie has 99% global brand awareness. In 2021, Mattel shipped more than 86 million Barbies globally, manufacturing 164 Barbies a minute (Tomkins). In 2022, Barbie generated gross sales of US$1.49 billion (Statista 2023). With this fiscal longevity and brand recognition, the success of the Barbie film is not surprising. The 2023 film, directed by Greta Gerwig and starring Australian Margot Robbie as Barbie and Canadian Ryan Gosling as Ken, as of March 2024 has a global box office revenue of US$1.45 billion, making it the 14th most successful movie of all time and the most successful movie directed by a woman (Statista 2024). Contested Barbie Despite her popularity, Barbie has been the subject of controversy. Original Barbie’s proportions have been criticised for promoting an unrealistic body image (Thong). Barbie’s appearance has received numerous critiques for “representing an unrealistic beauty standard through its former limited skin tone and hair combination” (Lopez). The original Barbie’s measurements, if scaled to life-size, would mean Barbie is unusually tall and has a slim figure, with a height of 5 feet 9 inches, a waist of just 18 inches, and hips of approximately 33 inches. Her bust would measure around 32 inches with an under-bust of 22 inches, and her shoulder width would be approximately 28 inches. Original Barbie’s legs, which are proportionally longer than an average human’s, would make up more than half her height (Thong). A 1996 Australian study scaled Barbie and Ken to adult sizes and compared this with the physical proportions of a range of women and men. They found that the likelihood of finding a man of comparable shape to Ken was 1 in 50. Barbie was more problematic. The chance of a woman being the same proportion as Barbie was 1 in 100,000 (Norton et al. 287). In 2011, The Huffington Post’s Galia Slayen built a life-sized Barbie based on Barbie’s body measurements for National Eating Disorder Awareness Week. Slayen concluded that “if Barbie was a real woman, she’d have to walk on all fours due to her proportions”. One report found that if Barbie’s measurements were those of a real woman her “bones would be so frail, it would be impossible for her to walk, and she would only have half a liver” (Golgowski). A 2006 study found that Barbie is a “possible cause” for young girls’ “body dissatisfaction”. In this study, 162 girls from age 5 to 8 were exposed to images of a thin doll (Barbie), a plus-size doll (US doll Emme, size 16), or no doll, and then completed assessments of body image. Girls exposed to Barbie reported “lower body esteem and greater desire for a thinner body shape than girls in the other exposure conditions”. The study concluded that “early exposure to dolls epitomizing an unrealistically thin body ideal may damage girls' body image, which would contribute to an increased risk of disordered eating and weight cycling” (Dittman and Halliwell 283). Another study in 2016 found that “exposure to Barbie” led to “higher thin-ideal internalization”, but found that Barbie had no “impact on body esteem or body dissatisfaction” (Rice et al. 142). In response to such criticism, Mattel slowly introduced a variety of Barbie dolls with more diverse body types, including tall, petite, and curvy models (Tamkin). These changes aim to reflect a broader range of beauty standards and promote a more positive body image. Barbie has always had to accommodate social norms. For this reason, Barbie always must have underpants, and has no nipples. One of the reasons why Ruth Handler’s husband Elliott (also a co-founder of Mattel) was initially against producing the Barbie doll was that she had breasts, reportedly saying mothers would not buy their daughters a doll with breasts (Gerber). Margot Robbie, on playing Barbie, told one news outlet that while Barbie is “sexualized”, she “should never be sexy” (Aguirre). Early prototypes of Barbie made in Japan in the 1950s sexualised her body, leaving her to look like a prostitute. In response, Mattel hired film make-up artist Bud Westmore to redo Barbie’s face and hair with a softer look. Mattel also removed the nipples from the prototypes (Gerber). Barbie’s body and fashion have always seemed to “replicate history and show what was what was happening at the time” (Mowbray), and they also reflect how the female body is continually surveilled. Feminists have had a long history of criticism of Barbie, particularly her projection of the thin ideal. At the 1970 New York Women’s Strike