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Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p = .02 by quartile) and survival (p = .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.

Incidence of venous thromboembolism (VTE) varies across different regimens in newly diagnosed multiple myeloma (NDMM) patients. Limited data exist on the use of direct oral anticoagulants as thromboprophylaxis in the setting of haematologic malignancies, specifically multiple myeloma. In this retrospective study of 305 NDMM patients, VTE rates in those treated with carfilzomib, lenalidomide, dexamethasone (KRD) + aspirin (ASA), bortezomib, lenalidomide, dexamethasone (RVD) + ASA, and KRD + rivaroxaban were statistically significant, 16·1%, 4·8%, and 4·8%, respectively. The findings confirm a higher incidence of VTE when using KRD induction compared to RVD induction and reveal that the use of low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.

PURPOSE OF REVIEW: Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a significant number of patients still progress on current available therapies. Here we review treatment modalities used to target BCMA in the treatment of MM, specifically antibody-drug conjugates (ADC), bispecific antibody constructs, and chimeric antigen receptor (CAR) modified T-cell therapies. We will provide an overview of therapies from these classes that have presented or published clinical data, as well as data on mechanisms of resistance to these novel agents. RECENT FINDINGS: Clinical trials exploring different BCMA-targeting modalities to treat multiple myeloma are underway and demonstrate promising results. In relapsed/refractory multiple myeloma, anti-BCMA ADCs and bispecific antibody constructs are showing impressive efficacy with manageable side effect profiles. In parallel, adoptive cellular therapy have induced dramatic durable responses in multiply relapsed and refractory myeloma patients. SUMMARY: Therapeutic approaches targeting BCMA hold significant potential in the management of multiple myeloma and will soon be incorporated in combination with current standard therapies to improve outcomes for patients with multiple myeloma. In addition, novel approaches are being evaluated to overcome resistance mechanisms to anti-BCMA therapies.

Introduction The current standard to assess chemotherapy tolerability and health related quality of life (HRQOL) relies on patient (PT) self-reporting. Continuous passive monitoring using mobile wearable devices can objectively aggregate and monitor "activity" over long periods of time without potential reporting bias. Due to the nature of the disease, multiple myeloma (MM) PTs are often ridden with bone disease and pain, thereby limiting activity while impacting HRQOL. In this prospective clinical study, we enrolled 40 newly diagnosed MM PTs and remotely monitored their activity (steps/24 hrs) while administering electronic PT reported outcome (ePRO) surveys at baseline (BL) and through induction therapy. The study aim was to assess whether wearables can establish patterns of physical activity while receiving therapy and how these activity bioprofiles correlate with HRQOL outcomes. Methods PTs were eligible for the study if they had newly diagnosed MM, not having received any systemic therapy, and if they owned a device (iOS or Android) compatible with Garmin Vivofit® (GV) device. Regimens were determined by treating physicians. PTs were given GV® devices and asked to download a GV® application and Medidata ePRO app. PTs were assigned to either Cohort A - PTs VGPR Responders (Res) vs. < PR Sub-responders (Sub-Res). Associations between physical activity measurements, QLQC30 and MY20 scores, and time from the start of treatment were estimated using a linear mixed model with a random intercept. A Wald-test was used to compute p-values for the significance of association. Results Between Feb 2017 and Sep 2019, 40 PTs (21 M and 19 F) were enrolled with 20 in cohort A (mean 54 yrs, 41-64) and 20 in cohort B (mean 71 yrs, 65-82). Treatment regimens included KRd 14(35%), RVd 12(30%), Dara-KRd 8(20%), VCd 5(12.5%), and Rd 1(2.5%). Activity bioprofiles were compiled among 24/40(60%) PTs: 14 full sets (7/7 cycle periods) and 10 partial sets [1 PT - 2/7(28.5%) cycle periods; 2 PTs - 3/7(42.8%); 1 PT - 4/7(57.1%); 2 PTs- 5/7(71.4%); 4 PTs 6/7(85.7%)]. PT activity increased over time by 179 steps/24 hrs per cycle (p=0.001, 95% CI: 68-289) for the entire study. Mean activity pre- vs. post- for cohort A was 6,041 vs. 7,266 steps/24 hrs, respectively with an increase of 116 steps/24 hrs per cycle (p=0.2, 95% CI: -60-293), and for cohort B 2,984 steps/24 hrs vs. 5,007 steps/24 hrs with an increase of 260 steps/24 hrs per cycle (p PTs reported improvement in ePRO MY20 disease burden symptoms over time, -1.6 score/cycle (p=0.001, 95% CI -2.6- -0.6). There was no observed change in time over self-body image (p=0.5), while PTs reported worsening of future perspective, -2.8 score/cycle (p Conclusion Our study demonstrates that passive wearable monitoring can successfully capture PT activity in newly diagnosed MM, and that PT activity bioprofiles correlate well with traditional HRQOL measurements. Of clinical relevance, our study shows that activity bioprofiles improve with therapy, regardless of depth of response. Significant gains in activity were attributable to the older cohort, suggesting a greater functional impact at BL in this population. Future studies are needed to elucidate how mobile wearables may aid the clinician in passive monitoring of therapy tolerability in the outpatient setting. Figure 1 Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Mailankody:PleXus Communications: Honoraria; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Allogene Therapeutics: Research Funding; Janssen Oncology: Research Funding; Takeda Oncology: Research Funding; Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Lesokhin:Takeda: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Genentech: Research Funding. Lendvai:Janssen: Current Employment. Smith:Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy; Precision Biosciences: Consultancy. Hultcrantz:Daiichi Sankyo: Research Funding; GSK: Research Funding; Intellisphere LLC: Consultancy; Amgen: Research Funding. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Giralt:Jazz: Research Funding; Kite: Research Funding; Actinuum: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Quintiles: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Celgene: Research Funding; Adienne: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.

