Abstract: INTRODUCTION Using Carfilzomib, Lenalidomide and Dexamethasone (KRd) combination therapy in newly diagnosed multiple myeloma patients lead to ~40% minimal residual disease (MRD) negativity rate. Here, we use KRd in combination with daratumumab (DKRd); and treatment response is assessed with extensive correlative science including parallel bone-marrow-based and blood-based MRD tracking, together with targeted DNA sequencing of baseline bone marrow samples. Primary end-point is to rule out 60% and to target up to 80% MRD negativity rate. METHODS This is a single-arm, Phase II clinical trial based on Simon's optimal two-stage design. The first cohort (twice-a-week carfilzomib) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; 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 second cohort (once-a-week carfilzomib) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the first cohort. For fit patients, stemcell 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 (10-color single tube flowcytometry, invivoscribe V(D)J sequencing) as well as blood-based (MALDI-TOF and QTOF-mass spectrometry [MS]) for MRD tracking. Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). Here, we present the first stage (N=28) of the first cohort (twice-a-week carfilzomib). We are waiting for the results to mature before the second stage (N=13) of the first cohort can open. The second cohort (once-a-week carfilzomib) is opening for enrollment in August 2018 (N=41). RESULTS The first stage of the first cohort is fully enrolled; 28 patients meeting eligibility criteria were enrolled onto study (14 males, 14 females) between October 2017 and July 2018. Baseline characteristics include; median age 60 years (range 32-80 years); 12(43%) 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, 20 patients have completed one or more cycles DKRd; among these, 3 patients have completed all 8 cycles. The median number of cycles delivered is currently 4 (range 1-8). Full assessments with MRD assays have been completed in 3 patients: -Pt #1 obtained complete response (CR) after 3 cycles, and workup after the last cycle of therapy showed MRD-negativity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was negative by MALDI-TOF MS after completion of cycle 2. -Pt#2 obtained CR after 4 cycles, however, workup after cycle 5 showed MRD-positivity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was positive by MALDI-TOF MS throughout the end of the last cycle. -Pt#3 obtained CR after 4 cycles and after 6 cycles both 10-color single tube flowcytometry and V(D)J sequencing showed MRD-negativity in the bone marrow. However, MALDI-TOF MS detected small abnormal serum proteins in peripheral blood and remained positive throughout the end of cycle 8. Overall, the DKRd therapy is well tolerated and it has similar toxicity profile as KRd. Grade 〉 3 adverse events were hypotension, musculoskeletal deformity, back pain, dyspnea, lung-infection, and febrile neutropenia. So far, 5 patients underwent dose reductions of lenalidomide. CONCLUSIONS In this pre-planned interim analysis of our phase II study, we show that DKRd is a highly effective and well tolerated combination therapy for newly diagnosed multiple myeloma patients. Based on small numbers of patients who have completed the planned DKRd cycles and been evaluated by bone marrow-based MRD and peripheral-blood based assays, we show that highly sensitive protein assays may allow longitudinal MRD tracking in peripheral-blood. At the meeting, we will present updated results using longitudinal testing with MALDI TOF-MS and QTOF-MS on the entire cohort. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Takeda: Consultancy, Honoraria; Janssen: Research Funding; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Korde:Amgen: Research Funding.

