Daratumumab is an anti-CD38 monoclonal antibody that has shown clinical benefit in both relapsed/refractory as well as newly diagnosed multiple myeloma (MM). Although daratumumab is very well-tolerated, randomized clinical trial data have consistently demonstrated an increased risk of infection, particularly along the respiratory tract, in patients receiving daratumumab. CD38 is present on healthy plasma cells, and their destruction can lead to hypogammaglobulinemia (HGG). In this study, we retrospectively reviewed all patients with MM treated with daratumumab and intravenous immunoglobulin (IVIG) at our institution from 2015-2019. The primary endpoints were the incidence rate ratios (IRR) of all-grade infections and grade 3-4 infections per patient-year during IVIG versus observation. In addition, a separate reference group of MM patients who were treated with daratumumab but never received IVIG was identified to establish baseline infection rates and to identify differences in baseline characteristics among patients who were selected to receive IVIG. A total of 43 patients received daratumumab and IVIG, primarily in the relapsed/refractory setting. All patients had HGG during treatment with daratumumab, with most (81%) experiencing moderate HGG (IgG

Background Etentamig is a second-generation B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Etentamig possesses a unique combination of 2 high-affinity BCMA binding domains, coupled to a low-affinity CD3 binding domain that have been shown to reduce the negative impact of soluble BCMA (sBCMA), decrease risk for cytokine release syndrome (CRS), and drive sustained T-cell activation with reduced immune exhaustion in preclinical models of MM (Blood 2023;142 [suppl 1]:4666). Here, we describe correlative biomarker analyses from Phase 1 (NCT03933735) and Phase 1b (NCT05650632) clinical trials of etentamig in RRMM designed to assess the impact of sBCMA on clinical response and pharmacodynamic changes in proinflammatory cytokines, and T-cell redistribution, activation, proliferation, and exhaustion. Methods Peripheral blood and serum samples from patients with RRMM enrolled in Phase 1 and Phase 1b open-label studies who received etentamig monotherapy were collected at baseline, on treatment, and at disease progression. The Phase 1b study consisted of dose-optimization (DO) and dose-expansion (DE) phases. During DO, patients received a single step-up dose (SUD) of intravenous etentamig (2 or 4 mg) on Cycle (C) 1 Day (D) 1, followed by the target dose of 60 mg on D4. In DE, based on DO findings, patients received the recommended etentamig SUD (2 mg) on C1D1, followed by 60 mg on D4 with modified dexamethasone predosing. Samples were analyzed by flow cytometry for immune cell populations, Luminex® for cytokines, and electrochemiluminescence for sBCMA. Peripheral blood mononuclear cells and bone marrow mononuclear cells (BMMC) at baseline and on-treatment were subjected to single-cell Cellular Indexing of Transcriptomes and Epitopes sequencing (scCITEseq) and single-cell T-cell receptors (scTCR) / B-cell receptors clonality analyses. Results While baseline serum sBCMA levels did not correlate with clinical response to etentamig at the selected dose level of 60 mg every 4 weeks (Q4W) with 2 mg SUD, a reduction in sBCMA levels over time was associated with best International Myeloma Working Group response. Etentamig treatment led to a rapid and transient increase of proinflammatory cytokines and promoted T-cell redistribution, activation, and proliferation. Maximum reduction in peak levels of CRS-related cytokines, including (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor–a), were observed in DE compared with DO and 60 mg Q4W without SUD. Peak induction levels of proinflammatory cytokines during C1 correlated with occurrence of CRS (≥Grade [G] 1) as well as clinical response across dose levels. A modified dexamethasone premedication schedule of 2 mg/60 mg Q4W cohort for C1 resulted in significantly reduced baseline levels of IL-6 and key macrophage-associated cytokine/chemokines (eg, monocyte chemoattractant protein-1 and macrophage inflammatory protein-3 beta). Incidence of CRS was lowest in the 2 mg/60 mg Q4W cohort (26% G1, 4% G2, 0% ≥G3). Higher T-cell to myeloma cell ratio in BMMCs at baseline correlated with better response to etentamig. scCITEseq and scTCR analysis revealed that at baseline, responders also had greater CD8+ T-cell cytotoxic activities, increased TCR clonality, and elevated inflammatory signatures in T-cells from both peripheral blood and bone marrow. Etentamig at a dosage of 60 mg Q4W resulted in significant clonal expansion of CD8+ effector T-cells and enhanced gene expression signatures related to activation and cytotoxicity in both CD8+ T effector and natural killer cells. Along treatment cycles, responders maintained their T-cell fitness, high clonality, and low T-cell exhaustion levels. Frequency of baseline CD4+ or CD8+ T-cell exhaustion (programmed cell death receptor 1+/ T cell immunoglobulin and mucin-domain containing-3 +) did not impact clinical response at optimal dose level of 2 mg/60 mg Q4W etentamig. Conclusions Responses to etentamig were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation indicating that the optimal dose of etentamig (2 mg/60 mg Q4W) maximizes its clinical potential as a convenient, safe, and effective therapy for MM.

