Safety and Preliminary Efficacy from the Expansion Cohort of a Phase 1/2 Study of Venetoclax Plus Daratumumab and Dexamethasone Vs Daratumumab Plus Bortezomib and Dexamethasone in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

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.

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