Abstract: Background The use of immunomodulatory agents and proteasome inhibitors in newly diagnosed multiple myeloma (NDMM) patients has improved outcomes and led to their widespread use as induction regimens independent of transplant eligibility. Although the overall toxicity profiles of these regimens are considered favorable, their prolonged use warrants a heightened vigilance for toxicities during therapy, and treating physicians need to carefully balance efficacy and toxicity profiles for each patient. Given that patients enrolled on clinical trials, per eligibility criteria, are less frail and/or have fewer comorbidities than patients in the general population, we were motivated to conduct a large study designed to define the safety profiles of the most commonly used induction regimens in the US, based on real-world evidence data. Methods We identified 185 consecutive NDMM patients treated with bortezomib, lenalidomide, and dexamethasone (VRd) vs. carfilzomib, lenalidomide, and dexamethasone (KRd) at MSKCC between 2015 and 2019. By reviewing all available data for these patients, we defined the incidence of cardiopulmonary toxicities, hypertension, renal complications, and peripheral motor or sensory neuropathy. Results A total of 81 and 104 patients were treated with VRd and KRd induction, respectively (Table 1). The VRd (compared to KRd) group had a smaller proportion of patients with high-risk cytogenetics (36% vs. 55%, P=0.01); yet, the & gt;CR rate was lower in the VRd (compared to KRd) group (28% vs. 45%, P=0.02) (Table 2). Table 3 summarizes select toxicities. The incidence of cardiopulmonary AEs was similar in both groups: 12% (N=9) and 10% (N=11) in the VRd and KRd groups, respectively, with the majority limited to grade 1 and 2 (P=1.00); observed cardiac toxicity was reversible in 8 of 9 (89%) vs. 9 of 11 (82%) patients. Renal toxicity was rare in both groups (2% vs. 4% for VRd vs. KRd, P=0.70). New onset or worsening of pre-existing (at baseline) neuropathy was significantly (P & lt;0.00001) more common in the VRd group with 45 (56%) patients developing all grades of peripheral neuropathy. In the KRd group, 13 (12%) patients reported new onset or worsening of pre-existing (at baseline) grade 1 peripheral neuropathy during therapy, and it resolved in 9/13 patients after completing therapy. Of the 45 patients with neuropathy in the VRd group, 16/45 (35%) developed sensory alteration or paresthesia (including tingling) interfering with function and/or symptomatic weakness interfering with function, or more severe forms of neuropathy (grade & gt;2), and 26/45 (58%) patients developed chronic neuropathy after completion of induction therapy. These patients required various interventions, including opiates (N=7), pregabalin/gabapentin/duloxetine (N=17), rehabilitation/physical therapy (N=2), assistive devices such as canes, walkers, and wheelchairs (N=3). None of the patients treated with KRd had new onset neuropathy requiring pain medication. In the VRd group, neuropathy resulted in treatment discontinuation for 6 (7%) patients. Overall, 9% and 4% of patients treated with VRd and KRd, respectively, had treatment discontinuation due to AEs (P=0.22). There were no deaths in the two groups. Conclusion Using real-world evidence data, we defined the safety profiles of VRd and KRd. In sharp contrast to clinical trials mandating recurrent IV fluids before/after administration of carfilzomib, we use optimized IV fluid management (250 ml saline before dose 1 of cycle 1, thereafter no IV fluids) coupled with baseline work-up, including EKG and echocardiogram, for all patients treated with KRd. Therefore, we did not observe excess rates of cardiopulmonary or renal AEs with KRd, and the majority were reversible. In the VRd group, 45 (56%) patients developed new onset or worsening neuropathy, and a third of these developed sensory alteration or paresthesia interfering with function and/or symptomatic weakness interfering with function, or more severe forms of neuropathy. Overall, about 30% of all VRd treated patients developed chronic neuropathy after induction therapy, including disabling neuropathy in some patients and often with need for continued pain treatment. Neuropathy resulted in treatment discontinuation for 7% of patients treated with VRd. These real-world evidence data demonstrate the general tolerability and efficacy of KRd induction, with less severe neuropathy compared to VRd. Disclosures Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy; GSK: Research Funding. Korde:Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:GenMab: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; Janssen: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding. Mailankody:Allogene Therapeutics: Research Funding; Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Janssen Oncology: Research Funding. Hassoun:Takeda: Research Funding; Novartis: Consultancy; Celgene: Research Funding. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Scordo:Kite - A Gilead Company: Other: Ad-hoc advisory board; Omeros Corporation: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; McKinsey & Company: Consultancy. Chung:Genentech: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Giralt:Actinuum: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Quintiles: Research Funding; Pfizer: Research Funding; CSL Behring: Research Funding; Jazz: Research Funding; Kite: Research Funding; Sanofi: Research Funding; Adienne: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Other; Pfizer: 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; BMS: 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; 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; Celgene: Consultancy, Honoraria, Research Funding.

