KEY TAKEAWAYS
- The phase II trial aimed to assess two venetoclax doses with Dd vs. bortezomib-Dd in t(11;14)+ RRMM for safety and efficacy.
- The study analyzed ORR and MRD using next-generation sequencing.
- The result demonstrated that VenDd outperformed DVd in t(11;14)+ relapsed myeloma with deeper, longer responses and manageable safety.
Early results from a Phase 1/2 trial suggest venetoclax(Ven), daratumumab dexamethasone(Dd) offer promising anti-tumor activity against t(11;14)+ relapsed/refractory multiple myeloma(RRMM).
The study divided the patients into two cohorts, part 1 (nonrandomized) and 3 (randomized among 400 mg VenDd, 800 mg VenDd, and DVd arms), compared VenDd to DVd in patients with t(11;14)+ RRMM.
Eligible patients had received at least one prior line of therapy(LOT), including exposure to a proteasome inhibitor and immunomodulatory drug. In the VenDd arm (VenDd, 28 days [D] cycles [C]), patients received daily oral ven (400 mg or 800 mg), D (either 16 mg/kg IV or 1800 mg subcutaneous [C1–2: D1, {D2 if split dosing in C1 for IV daratumumab}, 8, 15, 22; C3–6: D1 and 15; C7+: D1]) ), and d (40 mg weekly; oral/IV). DVd arm followed label recommendations.
The overall response rate (ORR) was assessed per IMWG criteria, and minimal residual disease negativity (MRD˗) was evaluated using next-generation sequencing in the bone marrow. The trial aimed to compare the safety and preliminary efficacy of VenDd (at 400 or 800 mg) with DVd (control).
Part 1 of the study included 5 patients (400 mg VenDd) and 19 patients (800 mg VenDd). In Parts 3, 21, 10, and 26, patients were enrolled in the 400 mg VenDd, 800 mg VenDd, and DVd arms, respectively. About 80 patients were enrolled in Parts 1 and 3 combined. Of these, 55 received VenDd (11% del17p, 13% 1q21abn; 53% 1 prior LOT, 2% prior anti-CD38 mAb), and 24 received DVd (21% del17p; 38% 1 prior LOT, 4% anti-CD38 mAb).
The median (range) follow-up and treatment exposure (months) were longer with VenDd compared to DVd (28.2 [1.0–55.7] and 23.3 [1.2–56.3] with VenDd vs. 16.9 [0.0–34.1] and 9.6 [0.5–33.9] with DVd). The most common adverse events(AEs) (>30%) with DVd included diarrhea, insomnia, and fatigue, while with VenDd, they included nausea, upper respiratory tract infection, and COVID-19.
Serious AEs rates were 51% (VenDd) and 25% (DVd). Discontinuation due to AEs occurred in 6% of patients with VenDd (none with DVd). VenDd achieved a 96% ORR, with 93% achieving very good partial response (VGPR), 67% achieving complete response (CR), and 35% achieving MRD negativity (MRD˗) at 10^-5.
The median progression-free survival (PFS) for VenDd was not reached (95% CI: 35.0–NE). DVd achieved a 65% ORR, with 39% achieving VGPR, 19% achieving CR, and 8% achieving MRD˗ at 10^-5. The median PFS for DVd was 15.5 months (7.5–NE).
The 33-month PFS rate was 73.4% (95% CI: 56.4–84.6) for VenDd vs. 38.8% (16.3–61.1) for DVd. Among 8 VenDd-treated patients assessed for the duration of MRD˗, 6 had MRD˗ for >6 months and 2 had MRD˗ for >12 months. No DVd-treated patients had durable MRD˗ for >6 months.
The result demonstrated that VenDd outperformed DVd in t(11;14)+ relapsed myeloma with deeper, longer responses and manageable safety. Dose selection data for venetoclax will follow.
Clinical Trial: https://clinicaltrials.gov/study/NCT03314181
Kaufman, J. L. (2023). “Venetoclax Versus Bortezomib, in Combination with Daratumumab and Dexamethasone, in Patients With t(11;14)-Positive Relapsed or Refractory Multiple Myeloma.” Presented at the 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-29.