for Equality, feminists shouted “I am not a Barbie doll!” Such debates exemplify the role and impact of toys in shaping and reforming societal norms and expectations. Even the more recent debates regarding the 2023 Barbie film show that Barbie is still a “lightning rod for the messy, knotty contradictions of feminism, sexism, misogyny and body image” (Chappet). Decades of criticism about Barbie, her meaning and influence, have left some to ask “Is Barbie a feminist icon, or a doll which props up the patriarchy?” Of course, she’s both, because “like all real women, Barbie has always been expected to conform to impossible standards” (Chappet). Diversifying Barbie Over the decades Mattel has slowly changed Barbie’s body, including early versions of a black Barbie-like dolls in the 1960s and 1970s such as Francie, Christie, Julia, and Cara. However, it was not until 1980 that Mattel introduced the first black Barbie. African American fashion designer Kitty Black-Perkins, who worked for Mattel from 1971, was the principal designer for black Barbie, saying that “there was a need for the little Black girl to really have something she could play with that looked like her” (cited in Lafond). Black Barbie was marketed as She’s black! She’s beautiful! She’s dynamite! The following year, Asian Barbie was introduced. She was criticised for her nondescript country of origin and dressed in an “outfit that was a mishmash of Chinese, Korean and Japanese ethnic costumes” (Wong). More recently, the Asian Barbies were again criticised for portraying stereotypes, with a recent Asian Barbie dressed as a veterinarian caring for pandas, and Asian violinist Barbie with accompanying violin props, reflecting typical stereotypes of Asians in the US (Wong). In 2016, Mattel introduced a range of Barbie and Ken dolls with seven body types, including more curvy body shapes, 11 skin tones and 28 hairstyles (Siazon). In 2019, other Barbie body types appeared, with smaller busts, less defined waist, and more defined arms. The 2019 range also included Barbies with permanent physical disabilities, one using a wheelchair and one with a prosthetic leg (Siazon). Wheelchair Barbie comes with a wheelchair, and her body has 22 joints for body movement while sitting in the wheelchair. The Prosthetic Barbie comes with a prosthetic leg which can be removed, and was made in collaboration with Jordan Reeve, a 13-year-old disability activist born without a left forearm. In 2020, a No Hair Barbie and a Barbie with the skin condition vitiligo were introduced, and in 2022, Hearing Aid Barbie was also launched. In 2022 other changes were made to Barbie’s and Ken’s bodies, with bodies that became fuller figured and Kens with smaller chests and less masculine body shapes (Dolan). Down Syndrome Barbie was released in 2023, designed in collaboration with the US National Down Syndrome Society to ensure accurate representation. By 2024, Barbie dolls come in 35 skin tones, 97 hairstyles, and nine body types (Mattel 2024). Spanning hundreds of iterations, today the Barbie doll is no longer a homogenous, blond-haired, blue-eyed toy, but rather an evolving social phenomenon, adapting with the times and the markets Mattel expands into. With dolls of numerous ethnicities and body types, Barbie has also embraced inclusivity, catering to the plethora of different consumers across the world (Green and Gellene 1989). Career Barbie While not dismissing Barbie’s problematic place in feminist, gender and racial critiques, Barbie has always been a social influencer. Her early years were marked by a variety of makeovers and modernisations, as have recent changes to Barbie’s body, reflecting the changing social norms of the times. Stereotypical Barbie had her first major makeover in 1961, with her ponytail swapped for a short ‘Bubble Bob’ hairstyle inspired by Jackie Kennedy and Marilyn Monroe, reflecting women’s emerging social independence (Foreman). In the early 1970s, Barbie’s original demure face with averted eyes was replaced by a new one that “depicted confidence and a forward-facing gaze” (Vander Bent). Her “soft look” was a departure from the mature image of the original 1959 Barbie (Lafond). The ‘soft look’ on Malibu Barbie with her newly sculpted face featured an open smile for the first time, as well as sun-tanned, make-up free skin and sun-kissed blonde hair. The disappearance of Barbie’s coy, sideways glance and the introduction of forward-looking eyes was a development “welcomed by