Abstract: This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody. Methods RO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model. Results Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%). Conclusions RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma. Trial Registration ClinicalTrials.gov: NCT04434469; Registered June 16, 2020; https://www.clinicaltrials.gov/ct2/show/NCT04434469 .

Abstract: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Abstract: Background: RO7297089 is a bispecific tetravalent antibody targeting BCMA (Genentech licensed from Affimed GMBH), which is highly expressed on MM cells and CD16a, which is expressed on innate immune cells including natural killer (NK) cells, macrophages, and monocyte subsets. Here we report findings from a Phase I dose-escalation study of RO7297089 in patients with RRMM (GO41582, Study registration NCT04434469). Methods: All patients had RRMM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bispecific antibodies, and therapies targeting BCMA was permitted. Patients received RO7297089 as weekly IV infusions in 14-day cycles with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In Arm A the first dose was given over a single-day infusion, and in Arm B the first dose was divided over two consecutive days. Dose limiting toxicities (DLT) were assessed from Cycle 1. Study objectives included safety, pharmacokinetics (PK), and biologic activity as assessed by the IMWG Uniform Response Criteria. Results: As of 30 April 2021, 21 patients received RO7297089 at 5 dose levels (60 mg [n=3], 180 mg [n=5] , 360 mg [n=4], 1080 mg [n=6] , and 1850 mg [n=3]). Median age was 63 years (range 41-76) and median number of prior lines of therapy was 8 (range 2-11). Patients received a median of 8 doses (range 2-42) of RO7297089; 5 patients had prior BCMA-targeted therapy. The most common AEs were anemia (n=11), infusion related reaction (IRR; n=10), back pain (n=5), ALT increased (n=4), and thrombocytopenia (n=4). Eleven (52%) patients had ≥1 treatment-related adverse event (AE) which included IRR (n=9), C-reactive protein increase (n=3), ALT increase (n=3), AST increase (n=2), and thrombocytopenia (n=2). Grade ≥ 3 AEs included anemia (n=9), and platelet count decreased (n=5). Related Grade ≥ 3 AEs were ALT increase and AST increase and lymphocyte count decreased (both n=1). No DLTs or dose-dependent toxicities were reported. Fifteen patients discontinued study treatment due to disease progression (n=12), clinical relapse (n=2), and symptomatic deterioration (n=1). Four deaths were reported in the AE follow-up period, all due to disease progression. Thirteen IRR events (1 Grade 1, 12 Grade 2) were observed in 10 patients (48%). IRR was most common in Cycle 1 (12 events in 10 patients) and was uncommon in subsequent cycles (1 patient). Symptoms of IRR occurring in & gt;1 patient included fever, rigors/chills, and dyspnea. To mitigate IRRs, additional measures were implemented from the 180 mg dose level including steroid premedication and slow infusion for the first dose. Dividing the first dose over 2 days (Arm B) was also implemented from the 1080 mg dose level for improved convenience. Preliminary PK assessments demonstrated a more than dose proportional increase in the exposure of RO7297089 with increasing dose levels from 60-1080 mg, suggesting non-linear PK and target-mediated drug disposition, with a trend of approaching linear PK at doses higher than 1080 mg. The estimated half-life was supportive of weekly dosing. Preliminary observation showed 1/18 patients with treatment-induced anti-drug antibodies, which did not appear to impact PK. BCMA expression was detected in the bone marrow in all patients regardless of prior BCMA-targeted therapy. Levels of total soluble BCMA and soluble CD16a increased immediately after the first dose as expected suggesting engagement and stabilization of soluble factors by RO7297089. Of the 18 response-evaluable patients, 1 patient experienced a partial response (1080 mg cohort) per IMWG criteria. Ten patients had stable disease as their best response at dose levels of 60 mg (1/3 patients), 180 mg (2/5 patients), 360 mg (3/4 patients), 1080 mg (4/6 patients). One patient who started at the 60 mg dose and gradually escalated to the 1080 mg dose has been on treatment for 9.5 months with stable disease at the time of the clinical cut-off date. Conclusions: Treatment with RO7297089 was well-tolerated at the dose levels tested, although infusion reactions necessitated long infusion duration for the first dose. Modest activity has been observed to date with doses up to 1080 mg. There were no DLTs and a recommended phase 2 dose has not been identified. The latest clinical, biomarker, and PK data will be presented including data from higher dose level cohorts. Disclosures Plesner: AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding; Janssen: Other: Advisor, Research Funding. Harrison: Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Takeda: 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, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: BMS: Other: Advisor, Research Funding; Janssen: Other: Advisor; Amgen: Other: Advisor. Bryant: Sandoz: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria. Estell: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Delforge: Bristol Myers Squibb: 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. Twomey: Genentech: Current Employment. Choeurng: Genentech: Current Employment. Li: Genentech: Current Employment. Hendricks: Genentech: Current Employment. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Miller: Genentech: Current Employment. Choi: Genentech: Current Employment. Schjesvold: Schain: Honoraria; AbbVie: Honoraria; Adaptive Biotechnologies: Consultancy; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Sanofi: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; Bayer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. OffLabel Disclosure: RO7297089 is a Bâ€'Cell maturation antigen (BCMA)-CD16a bispecific antibody intended for use if approved in patients with relapsed/refractory multiple myeloma

Abstract: Introduction: The phase 3 MAIA study (NCT02252172) evaluated the addition of daratumumab (D) to lenalidomide and dexamethasone (Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM). At a median follow-up of 56.2 months, D-Rd prolonged progression-free survival (PFS) and overall survival (OS) versus Rd alone, despite almost half of the pts in the Rd arm who received subsequent therapy receiving a daratumumab-containing regimen as any subsequent line of therapy (Facon T, et al. Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1901). Approximately 20% to 50% of pts with MM have baseline renal impairment that can affect the choice and efficacy of therapy (Dimopoulos MA, et al. Journal of Clinical Oncology. 2016;34[13]:1544-1557). Here, we report results from MAIA for D-Rd vs Rd in pts with impaired renal function based on lenalidomide starting dose at a median follow-up of 56.2 months. Methods: Pts with NDMM ineligible for high-dose chemotherapy and autologous stem-cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to receive D-Rd or Rd. Pts in both arms received 28-day cycles of oral Rd (R: 25 mg [10 mg recommended if creatinine clearance (CrCl) was 30-50 mL/min] on Days 1-21; d: 40 mg [20 mg if aged & gt;75 years or body-mass index & lt;18.5 kg/m 2] on Days 1, 8, 15, 22). Pts in the D-Rd arm also received intravenous D (16 mg/kg once weekly for Cycles 1-2, once every 2 weeks for Cycles 3-6, and once every 4 weeks thereafter). Pts in both arms were treated until disease progression or unacceptable safety events. The primary endpoint was PFS, and a secondary endpoint was OS. Renal impairment was defined as a baseline CrCl of ≤60 mL/min. Results: 737 pts were randomized (D-Rd, n=368; Rd, n=369); 162 (44%) pts in the D-Rd arm and 142 (38%) pts in the Rd arm had renal impairment as defined. At a median follow-up of 56.2 months, in pts with renal impairment who received a lenalidomide starting dose of 25 mg (25 mg subgroup; D-Rd, n=60 [37%]; Rd, n=62 [44%] ), a PFS and OS advantage was observed with D-Rd versus Rd (Table). In pts with renal impairment who received a lenalidomide starting dose of & lt;25 mg ( & lt;25 mg subgroup; D-Rd, n=98 [60%]; Rd, n=75 [53%] ), median PFS and OS were prolonged with D-Rd versus Rd (Table). Among pts in the 25 mg subgroup who died (D-Rd, n=12; Rd, n=29), disease progression was the primary cause of death in 6 (50%) pts in the D-Rd arm and 10 (34%) pts in the Rd arm. Among pts in the & lt;25 mg subgroup who died (D-Rd, n=44; Rd, n=37), disease progression was the primary cause of death in 16 (36%) pts in the D-Rd arm and 11 (30%) pts in the Rd arm. Conclusion: After ~5 years of follow-up, D-Rd showed a PFS improvement versus Rd in transplant-ineligible pts with NDMM and renal impairment regardless of lenalidomide starting dose. An OS advantage for D-Rd versus Rd was observed in pts with renal impairment who received a lenalidomide starting dose of 25 mg; in pts with renal impairment who received a lenalidomide starting dose of & lt;25 mg, median OS was prolonged for D-Rd versus Rd, but the OS benefit was less pronounced. Overall, among pts with renal impairment, PFS and OS benefits of D-Rd versus Rd were observed regardless of lenalidomide starting dose; however, dose recommendations per the lenalidomide prescribing information should be followed. Many transplant-ineligible pts with NDMM may not receive a second line of therapy; our results support the frontline use of D-Rd to provide prolonged disease control in transplant-ineligible pts with NDMM and renal impairment. Figure 1 Figure 1. Disclosures Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Bahlis: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: Janssen: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; Incyte: Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Janssen: Consultancy. Perrot: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: 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; Abbvie: Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Amgen: Research Funding. Weisel: Novartis: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh: Janssen: Current Employment. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment.