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.

PURPOSE:Bispecific antibodies emerged as a new class of treatment for patients with relapsed/refractory multiple myeloma. Education on the practicalities of delivery and patient management is vital to optimize outcomes with these novel agents. METHODS:A group of 5 experienced hematologists from centers in the United States, Europe and Latin America met to discuss key considerations for bispecific antibody therapy and agree on best practice advice. RESULTS AND DISCUSSION:This paper presents advice for best practice at each stage of the bispecific antibody therapy patient journey: patient eligibility, pretreatment medication, step-up dosing, treatment, management of adverse events and long-term care. CONCLUSION:We believe that the expert insights presented here will help to educate healthcare professionals and optimize patient outcomes by guiding the implementation of bispecific antibody therapy into real-world practice.

BACKGROUND:Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.METHODS:GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022.FINDINGS:Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy.INTERPRETATION:Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies.FUNDING:Janssen Oncology.

MM remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies, highlighting the need for novel agents. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. In the phase 1 MonumenTAL-1 study, an overall response rate of 70% at median 6.3-month follow-up was observed at the recommended phase 2 dose (RP2D) of Tal in pts with RRMM. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for treatment of MM. In preclinical studies, Dara enhanced Tal-mediated lysis of MM cells, suggesting the potential to increase clinical activity in pts with RRMM when the agents are combined. We report initial findings for pts with RRMM who received Tal + Dara in the phase 1b multicohort TRIMM-2 study (NCT04108195). Eligible pts (≥18 years) had MM and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts who received anti-CD38 therapy ≤90 days were excluded. The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). As of Jul 23, 2021, 23 pts received SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 μg/kg weekly (n=8), + Tal 400 μg/kg biweekly (n=5), and + Tal 800 μg/kg biweekly (n=10). Median follow-up across the cohorts was 2.9 months (range 0.3–11.2). Median age was 68 years (range 44–81), and 52.2% of pts were male. Pts had a median of 6 prior LOT (range 3–18); 82.6% were triple-class exposed (82.6% had prior Dara and 8.7% had prior isatuximab) and 73.9% were penta-drug exposed. Most frequently reported AEs (≥30%) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). Grade 3/4 AEs were reported in 78.3%. Median time to CRS onset was 2.5 days (range 2–4), and median duration was 2 days (range 1–3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2). Two ICANS events were reported (grade 1 [concurrent with CRS] and grade 3); both resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died from disease progression. Responses are shown in the Table. The median time to first response across the cohorts was 1.0 month (range 0.9–2.4), and median duration of response was not reached. Tal pharmacokinetics was similar to that reported in the MonumenTAL-1 study. Proinflammatory cytokine production and T cell activation were observed after Tal + Dara treatment. The combination of Tal with Dara was well tolerated, with a safety profile comparable to the monotherapies. The combination showed promising efficacy in pts with RRMM, supporting further clinical development of Tal + Dara combination therapy.