feminists” (Ford). Barbie’s early makeovers, along with her fashion and accessories, including her homes, cars, and pets, contributed to shaping her image as a fashionable and independent woman. Barbie’s various careers and roles have been used to promote ideas of female empowerment. From astronaut to presidential candidate, Barbie has broken barriers in traditionally male-dominated fields. However, the effectiveness of these efforts in promoting female empowerment is a topic of debate. The post-war period in America saw a significant shift in the pattern of living, with a move from urban areas to the suburbs. This was facilitated by a robust post-war economy, favourable government policies like the GI Bill, and increasing urbanisation. The GI Bill played a crucial role by providing low-interest home loans to veterans, making home ownership accessible to a large segment of the population. It was a significant transformation of the American lifestyle and shaped the country’s socio-economic landscape. It is in this context that Barbie’s first Dreamhouse was introduced in the early 1960s, with its mid-century modern décor, hi-fi stereo, and slim-line furniture. This was at a time when most American women could not get a mortgage. Barbie got her first car in 1962, a peach-colored Austin-Healey 3000 MKII convertible, followed short afterwards by a Porsche 911. She has also owned a pink Jaguar XJS, a pink Mustang, a red Ferrari, and a Corvette. Barbie’s car choices of luxurious convertibles spoke to Barbie’s social and economic success. In 1998, Barbie became a NASCAR driver and also signed up to race in a Ferrari in the Formula 1. Barbie’s ‘I Can Be Anything’ range from 2008 was designed to draw kids playing with the dolls toward ambitious careers; one of those careers was as a race car driver (Southwell). While Barbie’s first job as a baby-sitter was not as glamourous or well-paying as her most of her other over 250 careers, it does reflect the cultural landscape Barbie was living in in the 1960s. Babysitter Barbie (1963) featured Barbie wearing a long, pink-striped skirt with ‘babysitter’ emblasoned along the hem and thick-framed glasses. She came with a baby in a crib, a telephone, bottles of soda, and a book. The book was called How to Lose Weight and had only two words of advice, ‘Don’t Eat’. Even though there was a backlash to the extreme dieting advice, Mattel included the book in the 1965 Slumber Party Barbie. Barbie wore pink silk pajamas with a matching robe and came prepared for her sleepover with toiletries, a mirror, the controversial diet book, and a set of scales permanently set at 110 pounds (approx. 50kg), which caused further backlash (Ford). Barbie’s early careers were those either acceptable or accessible to women of the era, such as the Fashion Designer Barbie (1960), Flight Attendant Barbie (1961), and Nurse Barbie (1962). However, in 1965 Barbie went into space, two years after cosmonaut Valentina Tereshkova became the first woman in space, and four years before the American moon landing. Barbie’s career stagnated in the 1970s, and she spends the decade being sports Barbie, perhaps as a response to her unpopularity among vocal second wave feminists and reflecting the economic downturn of the era. America’s shift to the right in the 1980s saw in the introduction of the Yuppie, the young urban professional who lived in the city, had a high-powered career, and was consumption-driven. More women were entering the workforce than ever before. Barbie also entered the workforce, spending less time doing the passive leisure of her earlier self (Ford). It also signals the beginning of neoliberalism in America, and a shift to individualism and the rise of the free market ethos. In 1985, Day-to-Night Barbie was sold as the first CEO Barbie who “could go from running the boardroom in her pink power suit to a fun night out on the town”. For Mattel she “celebrated the workplace evolution of the era and showed girls they could have it all”. But despite Barbie’s early careers, the focus was on her "emphasized femininity”, meaning that while she was now a career woman, her appearance and demeanor did not reflect her job. Astronaut Barbie (1985) is a good example of Barbie’s ‘emphasised femininity’ in how career Barbies were designed and dressed. Astronaut Barbie is clearly reflecting the fashion and culture trends of the 1980s by going into space in a “shiny, hot pink spacesuit”, comes with a second space outfit, a shiny “peplum