Background and Scientific Rationale Solitary plasmacytoma of the bone (SPB) is a rare entity representing 5% of all plasma cell dyscrasias. SPB treated with radiation therapy (RT) has a 10% risk of progression to multiple myeloma (MM) over 3 years if there is no marrow involvement, whereas there is a 60% chance of progression over 3 years in patients with minimal marrow involvement. Median time to progression in the latter group is 26 months. Presently, despite mounting evidence of a significant risk of progression to MM, there is no FDA-approved therapy and patients are usually treated with localized RT. This is an area of unmet need. A similar opportunity exists in the setting of MM patients relapsing with localized disease amenable to RT. This group of patients may not immediately require long-term systemic therapy especially if RT combined with epigenetic modulation and lenalidomide results in therapeutically relevant immune responses. A few studies combining lenalidomide and azacitidine have shown responses even in a lenalidomide refractory population with upregulation of cancer testis antigen (CTA) as well as CTA specific T cell responses (Table 1). These synergistic mechanisms focus on: 1) manipulating antigen expression and enhancing antigen presentation (both neoantigens and cancer testis antigens) with oral azacitidine (CC-486), and 2) augmentation of antigen specific immune responses via increased IL2 production leading to an increase in the proliferation of T cells with lenalidomide. This combination with RT would serve to inflame the tumor microenvironment and potentially lead to therapeutically active systemic immune responses via an abscopal effect. Study Design and Methods This is an open-label, single center, single-arm study of CC-486, lenalidomide plus RT, which will enroll a total of 20 patients in two cohorts. Clinical trial registry number NCT04174196, actively recruiting. Study population and inclusion criteria Each cohort will enroll ten patients - Cohort 1: i) Histologically confirmed newly diagnosed solitary plasmacytoma of the bone or lytic bone lesion ii) Minimal marrow involvement (Detectable clonal bone marrow (BM) plasma cells by multicolor flow cytometry and ≤ 10% clonal plasma cells in a BM biopsy by immunohistochemistry, morphology, or flow cytometry) iii) Secretory M protein < 3 g/dL Cohort 2: i) Relapsed multiple myeloma with plasmacytomas appropriate for RT on imaging ii) Relapsed (reappearance of M-spike/serum FLC) or progressive myeloma defined by a 25% increase from nadir in M-spike or involved serum FLC on 2 separate measurements; or with BM involvement by clonal plasma cells detectable by IHC iii) Any prior number of therapies is permitted, including prior RT iv) Allogeneic transplant patients are permitted Statistical methods We estimate the historical rate of stringent complete response (sCR) is approximately 5% (based on the rate for newly diagnosed myeloma with lenalidomide and dexamethasone on the MAIA study of 7.3% and for relapsed myeloma with Rd based on the POLLUX study of 4.6%). The primary endpoint of the study will be reported separately for the two cohorts. With 10 patients in each cohort, the maximum half-width of the exact 95% confidence interval for the response rate is +/- 0.31. A sCR rate of ≥20% would be considered promising for either cohort. Study treatment In the study, patients will be treated with CC-486 100 mg on day 1-21 and lenalidomide 25 mg on day 1-21 for 6 cycles. RT to the plasmacytoma will be initiated after cycle 2. Total dose may vary between 30-50 Gy (45-50 Gy for cohort 1) based on clinical judgement. (Figure 1) Endpoints Primary To provide preliminary efficacy data based on the rate of sCR by 2016 IMWG Criteria on post-treatment BM biopsy and aspirate specimens with no new lesions by PET. Secondary - To assess the safety of this combination. - To estimate the progression free survival and overall survival Exploratory - To evaluate antigen expression at the tumor site pre and post RT - To further characterize the antigen specific T cell response pre and post RT at the tumor site - To assess changes in epigenetic marks - To assess changes in the tumor microenvironment Disclosures Shah: Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Allogene Therapeutics: Research Funding; Janssen Oncology: Research Funding; Takeda Oncology: Research Funding; PleXus Communications: Honoraria; Physician Education Resource: Honoraria. Korde:Astra Zeneca: Other: Advisory Board; Amgen: Research Funding. Hultcrantz:GSK: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Smith:Precision Biosciences: Consultancy; Fate Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Dahi:Kite: Consultancy. Chung:Genentech: Research Funding. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Barker:Elekta: Research Funding; Amgen: Research Funding; Alpha Tau Medical: Other: Travel expenses, Research Funding; Merck: Research Funding. Giralt:KITE: Consultancy; MILTENYI: Consultancy, Research Funding; OMEROS: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other; Glenmark: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Lesokhin:Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Serametrix Inc.: Patents & Royalties. OffLabel Disclosure: CC-486 is an is an oral hypomethylating agent that has been studied in acute myeloid leukemia. This study combines CC-486 with lenalidomide and radiation therapy in plasma cell disorders.

Background Despite major advances in multiple myeloma (MM) therapy, most patients relapse after primary treatment. We present the interim analysis of a phase II multicenter trial evaluating the efficacy of daratumumab, carfilzomib (27 mg/m2 twice weekly), lenalidomide, & dexamethasone (Dara-KRD) with high-dose melphalan and autologous hematopoietic cell transplantation (AHCT) in patients after 1-3 prior lines to induce a complete response and provide patients a 2nd chance at long term disease control. Methods Patients received 4 cycles of Dara-KRD followed by AHCT and 4 additional cycles of Dara-KRD followed by maintenance at investigator discretion with a primary endpoint of best overall response by the end of cycle 8. Using a Simon’s two-stage optimal design, 7/22 patients need to achieve a CR to continue. Patient reported outcomes were monitored monthly using the MDASI-MM and NCI PRO-CTCAE. Data cutoff was 7/15/21. Results Between 7/2018 and 7/2020, 23 patients enrolled with 22 evaluable for interim analysis (one did not complete one cycle of treatment and was replaced). Patients had a median age of 65 (range 29-73), with 68% male, 64% white, and 18% black. Time from initial MM diagnosis to enrollment was a median of 4.4 years (range 0.4 -10.6). At initial diagnosis, 36% of patients had ISS stage I disease and 31% had unknown ISS staging. High risk cytogenetics were seen in 36%, with 2 patients having del17p, 2 t(4;14), 1 t(14;16), and 4 gain 1q. Eight-six percent had 1 line of treatment before enrollment with no patients having prior daratumumab, 14% receiving prior carfilzomib, and 86% having had a prior AHCT a median of 3.6 years (range 0.8-9.3) prior to enrollment. Eighty-two percent underwent AHCT and 59% completed all study treatments. Responses deepened post-AHCT prior to the second 4 cycles of Dara-KRD in most cases. Best overall response on study was a CR in 45% (10/22), >VGPR in 77%, and >PR in 82%. Three patients have died, 1 from infection during the pre-HCT cycles and 2 from disease progression. Conclusion Dara-KRD with salvage AHCT induced high overall response rates, meeting the pre-specified cutoff for promising results. Enrollment is ongoing for the second stage of the study using subcutaneous daratumumab and weekly carfilzomib. Full interim analysis and patient reported outcomes will be presented.