Abstract: 8049 Background: Teclistamab (Tec) is the first CD3 x BCMA bispecific antibody (BsAb) receiving accelerated FDA approval for treatment of relapsed or refractory multiple myeloma (RRMM) in patients who have received ≥4 prior lines of therapy, including a PI, IMiD and an anti-CD38 monoclonal antibody. The approval was based on the results of the MajesTec-1 study (Usmani S et al Lancet 2021, Moreau P et al NEJM 2022), demonstrating a 63% overall response rate in a heavily pretreated RRMM population. Patients with prior exposure to anti-BCMA therapies, such as BCMA targeted ADCs, CAR T-cell products and BsAbs were excluded from this study. Herein, we present our institutional experience with commercial Tec for RRMM including patients with prior BCMA and GPRC5D directed therapies. Methods: We have performed an IRB-approved, retrospective analysis of clinical outcomes of all patients who have received commercial Tec at MSKCC since its approval on 10/26/2022 using the PCD research database. Descriptive analyses were performed for baseline characteristics. The IMWG criteria (Kumar S et al, Lancet Oncol 2016) were used to assess response and define prior therapy refractoriness. Immune profile was assessed via high-dimensional flow cytometry using lineage, exhaustion, and activation markers. Serum soluble BCMA levels were assessed using an immunoassay. Results: As of 2/4/2023, 24 patients have received commercial Tec and 15 are response evaluable with ≥1 month of clinical follow-up. Median age was 66 (51-80), prior lines of therapy was 7 (4-13), time from diagnosis was 7 years (1.5-16), 53% had high-risk cytogenetics, and 40% had EMD. All patients were triple class refractory and 80% were penta-drug refractory. Ten had prior anti-BCMA therapy (7 Belamaf, 8 BCMA CART, 1 BCMA BsAb, 5 with ≥2 anti-BCMA therapies). With a median follow-up time of 1.3 months, the median time to response was 16 days. ORR was 60% (9/15) in all patients and 50% (5/10) in the prior anti-BCMA therapy group. Pts with ≥2 anti-BCMA therapies had a 40% (2/5) response rate to Tec. Clinical benefit rate (CBR) in all patients was 73% (11/15). None of the responders have progressed at this short follow-up time. Cytokine release syndrome was observed in 7/15 patients (41%) during step-up dosing (5/7 with g1 and 2/7 with g2 CRS) and CBR was 100% in patients with CRS (71% ORR). Other notable toxicities include 2 patients with grade 2 neurotoxicity that improved with therapy discontinuation. Conclusions: To our knowledge, this is the first report of commercial Tec in RRMM. Tec remains effective in RRMM despite prior exposure to anti-BCMA therapies, though exposure to multiple prior anti-BCMA therapies may be predictive of diminished efficacy. Clinical data on additional patients will be presented at the meeting. Ongoing translational investigations on soluble BCMA levels and patient-specific immune phenotype will also be presented at the meeting.

Abstract: Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48–64%) for VRd and 67% (60–75%) for KRd ( P  = 0.027). Estimated 5-year EFS was 34% (95%CI, 27–42%) for VRd and 52% (45–60%) for KRd ( P   〈  0.001) with corresponding 5-year OS of 80% (95%CI, 75–87%) and 90% (85–95%), respectively ( P  = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60–78%) for VRd and 75% (65–85%) for KRd ( P  = 0.20) with 5-year OS of 87% (95%CI, 81–94%) and 93% (87–99%), respectively ( P  = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8–61.1) for VRd and 70.9 months (58.2-NR) for KRd ( P  = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24–51%) and 69% (58–82%) for VRd and 58% (47–71%) and 88% (80–97%, P  = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.