In the phase 1 MajesTEC-1 trial, teclistamab (Tec), a B-cell maturation antigen × CD3 T cell redirecting bispecific antibody, showed an overall response rate of 65% at 6.1-month follow-up. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In MM cell lines, the lytic activity of Tec was enhanced by pretreatment and combination treatment with Dara; thus, the combination of both agents may improve efficacy in RRMM by targeting discrete yet complementary antigens. We present data on patients (pts) with RRMM who received Tec + Dara in the phase 1b TRIMM-2 study (NCT04108195). Eligible pts were ≥18 years of age, had a MM diagnosis, and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Receipt of anti-CD38 therapy ≤90 days was not allowed. The primary objectives were to identify the RP2D for the Tec + Dara combination and to assess safety of the combination. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG criteria and adverse events (AEs) by CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] were graded per ASTCT guidelines). 33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 μg/kg weekly (n=21), + Tec 3000 μg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (C3D1; Tec 150 mg weekly in C1–C2; n=2), and + Tec 3000 μg/kg biweekly (n=5). 9 pts in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after C3D1. As of Jun 22, 2021, median follow-up across the cohorts was 3.6 months (range 0.1–10.4). Median age was 67 years (range 51–78) and 57.6% were female. Median number of prior LOT was 5 (range 2–16); 69.7% were triple-class exposed (prior Dara in all 69.7%) and 60.6% were penta-drug exposed. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1–6), and median duration was 2 days (range 1–7). Other AEs (≥30%) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Overall, 66.7% of pts had grade 3/4 AEs. Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 μg/kg weekly cohort died from treatment-unrelated bacterial pneumonia during C1, and 1 pt in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort died from progressive disease. Responses are shown in the Table. Across the cohorts, median time to first response was 1.0 month (range 0–1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production and T cell activation. The Tec pharmacokinetic profile was similar to that reported in the MajesTEC-1 study. The combination of Tec + Dara had a manageable safety profile and showed preliminary efficacy in pretreated pts with MM. These findings warrant further investigation, and the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM.

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. 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. 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. 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. 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.

Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care (SoC) regimens for multiple myeloma (MM). In randomized studies, DARA-based regimens significantly improved response rates, depth of response including minimal residual disease (MRD) negativity, and progression-free survival (PFS) in NDMM and relapsed/refractory MM pts. RVd followed by high-dose therapy (HDT), autologous stem cell transplant (ASCT), and consolidation is a SoC regimen for US pts with NDMM. This phase 2, randomized study (GRIFFIN; NCT02874742) evaluated DARA plus RVd (D-RVd) in ASCT-eligible NDMM pts. A 16-pt safety run-in showed no safety concerns. Here, we present results that adding DARA to RVd improves responses rapidly, including depth of response, which increases with longer duration of therapy. Methods: Pts were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance. Pts received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 mo. During induction and consolidation (Cycles 1-6), pts received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), pts received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per pt decision after Amendment 2). The primary endpoint was the stringent complete response (sCR) rate by the end of consolidation per IMWG computer algorithm. The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1 (equivalent to 2-sided alpha of 0.2). MRD (10-5 per IMWG criteria) was assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). Results: A total of 207 pts (D-RVd n = 104; RVd n =103) were randomized. Baseline demographics and disease characteristics were well balanced between arms. Median age was 60 yrs; 48%, 37%, and 14% of pts were ISS stage I, II, or III, respectively; 30 (15%) pts had high cytogenetic risk defined by FISH for del(17p), t(4;14), or t(14;16). The study met its primary endpoint; D-RVd improved the sCR rate by the end of consolidation (42.4% vs 32.0%; odds ratio 1.57; 95% CI, 0.87-2.82; 2-sided P = 0.1359); at the pre-set 2-sided alpha of 0.2. This improvement was observed in all pt subgroups except for the small subsets of ISS stage III or high-cytogenetic risk pts. Responses deepened over time (Figure); the sCR rate was 12% vs 7% with D-RVd vs RVd at the end of induction, increasing to 21% vs 14% after ASCT, and 50% vs 37% at the clinical cutoff (CCO; 13.5 mo median follow-up). D-RVd achieved higher overall response (99% vs 92%), ≥VGPR (91% vs 73%), and ≥CR (52% vs 42%) rates vs RVd by the end of consolidation. At the end of induction, 8/19 (42%) pts achieving ≥CR with D-RVd were MRD negative, compared to 1/13 (8%) pts achieving ≥CR with RVd. At the end of consolidation, 30/51 (59%) pts achieving ≥CR with D-RVd were MRD negative vs 10/41 (24%) pts achieving ≥CR with RVd. Due to the short median follow-up at CCO, PFS and OS were immature, with 6 PFS events in each arm. Median stem cell yield was 8.1 vs 9.4 × 106 cells/kg for D-RVd vs RVd. Median (range) time to platelet engraftment was 13 (2-31) and 12 (1-23) days for D-RVd vs RVd; median (range) time to neutrophil engraftment was 12 (3-31) and 12 (2-23) days for D-RVd vs RVd. Grade 3/4 TEAEs (≥10%) with D-RVd vs RVd included neutropenia (32% vs 15%), lymphopenia (23% vs 23%), thrombocytopenia (16% vs 8%), and leukopenia (15% vs 7%). There was no difference in the rate of grade 3/4 infections between arms. IRRs occurred in 41% of DARA-treated pts, which were primarily grade 1-2. Updated data will be presented. Conclusions: These data demonstrate that adding DARA to RVd significantly improves response rates and depth of response, including sCR and MRD negativity. As seen in other randomized studies, continued use of daratumumab improved depth of response. The overall safety profile of D-RVd is consistent with previous reports with DARA plus SoC. Likewise, similar to what was reported from CASSIOPEIA, stem cell mobilization and ASCT are feasible with D-RVd, without a significant effect on hematopoietic reconstitution. The study is ongoing, with pts continuing maintenance therapy. Disclosures Voorhees: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Research Funding; Novartis: Consultancy; Oncopeptides: Consultancy; Takeda: Honoraria, Research Funding; TeneBio: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; AbbVie: Consultancy; Amgen: Consultancy. Sborov:Celgene: Honoraria; Janssen: Consultancy. Reeves:Celgene: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Rodriguez:Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Costa:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Shah:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria, 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; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Carevive: Consultancy; Janssen: Research Funding. Orlowski:BioTheryX, Spectrum Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kita Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ionis Pharmaceuticals; Legend Biotech; Molecular Partners; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Cowan:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Juno: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy. Murphy:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Vermeulen:Janssen R&D, LLC: Employment, Equity Ownership. de Boer:Janssen: Employment, Equity Ownership. Hoehn:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Richardson:Karyopharm: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. OffLabel Disclosure: D-RVd is being investigated in transplant-eligible NDMM

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf(CA) mice, where Braf(V600E) causes premalignant melanocytic hyperplasia, and Braf(CA)/Pten(-/-) mice, where Braf(V600E) and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf(CA) mice but did not affect formation and growth of Braf(CA)/Pten(-/-) primary melanomas. It also, as expected, promoted Braf(CA)/Pten(-/-) metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in Braf(CA) and Braf(CA)/Pten(-/-) melanocytic cells. Mechanistically, we demonstrated that BRAF(V600E) signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAF(V600E). PTEN depletion in BRAF(V600E)-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAF(V600E) signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.

Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved as monotherapy and in combination with Vd, Rd, and pomalidomide-d for the treatment of relapsed MM and in combination with V, melphalan, and prednisone (VMP) for treatment of ASCT-ineligible ND MM. Addition of dara to these regimens improved the depth of response including complete response (CR), stringent CR (sCR), and minimal residual disease (MRD) negativity rates. VRd followed by HDT, ASCT, and consolidation VRd has yielded high response rates in ND MM. Therefore, a safety run-in was first conducted to determine the tolerability of dara-VRd before proceeding with a larger randomized phase 2 study of dara-VRd vs. VRd in ASCT-eligible ND MM pts.

Background: Addition of Dara to Vd and Rd improved complete (CR) and overall response rates (ORR) and progression‐free survival (PFS) in relapsed MM. RVd followed by HDT, ASCT, and consolidation RVd achieves high response rates in previously untreated MM. The primary objective of this study is to determine if the addition of Dara to RVd will increase the stringent CR (sCR) rate by the end of post‐ASCT consolidation therapy.