Background Plasma cell disorders (PCDs) are chronic incurable conditions with an opportunity to positively impact outcomes with nutritional changes. Epidemiologic studies show that inflammatory/insulinemic diets are linked to PCDs (Lee IJC 2020), while vegetarians/vegans have a reduced risk (Key AJCN 2014). MGUS/SMM present a unique opportunity for early intervention, given the standard of care is observation. Though patients often inquire about the role of nutrition and whether they should alter habits to eat healthfully, their oncologists are frequently not prepared to address these concerns. The purpose of this survey was to provide insights into patient nutrition perceptions/practices and identify areas for further research. Methods We utilized HealthTree® Cure Hub (HealthTree® Foundation, Lehi, Utah, USA) and invited participants with PCDs to answer questions pertaining to their diet/nutrition and related experience with their oncologist in an online survey. De-identified aggregated responses were reviewed. Results Of 421 participants, 82% reported having dietary questions post-diagnosis, yet 23% stated this was not addressed by their oncologists despite asking. Among those who discussed it with their oncologist, 50% received no specific advice or were recommended a ‘balanced diet’ lacking details. Of the participants that received clear guidance from their oncologists, 88% attempted to follow it, reflecting the positive influence their oncologists can have. Lack of knowledge/conflicting advice were barriers to change for 23%. Although the American Institute of Cancer Research (AICR) has published dietary guidelines, only 34% were aware of them. Patients also more frequently reported following a healthier diet after diagnosis – 75% pre-diagnosis vs 88% post-diagnosis. 78% patients with unhealthy diets pre-diagnosis improved their diet post-diagnosis and 7% with healthy diets pre-diagnosis worsened their diet post-diagnosis. Post-diagnosis, more patients reported consuming whole fruits and vegetables ≥1 times/day and whole grains and seafood ≥3 times/week. Post-diagnosis dietary changes were based on online/media information and advice from non-medical friends in 47%, compared to advice from PCPs/oncologists/nutritionists in 22%. Conclusions Patients with PCDs are interested in dietary advice and make dietary changes when faced with a cancer diagnosis. Most patients currently receive this advice from non-medical sources and report barriers related to lack of consistent information. Oncologists who provide clear guidance can positively impact dietary changes among patients. Our results reflect a missed opportunity between patients’ need for dietary advice and the potential for oncologists to provide helpful counsel. Our findings highlight a need for further research into standardized guideline (AICR) implementation as well as for the development of PCD-specific guidelines. Further disease focused dietary studies are needed to fill this gap.

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma.In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug.Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease.Memorial Sloan Kettering and Celgene.

Background and Scientific Rationale Lenalidomide maintenance after autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) patients has demonstrated an improved progression free survival (PFS) and overall survival (OS) when compared to placebo or observation in a meta-analysis (McCarthy et al. JCO 2017). Despite these improvements, patients on maintenance had higher rates of second primary malignancy and discontinuation due to treatment-emergent adverse events which may lead to decreased quality of life (QoL). Most MM patients are treated with lenalidomide maintenance in the absence of great alternatives. Thus, there is an unmet clinical need to develop alternative maintenance strategies. Daratumumab is well tolerated and effective in MM, with many studies continuing daratumumab as maintenance until disease progression. The proposed study seeks to further investigate and directly compare patient reported QoL between maintenance lenalidomide and daratumumab. Study Design and Methods This is an open-label single-center randomized pilot study of daratumumab versus lenalidomide maintenance in 100 newly diagnosed MM patients (Figure). Clinical trial registry number : NCT04497961, actively recruiting. Study population A total of 100 patients will be enrolled, randomized 1:1 to each arm (50 patients per arm). Randomization for enrollment will be stratified by patient age ( Inclusion criteria Newly diagnosed MM treated with combination therapy with or without ASCT Documentation of a very good partial response or better.Enrollment within 6 months of completing initial combination therapy.Enrollment following minimum 100-day washout per standard guidelines in ASCT recipients.ECOG performance status ≤ 2. Exclusion criteria Progressive or refractory MM.History of disease refractory to lenalidomide or daratumumab.History of prior anti-myeloma therapy for smoldering MM.Currently receiving other investigational agents to treat MM. Study treatment The length of therapy on both arms is 36 cycles of 28 days (~3 years), or until disease progression or unacceptable toxicity. Subjects under the lenalidomide arm will be treated with a maintenance dose of lenalidomide 10mg per day on days 1 to 21 of each cycle. Subjects under the daratumumab arm will be treated with a standard subcutaneous dose of 1800mg weekly in cycles 1 & 2, followed by every 2 weeks in cycles 3-6 and every 4 weeks cycles 7-36. Study assessments Subjects will complete three validated questionnaires - EORTC QLQ-C30 (general QOL in cancer patients), EORTC QLQ-MY20 (QOL in MM patients) and PRO-CTCAE (adverse events). These will be collected at baseline, day 1 of cycle 2, every cycle day 1 thereafter, at study/therapy discontinuation, and at 1-month post therapy follow-up. The GHS score will be calculated based on questions from the EORTC QLQ-C30. Endpoints Primary To compare differences in GHS scores between patients receiving lenalidomide versus daratumumab maintenance Secondary To explore differences in EORTC QLQ-C30, EORTC QLQ-MY20 and PRO-CTCAE scoresTo compare CTCAE adverse eventsTo evaluate differences in PFS and OSTo estimate differences in minimal residual disease statusTo explore the association between minimal residual disease status and clinical outcomes Exploratory To compare minimal residual disease techniques of multi-parametric flow with next-generation sequencing and mass spectrometryTo assess differences in T cell, NKT, NK cell subtypesTo explore associations between disease biology and clinical outcomes using genomic sequencing.To assess changes in the stool microbiome Statistical methods This protocol is a randomized pilot study to estimate the difference in the global health status for patients receiving lenalidomide maintenance to patients receiving daratumumab maintenance. The primary endpoint is the GHS from EORTC QLQ-C30. The primary analysis will be performed using a linear mixed effects model. The randomization stratification factors will be included as covariates in the regression model. The primary endpoint evaluation will use all GHS available up until the final evaluation at 36 cycles. Figure 1 Figure 1. Disclosures Shah: Celgene/BMS: Research Funding; Janssen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Evicore: Consultancy; Legend Biotech: Consultancy; Plexus Communications: Honoraria; Jansen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Takeda Oncology: Research Funding. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Intellisphere LLC: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Shah: Janssen: Research Funding; Amgen: Research Funding. Giralt: Actinnum: Membership on an entity's Board of Directors or advisory committees; SANOFI: 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; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Lesokhin: Behringer Ingelheim: Honoraria; bristol myers squibb: Research Funding; pfizer: Consultancy, Research Funding; Serametrix, Inc: Patents & Royalties; Trillium Therapeutics: Consultancy; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Landgren: Amgen: Honoraria; Janssen: Other: IDMC; Amgen: Research Funding; Janssen: Research Funding; Janssen: Honoraria; Celgene: Research Funding; Takeda: Other: IDMC; GSK: Honoraria.