miniskirt worn over silver leggings and knee-high pink boots” (Bertschi), and her hair is too big to fit into the helmet. A dark-skinned US Astronaut Barbie was released in 1994, which coincided with the start of the Shuttle-Mir Program, a collaboration between the US and Russia which between 1994 and 1998 would see seven American astronauts spend almost 1,000 days living in orbit with Russian cosmonauts on the Mir space station. Throughout the 1990s, Barbie increasingly takes on careers more typically considered to be male careers. But again, her femininity in design, dressing and packaging takes precedence over her career. Police Officer Barbie (1993), for example, has no gun or handcuffs. Instead, she comes with a "glittery evening dress" to wear to the awards dance where she will get the "Best Police Officer Award for her courageous acts in the community”. Police Office Barbie is pictured on the box "lov[ing] to teach safety tips to children". Barbie thus “feminizes, even maternalises, law enforcement” (Rogers 14). In 1992, Teen Talk Barbie was released. She had a voice box programmed to speak four distinct phrases out of a possible 270. She sold for US$25, and Mattel produced 350,000, expecting its popularity. The phrases included ‘I Love Shopping’ and ‘Math class is tough’. The phrase ‘Math class is tough’ was seen by many as reinforcing harmful stereotypes about girls and math. The National Council of American Teachers of Maths objected, as did the American Association of University Women (NYT 1992). In response to criticisms of the gendered representations of Barbie’s careers, Mattel have more recently featured Barbie in science and technology fields including Paleontologist Barbie (1996 and 2012), Computer Engineer Barbie (2010), Robotics Engineer Barbie (2018), Astrophysicist Barbie (2019), Wildlife Conservationist Barbie, Entomologist Barbie (2019), and Polar Marine Biologist Barbie (all in collaboration with National Geographic), Robotics Engineer Barbie (2018), Zoologist Barbie (2021), and Renewable Energy Barbie (2022), which go some way to providing representations that at least encompass the ideal that ‘Girls Can Do Anything’. Barbie over her lifetime has also taken on swimming, track and field, and has been a gymnast. Barbie was an Olympic gold medallist in the 1970s, with Mattel releasing four Barbie Olympians between 1975 and 1976, arguably cashing in on the 1976 Montreal Olympics. Gold Medal Barbie Doll Skier was dressed in a red, white, and blue ski suit completed with her gold medal. Gold Medal Barbie Doll is an Olympic swimmer wearing a red, white, and blue tricot swimsuit, and again wears an Olympic gold medal around her neck. The doll was also produced as a Canadian Olympian wearing a red and white swimsuit. Gold Medal Barbie Skater looks like Barbie Malibu and is dressed in a long-sleeved, pleated dress in red, white, and blue. The outfit included white ice skates and her gold medal. Mattel also made a Gold Medal P.J. Gymnast Doll who vaulted and somersaulted in a leotard of red, white, and blue tricot. She had a warm-up jacket with white sleeves, red cuffs, white slippers, and a gold medal. Mattel, as part of a licencing agreement with the International Olympic Committee, produced a range of toys for the 2020 Tokyo Olympics. The collection of five Barbies represented the new sports added to the 2020 Olympics: baseball and softball, sport climbing, karate, skateboarding, and surfing. Each Barbie was dressed in a sport-specific uniform and had a gold medal. Barbie Olympic Games Tokyo 2020 Surfer, for example, was dressed in a pink wetsuit top, with an orange surfboard and a Tokyo 2020 jacket. For the 2022 Winter Olympics and Paralympics, Mattel released a new collection of Barbie dolls featuring among others a para-skiing Barbie who sits on adaptive skis and comes with a championship medal (Douglas). As part of Mattel’s 2023 Barbie Career of the Year doll, the Women in Sports Barbie range shows Barbie in leadership roles in the sports industry, as manager, coach, referee, and sport reporter. General Manager Barbie wears a blue-and-white pinstripe suit accessorised with her staff pass and a smartphone. Coach Barbie has a pink megaphone, playbook, and wears a two-piece pink jacket and athletic shorts. Referee Barbie wears a headset and has a whistle. Sports Reporter Barbie wears a purple, geometric-patterned dress and carries a pink tablet and microphone (Jones). Political Barbie Barbie has run for president