ALBERT

Description: Background. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability. Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes. Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient. Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting. Disclosures Landgren: Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; 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: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC. Lesokhin:Genentech: Research Funding; GenMab: Consultancy, Honoraria; Janssen: Research Funding; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Landau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Description: INTRODUCTION. Bortezomib, lenalidomide and dexamethasone (VRd) is considered a standard of care combination therapy for newly diagnosed multiple myeloma patients. Prior studies show that ~25% of patients treated with 8 cycles of 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). Prior studies using 8 cycles of bi-weekly carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) combination therapy in newly diagnosed multiple myeloma show ~40% MRD negativity rates. We were motivated to develop a phase 2 study (total N=82) using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone (wKRd) in combination with daratumumab (wKRd-D). Our study also included a parallel cohort of bi-weekly dosing of carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) in combination with daratumumab (bKRd-D). Primary end-point of our study was to rule out 60% and to target up to 80% MRD negativity rate. METHODS. This is a two-arm, Phase II clinical trial based on Simon's optimal two-stage design. The once-a-week carfilzomib (wKRd) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and 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. The bi-weekly carfilzomib (bKRd) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the weekly cohort. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. 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 allow detection of 1 myeloma cell in 100,000 bone marrow cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The first stage of the weekly cohort (wKRd-D) is fully enrolled (N=28) and the second stage of the cohort (N=13) is anticipated to complete enrollment shortly (total N=41). Currently, 29 patients meeting eligibility criteria were enrolled (14 males, 15 females) between October 2018 and August 2019. Baseline characteristics include; median age 59 years (range 36-70 years); 12 (41%) 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 the submission of this abstract, 28 patients have completed one or more cycles wKRd-D; among these, 10 patients have completed therapy. The median number of cycles delivered is currently 6 (range 1-8). Seven of the 10 patients who have completed study treatment are MRD negative. So far, additional 8 patients have become MRD negative while on therapy. Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary end-point at this analysis, we found 15/18 (83%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care bKRd. The bi-weekly carfilzomib cohort (bKRd-D) shows similar results to the weekly cohort (wKRd-D). With a comparable efficacy and safety profile coupled with a substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively), we conclude that the weekly dosing (wKRd-D) may offer an attractive treatment modality for newly diagnosed multiple myeloma patients. CONCLUSIONS. Among patients evaluable for the MRD primary end-point, in the absence of an autologous bone marrow transplant, we show an unprecedented 15/18 (83%) MRD negativity rate among newly diagnosed multiple myeloma patients treated on the weekly cohort (wKRd-D) using carfilzomib 56 mg/m2 dosing. Our promising results have prompted the development of a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care, which is anticipated to start enrollment in Q3/Q4 of 2019. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Abbvie: 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. Lesokhin:GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Janssen: Research Funding. Smith:Fate Therapeutics and Precision Biosciences: Consultancy; Celgene: Consultancy, Patents & Royalties, Research Funding. Shah:Physicians' Education Resource: Honoraria. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Dogan:Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding. OffLabel Disclosure: Dara-KRd is not an FDA approved combination therapy for newly diagnosed multiple myeloma.

Description: Introduction The current standard to assess chemotherapy tolerability relies on patient self-reporting. However, as the sole mechanism of managing symptom burden, this may be inconsistent and fraught with bias. Mobile wearable health devices have the ability to monitor and aggregate objective activity and sleep data over long periods of time, but have not been systematically used in the oncology clinic. The aim of the study was to assess whether the use of mobile wearable technology establishes patterns of "sleep" and "wake" states in newly diagnosed Multiple Myeloma (NDMM) patients receiving therapy, and whether these patterns differ over time. Methods Patients presenting to the myeloma clinic at Memorial Sloan Kettering Cancer Center (MSKCC) with a new diagnosis of Multiple Myeloma and smart phone or tablet (iOS or Android) compatible with the Garmin Vivofit device were offered to participate in a mobile wearable bio-monitoring study. All eligible participants were required to receive primary chemotherapy treatment at a MSKCC facility. Treatment was determined by physician. NDMM patients were assigned to one of two cohorts (20 in each; Cohort A - patients