Introduction: Treatment combinations involving CD38 targeted monoclonal antibodies have significantly prolonged the median duration and depth of response in myeloma (MM), reflected in minimal residual disease-negativity (MRD-) rates of over 70% in newly diagnosed patients (Landgren et al. JAMA Onc 2021). Key to improving our understanding of treatment failures is the combined use of single cell analysis of the microenvironment with genome wide assessment of tumor genetics to decipher the mechanisms of disease resistance. Methods: We isolated malignant plasma cells from bone marrow (BM) samples using CD138+magnetic or flow (CD38, CD138, and CD45) sorting from 60 newly diagnosed MM patients treated with KRd with daratumumab (D-KRd n=46; NCT03290950) and without daratumumab combination therapy (KRd, n=14; NCT01402284). Fifty-five baseline samples underwent whole genome sequencing (WGS), median coverage of 80x using somatic DNA as a normal comparator. The BM cellular content of 22 patients (44 samples-5 failed) treated with D-KRd (10 MRD+ and 12 MRD-) underwent 5'single cell RNA-sequencing with an additional capture of the TCR and surface protein markers (CITEseq) to interrogate the single cell composition of the immune microenvironment at baseline (T1, n=20) and at the end of induction (T2, n=19). Paired (T1/T2) single-cell data were obtained in 17 patients and paired WGS and single cell data (T1) were available in 15 patients. MRD-, sustained MRD- (defined as two MRD- results, the first at the end of the induction (T2) and the subsequent at the first year of follow-up (T3)) and progression/loss of MRD- were used as clinical endpoints for this study. Results: After a median follow up of 29 months, 36 (54%) patients achieved MRD-; 34 (51%) had sustained MRD- >1 year after completion of combination therapy. Overall, 10 (15%) patients had clinical progression and two conversions from MRD- to MRD+. A comprehensive catalogue of MM-genomic events associated with these three clinical endpoints was defined. Deletion (del) 13, biallelic loss CYLD, del XBP1, del 20q13.12 (CD40), and 8q gains were associated with MRD+ and failure to achieve sustained MRD-. Presence of del RPL5 and multiple chromothripsis events significantly correlated with early progression and loss of MRD-. Interestingly, structural variants (SV) involving IKFZ3 were seen in all three negative clinical endpoints (p We interrogated the BM microenvironment at baseline and correlated its composition with the tumor genomic architecture. Across 15 evaluable patients, del XBP1 were associated with fewer memory B-cells (p=0.03), naïve B-cell (p=0.01) and dendritic cells (p=0.03) compared to the wild type. Also, low dendritic cell at baseline cases were observed in patients with del 20q13.12 (CD40) (p=0.03). Interestingly, low level of plasmacytoid dendritic cells at baseline was associated with failure to achieve MRD- and sustained MRD-. Patients with 6p24 amplification showed a reduced number of CD8 effectors 1 and 2 (p When comparing baseline (T1) and end of induction (T2), significant differences were seen between sustained MRD+ and MRD-. We identified significantly depleted NK, and naïve and memory B-cell after D-KRd MRD- patients had significantly more CD14+ monocytes both at T1 and T2 than their MRD+ counterparts (Fig. 1). Differential expression suggests that inflammatory response genes including IL1B are upregulated in the absence of sustained MRD- whereas genes implicated in IL2, IL6, and IFNα response as well as adipocyte differentiation are associated with sustained MRD response. Conclusion: We show, for the first time, evidence of complex interplay between MM tumor genetics and the microenvironment in the context of D-KRd treated patients. Our results highlight the importance of genomic-based mechanisms in the persistence of disease (IKZF3, XBP1) as well as heterogeneity in the composition of the BM microenvironment, with the monocytes pointing towards the importance of inflammation. Figure 1 Figure 1. Disclosures Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Jansen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Bristol Myers Squibb/Juno: Research Funding; Legend Biotech: Consultancy; Takeda Oncology: Research Funding; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Evicore: Consultancy. Hultcrantz: Intellisphere LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Scordo: Omeros Corporation: Consultancy; i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah: Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Giralt: SANOFI: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Dogan: Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Peer View: Honoraria. Lesokhin: Behringer Ingelheim: Honoraria; pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; Genetech: Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties. Davies: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Korde: Amgen: Research Funding; Medimmune: Membership on an entity's Board of Directors or advisory committees. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Landgren: Janssen: Other: IDMC; Celgene: Research Funding; Amgen: Honoraria; Janssen: Research Funding; Janssen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria.