Abstract: Background: Current therapies for multiple myeloma (MM) delay disease progression and prolong survival but most patients (pts) eventually relapse or become refractory (RR). Daratumumab (D), an anti-CD38 antibody (Ab), plus bortezomib (V), a proteasome inhibitor (PI) and dexamethasone (d), is approved for the treatment of MM in pts who have received ≥1 prior line of therapy. Venetoclax (Ven), a potent and selective oral BCL-2 inhibitor, demonstrated anti-myeloma activity in pts with t(11;14) RRMM. This 3-part Phase 1/2 study is investigating the combination therapy VenDd +/- V in pts with RRMM. Treatment of pts with t(11;14) RRMM using VenDd (part 1) and pts with RRMM (irrespective of t(11;14) status; part 2) with VenDVd demonstrated a tolerable safety profile and an overall response rate (ORR) of 95.8% and 91.7%, respectively (Bahlis N et al. J Clin Oncol 2021). Part 3 further evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM, with preliminary results presented here. Methods: Part 3 of this Phase 1/2, multicenter, dose-escalation and expansion study (NCT03314181) evaluates the safety and efficacy of VenDd vs DVd in pts with t(11;14) RRMM. The study was expanded to further interpret the pt safety profile in light of the increased incidence of infections in pts in the Ven arm of the BELLINI study (Kumar SK et al. Lancet Oncol 2020). Pts were randomized 4:2:5 to receive VenDd at 400 (Ven400Dd) or 800 mg (Ven800Dd), or DVd. Randomization was not stratified due to small sample size. Eligible pts must have received ≥1 prior line of therapy, including an immunomodulatory agent (IMiD), and be non-refractory to PIs or anti-CD38 Ab. This interim analysis was conducted to evaluate the safety profile of pts in part 3 only. No statistical comparisons were conducted for safety or efficacy. Treatments in Part 3 were as follows: VenDd cycles (C) were 28-day: daily, oral Ven (400 mg or 800 mg) + D (1800 mg SC [Cycle, C1, 2: Days 1, 8, 15, 22; C3-6: Days 1, 15; C7+: Day 1]) + d (40 mg total weekly); DVd C1 - 8 were 21-day, C9+ were 28-day: D (1800 mg SC [C1 - 3: Days 1, 8, 15; C4 - 8: Day 1; C9+: Day 1] ) + V (1.3mg/m 2 [C1 - 8: Days 1, 4, 8 and 11]) + d (20 mg [C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12 ,15; C4 - 8: Days 1, 2, 4, 5, 8, 9, 11,12; C9+: Day 1] ). Results: As of 10 May 2021, 11, 7 and 16 pts were enrolled in the Ven400Dd, Ven800Dd and DVd arms, respectively. The median age (range) was Ven400Dd: 58.0 (42 - 75); Ven800Dd: 57 (53 - 82); and DVd: 68.5 (51 - 77). Median prior lines of therapy (range) were 1.0 (1 - 6) in Ven400Dd; 1.0 (1 - 3) in Ven800Dd; and 2.0 (1 - 3) in DVd. Pts with ISS I%/II%/III% disease were Ven400Dd: 54.5/9.1/0; Ven800Dd: 57.1/14.3/0; DVd: 25.0/25.0/31.3. All pts in the Ven400Dd and Ven800Dd arms had an ECOG performance status of ≤1. In the DVd arm, 87.5% and 12.5% of pts had a ECOG performance status of ≤1 and 2, respectively. Prior PI%/IMiD%/anti-CD38 Ab% exposure were Ven400Dd: 100/90.9/0; Ven800Dd: 100/100/0; DVd: 93.8/100/0. The most common adverse events (AEs) occurring in ≥5% of pts in ≥2 treatment groups included insomnia, fatigue, diarrhea, and nausea (Table). Grade 3/4 AEs (≥5% of pts in ≥2 treatment groups) were mainly hematologic toxicities (Table). There were no grade 3/4 infections occurring in ≥2 treatment groups. Serious AEs were observed in a total of 6 pts. In the Ven400Dd arm, 1 pt had a femur fracture and 1 pt had non-cardiac chest pain. In the Ven800Dd arm, 1 pt had febrile neutropenia and 1 pt had tonsil cancer. In the DVd arm, 1 pt had pyrexia and upper respiratory tract infection, and a second pt had hyperglycemia, autonomic neuropathy, distributive shock, disseminated cryptococcosis, and cytomegalovirus infection. No deaths were reported in part 3 of the study. The median treatment duration based on D exposure at the time of data cut was 6.5, 5.6, and 3.9 months for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The preliminary ORR was 72.7%, 100%, and 62.5% for the Ven400Dd, Ven800Dd, and DVd arms. The preliminary rate of very good partial response or better (≥VGPR) was 72.7%, 100%, and 31.3% for the Ven400Dd, Ven800Dd, and DVd arms. Follow-up is still immature, and responses may deepen with time. Conclusion: The preliminary results from part 3 of this novel randomized, phase 2 study of t(11;14)-selected RRMM pts treated with VenDd vs DVd demonstrate a tolerable safety profile. Updated analyses, including response rates with longer follow-up and minimal residual disease status, will be included at presentation. Figure 1 Figure 1. Disclosures Kaufman: Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; Sutro, Takeda: Research Funding; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Quach: Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, 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, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baz: GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy; Merck: Research Funding; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding. Harrison: Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Plesner: Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding; Genmab, Genentech, Roche: Research Funding. Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Sehgal: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kang: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Lash-Fleming: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Bahlis: Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a potent and selective oral BCL-2 inhibitor being investigated in the treatment of relapsed/refractory multiple myeloma.

Abstract: 8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts 〈 75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age ( 〈 75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for 〈 75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both 〈 75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10 -5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs ( 〈 75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in 〈 75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]