OA-29: First Results From the Randomized Portion of a Phase 2 Study of Venetoclax Plus Carfilzomib-Dexamethasone vs Carfilzomib-Dexamethasone in Patients With t(11;14) Relapsed/Refractory Multiple Myeloma

Introduction: Venetoclax (Ven) is a potent, oral BCL-2 inhibitor under investigation for t(11;14)+ relapsed/refractory multiple myeloma (RRMM). The dose-finding part of a Phase 2 study (NCT02899052) of Ven plus carfilzomib (K) and dexamethasone (d) in RRMM showed an overall response rate (ORR) of 80%, and ORR was higher in patients (pts) who were t(11;14)+ vs t(11;14)− (92 vs 75%; Costa, Blood Adv. 2021;5:3748). Here, we report initial safety and efficacy data in patients with t(11;14)+ RRMM treated with Ven (400 or 800 mg) combined with K (70 mg/m2) and d (Ven400Kd or Ven800Kd) vs Kd alone in the dose-finding and randomized parts of the study.

Methods: Pts with t(11;14)+ RRMM were randomized 5:3:5 to receive K (70 mg/m2 weekly) and d (40 mg) plus daily Ven (Ven400Kd or Ven800Kd), or Kd alone. Pts in the randomized part had ≥1 prior line of therapy (LOT); pts in dose finding had 1–3 prior LOT. Primary objectives of the randomized part were to assess safety and efficacy. Secondary objectives were to assess progression-free survival (PFS), overall survival (OS), time to response (TTR), time to progression (TTP), and duration of response (DOR). Efficacy was analyzed in pts randomized to Ven400Kd, enrolled during dose finding or randomized to Ven800Kd, and randomized to Kd. Safety was analyzed in those who received ≥1 dose of study treatment.

Results: At the 19 Jan 2023 cutoff, 48 randomized pts and 8 pts from dose finding were included (Ven400Kd, n=17; Ven800Kd, n=20; Kd, n=19); 1 pt in the Kd group was not treated. Pts had median age of 70.5–73 years, median 2 prior LOT, and had prior exposure to proteasome inhibitors (89–94%), immunomodulatory drugs (85–89%), and anti-CD38 mAb (24−47%). Treatment-emergent adverse events (TEAEs) occurring at ≥50% in any group (Ven400Kd vs Ven800Kd vs Kd) were diarrhea (65 vs 75 vs 6%), nausea (53 vs 55 vs 28%), fatigue (35 vs 50 vs 22%), and vomiting (0 vs 50 vs 11%). Grade ≥3 TEAEs occurred in 88, 85, and 72% of pts. Grade ≥3 TEAEs occurring at ≥20% in any group were lymphopenia (18 vs 30 vs 6%), neutropenia (12 vs 25 vs 11%), and hypertension (24 vs 15 vs 17%). Few Grade ≥3 cardiac disorders occurred (0 vs 5 vs 6%). Grade ≥3 infection rates were higher in the VenKd groups vs Kd (29 vs 20 vs 11%).

At median follow-ups (range) of 16.8 (5.8–30.8), 21.1 (2.2–65.8), and 11.5 (0.0–28.3) months in the Ven400Kd, Ven800Kd, and Kd groups, respectively, corresponding ORRs (95% CI) were 94% (71−100), 95% (75−100), and 58% (34−80). Complete response (CR)/stringent CR rates were 29, 50, and 11%, respectively. Median TTR was 1.0, 1.0, and 2.4 months. 12-month PFS estimates were 67, 85, and 79%, with median PFS of 42.4 months (hazard ratio vs Kd=0.613 [95% CI, 0.153–2.456]) in the Ven800Kd group and not reached (NR) in the Ven400Kd and Kd groups. Medians for OS, TTP, and DOR were NR in any group. More mature data will be presented.

Conclusions: Treatment with VenKd was well tolerated and produced favorable responses in >90% of pts with t(11;14)+ RRMM. Enrollment is ongoing.