Introduction Belantamab mafodotin is an antibody drug conjugate targeting B-cell maturation antigen (BCMA) on plasma cells and was the first BCMA-targeted drug approved by the FDA. Single agent effect was around 31-34% in a recent phase II study (Lonial et al, Lancet Oncology 2020). Side effects, including keratopathy and reduced visual acuity, necessitate dose reduction and dose delays that may limit efficacy. Patients enrolled on clinical trials, however, often do not reflect a real-world population due to eligibility criteria that limit comorbidities and include wash-out periods not typical of clinical practice. The aim of this study was to assess response rates, dose modifications, and frequency of ocular adverse events in patients treated with belantamab mafodotin in a real-world setting. Methods All patients treated with commercial drug belantamab mafodotin at Memorial Sloan Kettering Cancer Center since October 2020 were included in the study. Descriptive statistics were used to assess patient characteristics, response rates, and rate of adverse events. Results Forty-two relapsed/refractory multiple myeloma patients were treated with belantamab mafodotin between October 2020 and the data cut off July 2021, including 55% (N=23) women; median age was 67 years. Twelve patients had been included in the Expanded Access Program with belantamab mafodotin prior to transitioning to commercial drug. Thirty patients (71%) had high risk cytogenetics, including gain 1q, t(4;14), t(14;16), t(14;20), complex karyotype, and MYC-translocations. Patients had been treated with a median of 7 (range 4-14) prior lines of therapy. All patients had received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Eleven patients had received a BCMA-targeted agent in clinical trials, including bi-specific antibodies, chimeric antigen receptor (CAR) T cells, and one patient had received prior trial therapy with belantamab mafodotin. Patients received a median of 3 cycles (range 1-17) of belantamab mafodotin. The majority, 95% (N=40) as single agent, while two patients were treated with belantamab mafodotin in combination with other standard myeloma treatments. The overall response rate (ORR) in all patients was 43%; 18/42 patients. Of these, 7 achieved a partial response (PR); 5 patients achieved a very good partial response (VGPR), 4 patients achieved a complete response (CR) and 1 patient achieved a stringent CR (Table 1). Median duration of response for patients in the ORR cohort was 11 months (95% confidence interval: 9.1-not reached). Three patients achieved a minimal response (MR), 6 patients had stable disease (SD), and 1 patient was not evaluable for response assessment. After a median follow up of 7.5 months, 14 patients had progressive disease and 10 patients had died. Sixteen patients continued on belantamab mafodotin therapy at the time of data cutoff, July 31 st 2021. In a separate analysis of patients not included in the Expanded Access Program, the ORR was 33%; 5 achieved a PR, 4 patients VGPR, 1 patient CR. Two patients achieved a MR, 3 patients had SD, and 14 patients had progressive disease. Twenty-seven patients (64%) had any grade of ocular toxicity on ophthalmology exam. Using the Keratopathy and Visual Acuity (KVA) scale, 12 patients had grade 1 keratopathy, 7 had grade 2, and 8 had grade 3 keratopathy. Fourteen patients had presence of corneal microcysts. Eighteen patients experienced a decline in best corrected visual acuity (BCVA); 10 patients had grade 1, 5 had grade 2, and 3 patients had grade 3 decline in BCVA. The dose of belantamab mafodotin was reduced from the starting dose of 2.5 mg/kg to 1.92 mg/kg in 17 patients: 16 patients due to ocular toxicity and 1 patient due to baseline cytopenia. Additionally, one or more doses were delayed in 9 patients due to keratopathy; the majority of patients (N=8) were able to continue therapy with maintained response on a lower dose after the delay. Conclusion In this heavily pre-treated multiple myeloma population, the ORR was 33-43% which is similar or better than reported in a recent phase II study. The rate of ocular toxicity (64% keratopathy) was also comparable to previous reports. These data demonstrate encouraging results for belantamab mafodotin treatment in the real-world setting with responses and toxicities comparable to clinical trial subjects. Additional patients and updated follow up will be reported at the meeting. Figure 1 Figure 1. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Peterson: GlaxoSmithKline: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Evicore: Consultancy; Legend Biotech: Consultancy. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker. Landgren: Celgene: Research Funding; Janssen: Other: IDMC; Janssen: Research Funding; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Giralt: CELGENE: 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; SANOFI: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Lesokhin: Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria; bristol myers squibb: Research Funding; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; Serametrix, Inc: Patents & Royalties.

Background and Scientific Rationale: Multiple myeloma (MM) is often preceded by the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Obesity, low adiponectin levels, and diets high in inflammatory, insulinemic foods or lacking plant-based foods are known risk factors for the development of MGUS/SMM, as well as for progression to MM. Therefore, there is an opportunity to study a dietary intervention in cancer progression among patients with MGUS/SMM, for which the standard of care is observation even though some patients will eventually progress to MM. This is a pilot nutrition-based intervention study of a whole food, plant-based diet (WFPBD) in overweight and obese MGUS and SMM patients to enable weight loss, assess associated changes in disease biomarkers, epigenetics, and the gut microbiome. We expect that the findings will enable larger lifestyle-based studies of prevention and survivorship in plasma cell disorders. Study Design and Methods: This is a single-arm, single-center pilot study of a WFPBD for 12 weeks and nutrition counseling for 24 weeks which will enroll 20 patients (Figure). Clinical trial registry number: NCT04920084, actively recruiting. Study Population and Inclusion Criteria i) SMM or MGUS ii) Body mass index ≥25 iii) Monoclonal protein spike ≥0.2 g/dL or abnormal free light chain ratio with increased level of the appropriate involved light chain iv) ECOG performance status 0-3 v) Willingness to comply with study-related procedures Statistical Methods: The average weight loss from baseline at 12 weeks will be reported as sample mean along with 95% confidence interval. Adherence will be estimated by sample proportion, with confidence intervals based on exact binomial distribution. Patients who have completed evaluation at 12 weeks will be evaluable for the weight loss outcome. All patients who have received at least one WFPBD intervention will be evaluable for adherence assessment. We will consider this intervention promising if 1) we detect weight loss at 12 weeks and 2) estimated adherence to the intervention is ≥70%. Study Treatment: For 12 weeks, patients will receive two premade meals per day, for lunch and dinner for 6 days per week, prepared and shipped by Plantable. The