Description: Background: Multiple myeloma (MM) patients who achieve minimal residual disease (MRD) negative status after upfront treatment have prolonged progression-free and overall survival compared with those who remain MRD(+) (Landgren CO, Devlin SM et al. Bone Marrow Transplant. 2016;51(12):1565-8). Commensal intestinal microbial composition has been associated with treatment outcomes in cancer patients. We sought to evaluate whether the composition of the intestinal microbiota is associated with MRD status in patients with MM. Methods: Stool samples were collected prospectively from 34 patients after completion of upfront therapy for MM at the time of MRD testing. MRD was assessed with next-generation flow cytometry of bone marrow aspirates (sensitivity 10-5). Microbial analysis was performed via sequencing of 16S rRNA V4-V5 regions using the Illumina MiSeq platform and sequence data was analyzed using UPARSE (Edgar RC, Nature Methods 2013;10(10):996-8). The linear discriminant effect size method (LEfSe) (Segata N et al. Genome Biol. 2011;12(6):R60.) was used to compare detected clades among all groups and evaluate for associations with outcomes, using MRD as class and autologous stem cell transplant (ASCT) as subclass. Alpha diversity was calculated by the Inverse Simpson index and differential relative abundance were calculated using the phyloseq package and compared using the Wilcoxon rank sum test on the R statistical computing platform. Results: Among 34 patients evaluable for microbiota composition and MRD status, the median age was 62.5 years and 16 (47.1%) were MRD(-) at time of stool collection. 24 (70.6%) were treated with carfilzomib, lenalidomide, and dexamethasone as induction therapy (MRD(-): 14 (87.5%), MRD(+):10 (55.5%). 4 (28.5%) MRD(-) patients had autologous stem cell transplant(ASCT), compared with 10 (55.5%) who were MRD(+). In the cohort's samples, we observed 19 phyla, 315 genera, 654 species, and 1549 operational taxonomic units (OTUs). There was no significant difference in alpha diversity between MRD(-) (median 12.24, IQR = 8.76-13.98) and MRD(+) patients (median 12.44, IQR = 8.36 -16.23), p=0.6 by Wilcoxon rank sum test. A positive association with MRD negativity was noted with two butyrate-producing organisms, Eubacterium hallii (p=0.001) and Faecalibacterium prausnitzii (p= 0.006). To further evaluate these relationships, we performed a differential abundance analysis of these selected taxa in MRD(+) and MRD(-) patients at the genus and species level. The relative abundance of the genera Eubacterium and Faecalibacterium were higher in fecal samples from MRD(-) patients than MRD(+) patients (Eubacterium MRD(-): median 4.51% (IQR = 2.83 - 7.32%) vs. MRD(+): median 3.07% (IQR = 1.35 - 3.87%), p=0.0326; Faecalibacterium MRD(-): median 1.68% (IQR = 0.69 - 7.48%) vs. MRD(+): median 0.003% (IQR = 0 - 3.19%), p=0.022. The relative abundance of both species of interest were higher in MRD(-) patients than in MRD(+) patients: E. hallii MRD(-): median 2.67% (IQR = 2.11 - 3.98%) vs. MRD(+): median 1.01% (IQR = 0 - 2.16%), p=0.001; F. prausnitzii MRD(-): median 1.43% (IQR = 0.53 - 7.28%) vs. MRD(+): median 0.3%, (IQR = 0 - 2.54%), p=0.022. Other species of Eubacterium and Faecalibacterium were not significantly differentially abundant between the two groups. Conclusions: Intestinal microbiota containing several butyrate-producing anaerobes appear to be associated with MRD-negativity in patients with myeloma, with higher relative abundance of Eubacterium hallii and Faecalibacterium prausnitzii in MRD(-) patients compared with MRD(+) patients. Butyrate and other short-chain fatty acids are biologically active metabolites formed during microbial fermentation of dietary or host-derived carbohydrates, which supply the host with energy and also modulate immunity, including exerting anti-inflammatory functions. Microbes of the genus Eubacterium have been associated with reduced risk of relapse in several hematologic cancers after allogeneic hematopoietic cell transplantation, including MM (Peled JU, Devlin SM et al. J Clin Oncol 2017;35(15):1650-9). This is first study to our knowledge to suggest an association between gut microbiota and MRD status in patients with myeloma and supports further investigation of a potential role for intestinal microbiota in the natural history and treatment of myeloma. Disclosures Peled: Seres Therapeutics: Research Funding. Landgren:Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Janssen: Research Funding.

Description: 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.

Description: 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