in every election year since 1992. The first President Barbie came with an American-themed dress for an inaugural ball and a red suit for her duties in the Oval Office. In 2016, Barbie released an all-female presidential ticket campaign set with a president and vice-president doll. The 2000 President Barbie doll wore a blue pantsuit and featured a short bob cut, red lipstick pearl necklace, and a red gown to change into, “presumably for President Barbie’s inaugural ball” (Lafond). This followed the introduction of UNICEF Ambassador Barbie in 1989. She is packaged as a member of the United States Committee for UNICEF (United Nations International Children’s Emergency Fund), which is mandated to provide humanitarian and development aid to children worldwide. Rather problematically, and again with a focus on her femininity rather than the importance of the organisation she represents, she wears a glittery white and blue full length ball gown with star patterning and a red sash. While some proceeds did go to the US Committee for UNICEF, the dressing and packaging featuring an American flag overshadows the career and its philanthropic message. The period signalled the end of the Cold War and was also the year the United States invaded Panama, resulting in a humanitarian disaster when US military forces attacked urban areas in order to overthrow the Noriega administration. Military Barbie Barbie has served in every US military branch (Sicard). Barbie joined the US army in 1989, wearing a female officer’s evening uniform, though with no sense of what she did. While it may be thought Barbie would increase female in interest in a military career, at the time more women were already enlisting that in any other period from the early 1970s to 2012 (Stillwell). Barbie rejoined the army for the 1990-1991 Gulf War, wearing a Desert Combat Uniform and the 101st Airborne "Screaming Eagle" patch, and serving as a medic. Barbie also joined the Air Force in 1990, three years before Jeannie Leavitt became the first female Air Force fighter pilot. Barbie wore a green flight suit and leather jacket, and gold-trimmed flight cap. She was a fighter pilot and in 1994, she joined the USAF aerial demonstration team, The Thunderbirds. Busy in the 1990s, she also enlisted in the US Navy wearing women's Navy whites. Marine Corps Barbie appeared in 1992, wearing service and conduct medals (Stillwell). All of Barbie’s uniforms were approved by the Pentagon (Military Women’s Memorial). The 2000 Paratrooper Barbie Special Edition was released with the packaging declaring “let’s make a support drop with first aid and food boxes”. She was dressed in undefined military attire which includes a helmet, dog tags, parachute, boots, and hairbrush. Barbie’s Influence In 2014, Barbie became a social media influencer with the launch of the @barbiestyle Instagram account, and in 2015, Barbie launched a vlog on YouTube to talk directly to girls about issues they face. The animated series features Barbie discussing a range of topics including depression, bullying, the health benefits of meditation, and how girls have a habit of apologising when they don’t have anything to be sorry about. The Official @Barbie YouTube channel has over eleven million global subscribers and 23 billion minutes of content watched, making Barbie the #1 girls’ brand on YouTube. Barbie apps average more than 7 million monthly active users and the Instagram count boasts over 2 million followers. The 2023 Barbie film really does attest to Barbie’s influence 70 years after her debut. Barbie, as this article has shown, is more than an influencer and more than a doll, if she ever really was only a doll. She is a popular culture icon, regardless of whether we love her or not. Barbie has sometimes been ahead of the game, and sometimes has been problematically represented, but she has always been influential. Her body, race, ability, careers, independence, and political aspirations have spoken different things to those who play with her. She is fiercely defended, strongly criticised, and shirks from neither. She is also liberating, empowering, straight, and queer. As the articles in this issue reflect, Barbie, it seems, really can be anything. Imagining and Interrogating Barbie in Popular Culture The feature article in this issue outlines how Australian Barbie fans in the 1960s expressed their creativity through the designing and making of their own wardrobes for the doll. Through examining articles from the