meals will have a low glycemic index and contain vegetables, whole grains, and plant-based fats that have undergone minimal processing. Detailed recommendations for snacks and breakfasts meeting the standard of a WFPBD will also be given to supplement their daily calorie needs with access to an online portal or phone application from Plantable which contains education materials and access to a coach daily for 24 weeks. Patients will receive dietary education and counseling from a research dietitian every 2 weeks for the 12-week intervention period. Endpoints: Primary: - To determine the feasibility of a WFPBD, as measured by weight loss and adherence at 12 weeks. Secondary: - To determine the feasibility of a WFPBD, as measured by safety, and quality of life. - To assess weight loss at 24, and 52 weeks. - To assess alterations in metabolic, and myeloma markers. Exploratory: - To assess alterations in T cell and plasma cell epigenetic markers - To assess alterations in the fecal microbiome - To assess changes in body composition as determined by PET imaging and correlate with weight change as well as disease markers. Figure 1 Figure 1. Disclosures Shah: Janssen: Research Funding; Celgene/BMS: Research Funding. Adintori: Vidafuel Inc.: Current holder of stock options in a privately-held company. Mailankody: Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Takeda Oncology: Research Funding; Allogene Therapeutics: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Curio Science LLC: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. D'Souza: Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JAZZ: 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; Actinnum: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees. Iyengar: Novartis: Consultancy; Seattle Genetics: Consultancy; Novartis: Research Funding. Landgren: Janssen: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. van den Brink: Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Wolters Kluwer: Patents & Royalties; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Notch Therapeutics: Honoraria; DKMS (nonprofit): Other; Pharmacyclics: Other; Kite Pharmaceuticals: Other; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; Nektar Therapeutics: Honoraria; Rheos: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Amgen: Honoraria; Therakos: Honoraria; WindMILTherapeutics: Honoraria; Juno Therapeutics: Other; Merck & Co, Inc: Honoraria; Frazier Healthcare Partners: Honoraria; Priothera: Research Funding; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Jazz Pharmaceuticals: Honoraria. Lesokhin: pfizer: Consultancy, Research Funding; Genetech: Research Funding; Trillium Therapeutics: Consultancy; Behringer Ingelheim: Honoraria; Serametrix, Inc: Patents & Royalties; bristol myers squibb: Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy.

Background: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (RRMM), but relapses are common. Additional treatment options with novel therapeutic targets or mechanisms of action are needed. Here we report on the safety and efficacy of MCARH109, the first-in-class G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) targeted CAR T cell therapy (Smith EL et al. Sci. Trans Med 2019) in RRMM including patients who relapsed post BCMA targeted CAR T cell therapy. Methods: This is a phase I first-in-human, dose escalation trial of MCARH109; patients received lymphodepleting chemotherapy with fludarabine 30 mg/m 2 daily and cyclophosphamide 300 mg/m 2 daily for 3 days followed by a single infusion of MCARH109. The trial followed a standard 3+3 design with the following dose cohorts to date: 25X10 6, 50X10 6, 150X10 6, 450X10 6 viable CAR + T cells. The primary objective is to assess safety of MCARH109; secondary objectives include anti-myeloma efficacy, expansion and persistence of MCARH109 using quantitative polymerase chain reaction (qPCR) on peripheral blood and bone marrow samples. Results: 18 patients with RRMM were enrolled and underwent apheresis between September 15, 2020 and July 14, 2021. 12 patients have completed MCARH109 infusion to date, with 6 patients currently undergoing manufacturing and pending treatment. Of the 12 patients treated, median age was 59 (37-76) years and patients received a median of 8 (4-14) lines of therapy. 11 (92%) were penta-exposed, all patients were triple refractory, and 7 (58%) had prior treatment with BCMA targeted therapy including 6 (50%) who received prior BCMA CAR T therapy. 3 (25%) patients had non-secretory myeloma and 6(50%) patients had extramedullary plasmacytoma at baseline. 11 (92%) were refractory to last line of therapy and 11 (92%) patients received bridging therapy after apheresis prior to MCARH109 infusion; all patients were refractory to bridging therapy. There were no dose limiting toxicities. Cytokine release syndrome (CRS) grade 1-3 occurred in 11 (92%) patients with only one patient with grade 3 event; 4 (25%) patients received tocilizumab and 1 (8%) received dexamethasone for the treatment of CRS (Table). There were no neurologic toxicities reported to date; 3 (25%) patients had grade 1 nail changes possibly related to MCARH109 (Table). As of July 28, 2021, all treated patients have been followed for at least 2 weeks (median: 13.0 weeks; range: 2.0-39.1 weeks) and 10 (83%) had at least a minimal response or better (2 responses unconfirmed): 2 minimal response, 3 partial response, 3 very good partial response, 2 stringent complete response (sCR). 5 (56%) of the first 9 patients were minimal residual disease (MRD) negative in the bone marrow by multicolor flow cytometry (sensitivity: 10 -5). 6 (100%) patients with prior BCMA CAR T therapy had a response with 2 patients achieving sCR. We also noted robust MCARH109 expansion in the peripheral blood using qPCR across the first 3 dose levels with available data (peak expansion vector copy number/mL, median: 404,467; range: 44,670- 3,560,000; Table). With a median follow-up of 13 weeks, 9 (75%) patients are progression free and followed without additional therapy. Conclusions: MCARH109 is the first-in-class GPRC5D targeted CAR T cell therapy for MM and has a very manageable safety profile with no serious or unexpected toxicities; this dose escalation study is ongoing with additional patients planned for treatment at higher doses. Efficacy is promising in heavily pre-treated RRMM, reflected in high rates of clinical response as well as MRD-negativity, including at doses as low as 25x10 6 CAR T cells. Clinically important, all 6 patients who relapsed after BCMA CAR T therapy responded to GPRC5D targeted CAR T therapy, including 2 patients who achieved sCR. Figure 1 Figure 1. Disclosures Mailankody: Allogene Therapeutics: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Takeda Oncology: Research Funding; Fate Therapeutics: Research Funding; Jansen Oncology: Research Funding; Evicore: Consultancy; Legend Biotech: Consultancy; Plexus Communications: Honoraria. Shah: Janssen: Research Funding; Celgene/BMS: Research Funding. Lesokhin: pfizer: Consultancy, Research Funding; Iteos: Consultancy; Trillium Therapeutics: Consultancy; Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; bristol myers squibb: Research Funding; Janssen: Honoraria, Research Funding; Behringer Ingelheim: Honoraria. