Venetoclax in Combination with Daratumumab and Dexamethasone Elicits Deep, Durable Responses in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma: Updated Analyses of Minimal Residual Disease Negativity in Phase 1/2 Study

Introduction: Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in patients with t(11;14)-positive relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown a high overall response rate (ORR) and tolerable safety profile in the Phase 1/2 study (Blood [2021] 138 [Supplement 1]: 817). Here, we report updated analyses of minimal residual disease (MRD) negativity from the Phase 1/2 trial of VenDd at 400 and 800 mg Ven dose levels, versus bortezomib plus Dd (DVd) in patients with t(11;14)-positive RRMM.

Methods: Parts 1 (nonrandomized) and 3 (randomized among Ven [400 mg] Dd, Ven [800 mg] Dd and DVd arms) in this Phase 1/2 multicenter study evaluated VenDd versus DVd in patients with t(11;14)-positive RRMM (as determined by central lab plasma-cell enriched fluorescence in situ hybridization), who had ≥1 prior line of therapy (LOT), including proteasome inhibitor and immunomodulatory drug exposure (NCT03314181). Patients in the investigational arm (VenDd, 28 day cycles [C]) received oral Ven once daily (400 mg or 800 mg) with D (either 16 mg/kg intravenous [IV] or 1800 mg subcutaneous [C1–2: Days 1, 8, 15, 22; C3–6: Days 1 and 15; C7+: Day 1]) and d (40 mg weekly; oral/IV); patients in the DVd arm were dosed per label. MRD negativity (<10⁻⁵) was assessed in bone marrow aspirates by next-generation sequencing (clonoSEQ®, Adaptive, Seattle, WA) at the time of suspected complete response (CR) / stringent CR (sCR), and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive.

Results: As of March 10, 2023, Part 1 enrolled 5 patients (Ven [400 mg] Dd) and 19 patients (Ven [800 mg] Dd). Part 3 enrolled 21 patients (Ven [400 mg] Dd), 10 patients (Ven [800 mg] Dd), and 26 patients (DVd). A total of 80 patients were enrolled (Parts 1 and 3 combined); 55 patients received VenDd (24% high-risk cytogenetics, 53% 1 prior LOT, 2% prior anti-CD38 monoclonal antibody [mAb], 76% lenalidomide-refractory); and 26 received DVd (23% high-risk cytogenetics, 38% 1 prior LOT, 4% anti-CD38 mAb, 92% lenalidomide-refractory). Median (range) follow-up for survivors was longer with VenDd than DVd (28.2 months [1.0–55.7 months] with VenDd vs 16.9 months [0.0–34.1 months] with DVd). VenDd achieved 96% ORR, 93% ≥ very good partial response (VGPR), 67% ≥ CR, and median progression-free survival (PFS) not reached (95% confidence interval [CI]: 35.0– not estimable [NE]). DVd achieved 65% ORR, 39% ≥ VGPR, 19% ≥ CR, and median PFS 15.5 months (7.5–NE). The 33-month PFS rate was 73.4% (95% CI: 56.4–84.6) versus 38.8% (16.3–61.1) for VenDd versus DVd. MRD negativity rates were 38% with VenDd and 8% with DVd. MRD negativity rates in key subgroups, including number of prior LOTs, lenalidomide refractory status, and high-risk cytogenetics, were higher with VenDd compared to DVd (Table). Of 8 VenDd-treated patients assessed for duration of MRD negativity, 6 were MRD negative >6 months, of whom 2 achieved MRD negativity >12 months. No DVd-treated patients had durable MRD negativity >6 months (Figure). No new safety signals were observed.

Conclusions: VenDd treatment showed higher rates of MRD-negativity and sustained MRD-negativity compared to DVd in patients with t(11;14)-positive RRMM, which was associated with longer PFS with VenDd.