Abstract: 8023 Background: Plinabulin is a selective immunomodulating microtubule-binding agent, which prevents chemotherapy induced neutropenia (CIN) via a mechanism of action different from that of G-CSF analogues. It has been studied for CIN and anti-solid tumor activity in phase 3 trials. To decrease the period of myelosuppression and obligate neutropenia after high dose melphalan with autologous hematopoietic stem cell transplantation (AHCT) for patients with multiple myeloma, we studied the addition of plinabulin to standard growth factors. Methods: To achieve the primary objective of reducing the duration of absolute neutropenia post AHCT, 40mg of intravenous plinabulin was given 1-3 hours after stem cell infusion (Day 0) with pegfilgrastim on Day +1 in this pilot trial (NCT05130827). Secondary objectives include the safety, tolerability, and toxicity profile of plinabulin in combination with pegfilgrastim, neutrophil and platelet engraftment rate, disease response, progression free and overall survival, patient reported outcome (PRO) assessment of symptom burden, and plinabulin pharmacokinetic profiling. Exploratory objectives include transfusion requirements, phenotypic characterization of neutrophil population through day 30, and analysis of cytokine levels early post AHCT. Results: Between January 2022 and February 2023, 15 patients with median age of 64 (range 54-74) and 33% female received plinabulin after melphalan 140 (n = 4) or 200mg/m2 (n = 11). Median CD34+ cells/kg infused was 4.12 x 10^6 (range 2.18 – 7.85). Half of the patients had hypertension immediately after the plinabulin infusion, which is a known toxicity and resolved within a few hours. Median WBC on Day 0, 1, and 2 was 7.67(3.6 – 11.5), 5.2 (3.2 – 13.6), and 17.1 (5.1-59.1), respectively. Of the 14 patients who have engrafted to date, median time to ANC 〉 0.5 x 10^9 cell/L was 11 days (range 9-16) with median days from AHCT to ANC 〈 0.5 of 5 days (range 5-6). The median number of days of ANC 〈 0.1 and 〈 0.5 were 2 (range 1-5) and 5 days (range 4-9), respectively. For the 7 patients who had a fever, the median time to fever was 8 days from AHCT (range 8-12), and all except one were peri-engraftment. Median length of stay was 17 days (range 15-21). Median pRBC and platelet transfusions were 0 (range 0-3) and 3 (range 0-11), respectively. Conclusions: Plinabulin appears well tolerated without additional major toxicities post AHCT and provided a high WBC on Day +2 and decreased rate of neutropenic fever. Plinabulin PK, quality of life data, and PROs will be presented. Adjusting the schedule of plinabulin to later post AHCT pre engraftment may further shorten the duration of neutropenia using this novel mechanism of action. Clinical trial information: NCT05130827 .

Abstract: 8045 Background: The incidence of multiple myeloma (MM) is two to threefold higher in African Americans (AAs) compared to whites when adjusted for socioeconomics, age, and sex. However, there is limited information on whether racial background affects the risk of progression from smoldering MM (SMM) to MM. Methods: Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2019 and who identified as either AA or white were included in the study. Baseline characteristics were collected at the time of diagnosis including laboratory, imaging, and pathology reports. Differences in distributions of continuous and discrete characteristics were assessed by Kruskal-Wallis and chi-square tests. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Univariate and multivariate Cox proportional hazard models were used to estimate effects of risk factors on TTP with hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 576 patients were included (70 were AA, 12%). Median follow-up time was 3 years in AAs and 4 years in whites. Differences in baseline characteristics between AAs and whites included median age (60 years in AAs vs 64 years in whites, p = 0.01), median hemoglobin level (12.3g/dL in AA vs 12.8g/dL in whites, p = 0.02), and immunoparesis including 1 or 2 uninvolved immunoglobulins (31% and 10% in AAs vs 56% and 27% in whites, p = 0.002). There was no difference in bone marrow plasma cells, M-spike, free light chain ratio, or Mayo-2018 SMM risk score. AA race was associated with a significantly decreased risk of progression in the univariate model (HR 0.57, CI 0.34-0.94). In the multivariate model adjusting for age, sex, and variables associated with an increased risk of progression in the univariate model (bone marrow plasma cells, M-spike, free light chain ratio, immunoparesis and low albumin), AA race remained associated with a decreased risk of progression (HR 0.39, CI 0.16-0.95). Overall, AA patients with SMM had a significantly (p = 0.027) longer median TTP (9.7 vs 6.2 years), and a lower 2-year (12.6% vs 20.1%) and 5-year (34% vs 44.6%) progression rate than whites. Because AA patients were younger at diagnosis, we stratified patients by age group, 〈 65 vs ≥65 years. In patients 〈 65 years, there was no difference in progression rate. In patients aged ≥65 years, AA patients continued to have a longer TTP than whites (9.8 vs 5.2 years, p = 0.02). Conclusions: In our retrospective single institution experience, AA patients with SMM had a lower risk of progression to MM compared to whites. Both groups had similar Mayo-2018 risk scores, however, AA patients had a lower degree of immunoparesis at baseline. Future studies are needed to better understand if these differences are explained by differences in disease biology including genomic mechanisms, immune microenvironment, and systemic immune response.