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hassoun: Celgene, Takeda, Janssen: Research Funding. Hultcrantz: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Daiichi Sankyo: Research Funding; Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy. Shah: Amgen: Research Funding; Janssen: Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Roshal: Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services; Physicians' Education Resource: Other: Provision of services. Landgren: Janssen: Other: IDMC; Janssen: Honoraria; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Dogan: Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy. Giralt: Actinnum: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: 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; PFIZER: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Park: Autolus: Consultancy; Kite Pharma: Consultancy; PrecisionBio: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy; Novartis: Consultancy; Servier: Consultancy; Kura Oncology: Consultancy; Artiva: Consultancy; BMS: Consultancy. Rivière: FloDesign Sonics: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Smith: Eureka Therapeutics: Consultancy; Fate Therapeutics: Research Funding; Chimeric Therapeutics: Consultancy; Novarits: Consultancy; Sanofi: Patents & Royalties: GPRC5D antibody based therapies; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: CAR T cells for MM. OffLabel Disclosure: MCARH109 is an experimental GPRC5D targeted CART therapy

Introduction The incidence of lymphoproliferative disorders (including plasma cell disorders) (LPD) and diabetes mellitus (DM) increase with age. The metabolic link between DM and multiple myeloma (MM) or LPD has been researched in other epidemiologic studies with a small number of cases suggesting an increased risk (Dankner et al Am J Epi 2016, Castillo et al Blood 2012). However, this link has not yet been studied in patients with related disorders such as monoclonal gammopathy of unknown significance (MGUS), AL amyloidosis (AL), or Waldenstrom macroglobulinemia (WM). This is the first study to evaluate the risk of DM on LPD in a large Swedish population-based case-control study. Methods We conducted a large population-based matched case-control study to evaluate the impact of a preceding diagnosis of DM on the development of a LPD. We included all cases of MM, WM, AL and other LPs (OLP) in the nationwide Swedish Cancer Registry and cases of AL and chronic lymphocytic leukemia (CLL) in the Swedish patient registry from 1987-2013. MGUS was acquired from a network of oncology and hematology clinics in Sweden. OLPs included the diagnoses of Hodgkin lymphoma, non-Hodgkin lymphoma, CLL, T cell lymphoma and other lymphocytic leukemias. For each case, up to four controls matched by age, gender, and county of residence from the general population were included. Cases with no controls were excluded. Diagnoses of DM were acquired from the Swedish patient registry where they were coded using ICD 9 and 10 codes. Conditional logistic regression was then performed controlling for the matching variables estimating the odds ratio (OR) of each LPD for a diagnosis of DM before the diagnosis of the LPD. OR of each LPD for the diagnosis of DM greater than one year and less than one year prior to the diagnosis of LPD was also calculated. For MGUS cases, we also assessed the risk of progression to LPD. To avoid immortal time bias we include DM as a time dependent covariate in a Cox-model adjusting for age, sex, and year of MGUS diagnosis. All analyses were performed in R using the survival, and survminer packages. Results Patients with a diagnosis of MGUS (OR: 1.58; p 1 year prior to the diagnosis were included (Table 1). However, patients with (vs. without) a diagnosis of DM are not more likely to progress from MGUS to MM, WM, AL or OLP (HR 0.89; p=0.11) (Table 2). Discussion The strength of our study lies in its large sample size and the availability of 4 matched controls for each case. The diagnosis of DM is associated with an increased risk of MGUS, MM, AL and OLP. This risk is greatest for DM diagnosis in the year prior to LPD diagnosis. This may be due to DM induced hyperglycemia leading to epigenetic changes that increase the odds of developing/accelerating early stage cancer given that they may have prediabetes/undiagnosed DM for many years prior (Huang et al Diabetologia 2014). It is also plausible that patients with DM for >1 year have been on metformin which has been shown to have a protective effect and are less likely to progress suggesting the role of hyperglycemia in its progression (Chang et al Lancet Haematol 2015). Alternatively, patients are likely to have DM diagnosed in the year prior due to similar symptoms of fatigue or weight loss, or a detection bias due to increased physician visits and laboratory testing. This lack of increased progression from MGUS in DM may be explained by the small numbers of patients that progressed in this dataset or the inability to control for factors such as DM treatment. Some other limitations include the lack of granular information related to DM, body mass index as well as prognostic information for the LPD. Conclusions Although, smaller prior studies have suggested a link between DM and cancer including MM and LPD, this is the largest study in patients with LPD. This is also the first epidemiologic study establishing a link between DM and MGUS as well as AL. Research into further understanding this association would enable us to provide patients with better treatment options in the future. Disclosures Shah: Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Korde:Astra Zeneca: Other: Advisory Board; Amgen: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Background. Consensus from prior studies shows that the use of maintenance therapy after completion of combination therapy leads to longer progression-free survival (PFS) for patients with multiple myeloma with some studies showing an overall survival (OS) benefit. Currently, lenalidomide is the standard of care; however, there are limited published data on long-term use regarding ability to sustain minimal residual disease (MRD)-negativity and late toxicities. We were motivated to develop a study focusing on continuous, induction-agnostic lenalidomide maintenance with integration of clinical and correlative data. Here, we report formal results of this phase II study with focus on MRD dynamics and tolerability. Methods. This single arm, phase II trial enrolled 100 evaluable patients. Lenalidomide 10 mg is given days 1-21 on a 28-day cycle. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT at baseline, annually, at progression/end of study; blood work was done every 3 months. The study was statistically powered for the primary endpoint of PFS at 36 months. Correlative assays included MRD testing (10-color single-tube flow cytometry and IGHV sequencing; sensitivity ≤10-5), genomic characterization of detectable disease, and profiling of the bone marrow microenvironment performed on serially banked samples. Results. 100 evaluable patients were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-87 years) and median ECOG score 1 (range 0-1). Prior to enrollment, 22 (30%) patients had high-risk FISH/SNP signature defined as one or more of: 1q+, t(4;14), t(14;16), t(14;20), and 17p- and 48 patients had undergone autologous hematopoietic cell transplantation (AHCT). At abstract submission, median cycles delivered is 39 (range 9-62). 