Australian Women’s Weekly, Donna Lee Brien reveals this rich cultural engagement that was partly driven by thrift, and mostly by enjoyment. Eva Boesenberg examines the social and environmental effects of a plastic doll that is positioned as an ecological ambassador. While there is no doubt that climate change is one of our most pressing social issues, Boesenberg questions the motivations behind Barbie’s eco-crusade: is she an apt role-model to teach children the importance of environmental issues, or is this just a case of corporate greenwashing? Emma Caroll Hudson shifts the focus to entertainment, with an exploration of the marketing of the 2023 blockbuster film Barbie. Here she argues that the marketing campaign was highly successful, utilising a multi-faceted approach centred on fan participation. She highlights key components of the campaign to reveal valuable insights into how marketing can foster a cultural phenomenon. Revna Altiok’s article zooms in on the depiction of Ken in the 2023 film, revealing his characterisation to be that of a ‘manic pixie dream boy’ whose lack of identity propels him on a journey to self-discovery. This positioning, argues Altiok, pulls into focus social questions around gender dynamics and how progress can be truly achieved. Rachel Wang turns the spotlight to Asian identity within the Barbie world, revealing how from early iterations a vague ‘Oriental’ Barbie was accompanied by cultural stereotyping. Despite later, more nuanced interpretations of country-specific Asian dolls, problematic features remained embedded. This, Wang argues, positions Asian Barbies as the racial ‘other’. Kaela Joseph, Tanya Cook, and Alena Karkanias’s article examines how the 2023 Barbie film reflects different forms of fandom. Firstly, Joseph interrogates how the Kens’ patriarchal identity is expressed through acts of collective affirmational fandom. Here, individual fans legitimise their positions within the group by mastering and demonstrating their knowledge of popular culture phenomena. Joseph contrasts this with transformational fandom, which is based upon reimagining the source material to create new forms. The transformation of the titular character of the Barbie movie forms the basis of Eli S’s analysis. S examines how the metaphor of ‘unboxing’ the doll provides an avenue through which to understand Barbie’s metamorphosis from constrained doll to aware human as she journeys from the pink plastic Barbie Land to the Real World. Anna Temel turns her critical gaze to how the 2023 film attempts to reposition Barbie’s image away from gender stereotypes to a symbol of feminist empowerment. Director Greta Gerwig, Temel argues, critiques the ‘ideal woman’ and positions Barbie as a vehicle through which contemporary feminism and womanhood can be interrogated. Temel finds that this is not always successfully articulated in the depiction of Barbie in the film. The reading of the Barbie movie’s Barbie Land as an Asexual Utopia is the focus of Anna Maria Broussard’s article. Here Broussard draws the focus to the harmonious community of dolls who live without social expectations of sexuality. Barbie provides a popular culture reflection of the Asexual experience, expressed through Barbie’s rejection of a heteronormative relationship both in Barbie Land and the Real World. Completing this collection is Daisy McManaman’s article interrogating the multiple iterations of the doll’s embodied femininity. Incorporating an ethnographic study of the author’s relationship with the doll, McManaman uncovers that Barbie serves as a site of queer joy and a role model through which to enjoy and explore femininity and gender. These articles have been both intellectually stimulating to edit, and a joy. We hope you enjoy this collection that brings a new academic lens to the popular cultural phenomenon that is Barbie. References Aguirre, Abby. “Barbiemania! Margot Robbie Opens Up about the Movie Everyone’s Waiting For.” Vogue, 24 May 2023. 16 Mar. 2024 <https://www.vogue.com/article/margot-robbie-barbie-summer-cover-2023-interview>. Bertschi, Jenna. “Barbie: An Astronaut for the Ages.” Smithsonian National Air and Space Museum, 18 Jul. 2023. 11 Mar. 2024 <https://airandspace.si.edu/stories/editorial/barbie-astronaut-ages>. Blackmore, Erin. “Barbie’s Secret Sister Was a German Novelty Doll.” History.com, 14 Jul. 2023. 11 mar. 2024 <https://www.history.com/news/barbie-inspiration-bild-lilli>. 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