An Updated Safety and Efficacy Analysis of Venetoclax Plus Daratumumab and Dexamethasone in an Expansion Cohort of a Phase 1/2 Study of Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is a plasma cell malignancy with no cure. Current therapies delay disease progression, prolong survival, and minimize symptoms but most patients (pts) eventually relapse or become refractory (RR). Therefore, there is an unmet need for new therapies. The combination of daratumumab (D), an anti-CD38 antibody, bortezomib (V), a proteasome inhibitor (PI) and dexamethasone (d), are approved for the treatment of MM in pts who have received ≥1 prior line of MM therapy. Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in pts with t(11;14) RRMM. This Phase 1/2 (3-part) study is investigating the combination of VenDd +/- V in RRMM. In parts 1 and 2, VenDd (in pts with t(11;14) RRMM) and VenDVd (in pts with RRMM irrespective of t(11;14) status) displayed tolerable safety profile and high overall response rate (ORR) (Bahlis N et al. J Clin Oncol 2021). Part 3 further evaluates VenDd and DVd in pts with t(11;14) RRMM with a previously reported overall response rate of 72.7%, 100% and 31.3% in the Ven400Dd, Ven800Dd, and DVd arms respectively (Blood (2021) 138 (Supplement 1): 817). Updated results of Part 3 are presented here.

Methods: Part 3 of this Phase 1/2, multicenter, dose-escalation and expansion study (NCT03314181) is evaluating the safety and efficacy of VenDd and DVd in pts with t(11;14) RRMM. Pts (≥ 18 years) with confirmed t(11;14) RRMM with measurable disease per International Myeloma Working Group (IMWG) criteria and who had received ≥1 prior line of MM therapy including an immunomodulatory agent (IMiD) and were non-refractory to PIs or anti-CD38 Ab were enrolled in this study. Pts were randomized 1:1 to receive VenDd or DVd treatment.

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/m² [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 31 May 2022, enrollment into Part 3 has completed with 21, 10 and 24 t(11;14) pts enrolled in the Ven400Dd, Ven800Dd and DVd arms, respectively. The median age (range) was Ven400Dd: 61 (31 - 88); Ven800Dd: 57 (53 - 84); and DVd: 70 (51 - 80) years. Median prior lines of therapy (range) were 1 (1 - 6) in Ven400Dd; 1 (1 - 4) in Ven800Dd; and 2 (1 - 4) in DVd. Pts with ISS I/II/III (%) disease was Ven400Dd: 38.1/28.6/4.8; Ven800Dd: 40.0/20.0/30.0; and DVd: 25.0/25.0/16.7. Pts with ECOG performance status of grade 0/1/2 (%) were Ven400Dd: 52.4/42.9/4.8; Ven800Dd: 60.0/40.0/0; DVd: 33.3/58.3/8.3. Prior PI/IMiD/anti-CD38Ab (%) exposure was Ven400Dd: 85.7/95.2/0; Ven800Dd: 100/100/10; DVd: 87.5/95.8/4.2.

The most common adverse events (AEs) included (Ven400Dd/Ven800Dd/DVd; %): insomnia (52.4/60.0/29.2), fatigue (47.6/50.0/37.5), diarrhea (33.3/50.0/33.3), and nausea (28.6/30.0/20.8). Grade ≥3 AEs were mainly hematologic toxicities. The most frequent serious AE was pneumonia (4.8/10.0/4.2). There were one (Ven800Dd) and three (DVd) pts with an SAE of pyrexia. There was one and three pts with an SAE of upper respiratory tract infection in the Ven800Dd and DVd arms respectively. There were four deaths (one in Ven800Dd and three in DVd arm) reported in part 3 of this study; all occurred following ≥1 post-study MM treatment.

The median treatment exposure at the time of data cut was 12.0, 12.0, and 6.9 months for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The ORR was 95%, 100%, and 62% for the Ven400Dd, Ven800Dd, and DVd arms. The ORR for the combined Ven arms was 98%. The preliminary rate of very good partial response or better (≥VGPR) was 86%, 100%, and 38% for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The preliminary 24-month progression-free survival (PFS) rate was 94% (95% CI 63.2, 99.1), 83% (95% CI 27.3, 97.5) and 47% (95% CI 20.6, 70.2) in the Ven400Dd, Ven800Dd, and DVd arms, respectively (Figure).

Conclusion: The updated results from part 3 of this randomized, phase 1/2 study of t(11;14) RRMM pts treated with VenDd vs DVd continue to demonstrate a tolerable safety profile and responses have deepened compared to our prior presentation. VenDd demonstrated deep responses that appear to be durable; data are not mature and follow-up is ongoing.

Kaufman:AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; AbbVie: Other: Member of steering committee; Incyte: Other: Member of data safety monitoring committee . Quach:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role , Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; Janssen: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: receipt of free drug for investigator-initiated study, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: leadership or fiduciary role, receipt of free drug for investigator-initiated study , Research Funding. Baz:celgene: Consultancy, Honoraria; genentech: Membership on an entity's Board of Directors or advisory committees; Shattuck labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; karyopharm: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria; Merck: Research Funding. Vangsted:Celgene: Honoraria. Harrison:Celgene/BMS, GSK, Janssen Cilag, Haemalogix: Research Funding; Haemalogix: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Eusa: Speakers Bureau; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Honoraria; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Consultancy. Plesner:Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, AbbVie, Roche, Bristol Myers Squibb: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, Genentech, CSL Behring, AbbVie: Membership on an entity's Board of Directors or advisory committees. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. Gibbs:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy; Pfizer: Consultancy, Honoraria. Jalaluddin:AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded 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; Sanofi: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Other; Celgene: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding.

Venetoclax is a BCL-2 inhibitor that is FDA approved for multiple indications. Venetoclax is not currently approved for the treatment of multiple myeloma. Daratumumab, plus bortezomib and dexamethasone is approved for the treatment of multiple myeloma in patients who have received more than one prior line of therapy.