74% of patients have completed ³24 cycles and 55% have completed ³36 cycles. Overall PFS at 36 months was 77% (95% CI: 0.69-0.87) and PFS at 60 months was 63% (95% CI: 0.51-0.78). All patients had MRD testing at least once. 46% were MRD-negative at enrollment. 7 patients who were MRD+ at enrollment converted to MRD-negative. At median follow up 39.4 months (range 7-56 months), 20/100 patients (20%) have progressed. In consideration of the entire follow-up time from initial MRD-negativity, 44 (of 95 tested; 46%) and 37 (of 73 tested; 51%) achieved sustained MRD-negativity at 1 and 2 years, respectively. 22 patients were MRD-negative at 3 years (of 51 tested; 43%). Among those who sustained MRD-negativity for 2 years, with median follow-up of 19 months past the 2-year landmark analysis (max 120 months), there were no progression events. Age, induction regimen, and MRD status at enrollment were the only significant variables associated with PFS regardless of cytogenetic risk or transplant status. At 1 and 2-year landmark analysis, MRD-negativity superseded all else as the most significant factor associated with PFS with HR 0.06(p=0.0004) and HR 1/Inf (p=0.015), respectively. Toxicities (grade 3) included neutrophil count decrease (20%), hypertension (3%), diarrhea (3%), lung infection (2%), and maculo-papular rash (2%), and toxicities (grade 4) include sepsis (2%) and platelet count decrease (7%). The most common non-grade 3/4 toxicities were diarrhea (55%), fatigue (36%), and upper respiratory infection (30%). 7% developed a secondary malignancy on study: 3 adenocarcinoma, 1 squamous cell carcinoma, 1 CMML, 1 MDS, 1 ALL, and 1 glioblastoma. One evaluable patient required dose reduction due to toxicities/tolerability. Conclusions. This prospective study of continuous lenalidomide maintenance, agnostic to induction regimen or AHCT usage, was designed to evaluate the dynamics of MRD-negativity in relation to PFS. It expands on the importance of MRD as a predictor of outcome and illustrates how continuous maintenance therapy can deepen and sustain MRD-negative responses achieved with modern combination therapy. For this cohort, MRD-negativity at each landmark profoundly outweighed the impact of all other variates. Among those who had sustained MRD-negativity at 2 years (37% of the cohort), regardless of MRD status at enrollment, none have had progression events at median 43 months. Our results support cross-sectional MRD testing as a surrogate endpoint for drug approval, and the use of longitudinal MRD tracking in clinical management. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding. Smith:Precision Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:Sebia: Research Funding; The Binding Site: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:AbbVie: Consultancy; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding. Giralt:MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; KITE: Consultancy; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Karyopharma: Research Funding; Merck: Other; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria.

INTRODUCTION. Recent studies show that ~25% of newly diagnosed multiple myeloma patients treated with 8 cycles of bortezomib, lenalidomide and dexamethasone (VRd) achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Here, we present the final results from a phase 2 study using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone in combination with daratumumab (wKRd-D). The primary endpoint of our study was to demonstrate >60% and to target up to 80% MRD negativity rate with wKRd-D. METHODS. This phase II clinical trial is based on Simon's optimal two-stage design. The wKRd-D dosing schedule is as follows: 8 cycles of treatment; 28-day cycles with IV carfilzomib 20/56 mg/m2 days 1, 8, and 15; PO lenalidomide 25 mg days 1-21; PO/IV dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and IV daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; wKRd-D therapy resumed after collection to a total of 8 cycles wKRd-D. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allows detection of 1 myeloma cell in 100,000 cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The study is fully enrolled; between October 2018 and November 2019 a total of 41 evaluable patients were enrolled. Baseline characteristics include; median age 59 years (range 30-70 years); 25 (61%) females;16 (39%) males; 20 (49%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At submission of this abstract, 39 out of 41 patients have completed 8 cycles of treatment and end of treatment evaluations. Of those 39, 29 patients were MRD negative and 10 patients MRD positive. Two patients are pending end of treatment evaluations for response (currently receiving cycle 8 of wKRd-D). Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary endpoint at this analysis, we found 29/39 (74%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care KRd. At a median follow-up of 10 months, none of the MRD negative patients have progressed. Among 29 patients found to be MRD negative after 8 cycles of wKRd-D, 2 patients have been assessed for MRD at 1 year of follow-up and 2/2 (100%) show 1-year sustained MRD negativity. There are no deaths on the study. CONCLUSIONS. Among patients evaluable for the MRD primary endpoint, in the absence of an autologous bone marrow transplant, here we show a 29/39 (74%) MRD negativity rate among newly diagnosed multiple myeloma patients treated with wKRd-D, including weekly carfilzomib 56 mg/m2 dosing. At a median follow-up of 10 months, none of the MRD negative patients have progressed. These results compare favorably with previously published results with KRd, VRd, or VRd-D. Using optimized IV fluid management (250 ml saline prior to first dose of carfilzomib only, and thereafter no IV fluids) coupled with baseline work-up with EKG/echocardiograms for all patients, we did not observe excess rates of cardiovascular or renal adverse event. The wKRd-D dosing schedule has a total of 27 infusions and offers an attractive treatment modality for newly diagnosed multiple myeloma patients. Based on these promising results, a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care has been opened for enrollment. Disclosures Landgren: Adaptive: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; GSK: Research Funding; Daiichi Sankyo: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Janssen Oncology: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Allogene Therapeutics: Research Funding; PleXus Communications: Honoraria; Physician Education Resource: Honoraria; Takeda Oncology: Research Funding. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Shah:Celgene/BMS: Research Funding; Physicians Education Resource: Honoraria. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:The Binding Site: Research Funding; Sebia: Research Funding. Murata:Abbott Laboratories: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Giralt:CSL Behring: Research Funding; Jazz: Research Funding; Actinuum: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Quintiles: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Adienne: Research Funding; Kite: Research Funding. Korde:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Newly-Diagnosed Multiple Myeloma. These drugs are included in the current clinical and correlative Phase II study