First Analysis from a Phase 1/2 Study of Venetoclax in Combination with Daratumumab and Dexamethasone, +/- Bortezomib, in Patients with Relapsed/Refractory Multiple Myeloma

Background: Novel and more effective therapies for multiple myeloma (MM) have led to increasing overall survival, but most patients (pts) will eventually relapse or become refractory (RR). The proteasome inhibitor (PI) bortezomib (V), the anti-CD38 antibody daratumumab (D), and dexamethasone (d) are key agents for combination therapy in first-line and RR settings. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in BCL-2-dependent MM cells in vitro. Encouraging clinical efficacy has been observed with Ven monotherapy in t(11;14) pts, and with VenV in pts irrespective of disease genetic background. In view of MM intraclonal heterogeneity, the addition of D to Ven +/- PI is postulated to further enhance antitumor activity of Ven-based regimens in RRMM.

Methods: M15-654 (NCT03314181) is an ongoing Phase 1/2, nonrandomized, multicenter study of combination therapy consisting of VenDd +/- V in pts with RRMM. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of VenDd +/- V. In Part 1, VenDd was evaluated in t(11;14) MM pts who received ≥1 prior line of therapy that included a PI and an immunomodulatory drug (IMiD). In Part 2, VenDVd was evaluated in MM pts irrespective of t(11;14) status who were non-refractory to PIs and received 1 - 3 prior lines of therapy.

Each regimen was evaluated in a dose escalation and expansion phase. In each part, Ven dose escalation was initiated at 400 mg daily (QD) and escalated to 800 mg QD if acceptable safety and tolerability were observed. Escalation cohorts had ≥3 pts, and escalation decisions were based on a Bayesian optimal interval design and the number of pts with a dose limiting toxicity (DLT). In Part 1, cycles (C) were 28-day: Ven QD + D 16 mg/kg intravenous (IV) (C1, 2: Days 1, 8, 15, 22; C3 - 6: Days 1, 15; C7+: Day 1) + d 40 mg total weekly. In Part 2, C1 - 8 were 21-day, C9+ were 28-day: Ven QD + D 16 mg/kg IV (C1 - 3: Days 1, 8, 15; C4+: Day 1) + V 1.3 mg/m² subcutaneous (C1 - 8, Days 1, 4, 8, 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) and 40 mg weekly for C9+.

Results: As of 13 May 2019, 48 pts were enrolled. Of 24 t(11;14) pts treated in Part 1 with VenDd, median age was 63 (range, 51 - 76), median prior lines of therapy was 2.5 (range, 1 - 8), 14 (58%) had ISS II/III disease, and 24 (100%) received both prior PI and IMiD (46% refractory to PI, 71% refractory to IMiD, 42% double refractory). Of 24 pts treated in Part 2 with VenDVd, median age was 64 (range, 41 - 80), median prior lines of therapy was 1 (range, 1 - 3), 14 (58%) had ISS II/III disease, and 6 (25%) were t(11;14). Twenty-two (92%) pts received prior PI, 17 (71%) received prior IMiD (33% refractory), and 15 (63%) received prior PI + IMiD.

The most common adverse events (AEs; VenDd/VenDVd) were fatigue (54%/21%), diarrhea (50%/42%), nausea (33%/38%), insomnia (29%/42%), cough (21%/8%), headache (21%/4%), upper respiratory tract infection (21%/17%), constipation (8%/33%), infusion related reaction (8%/33%), peripheral neuropathy (4%/25%), and dyspepsia (4%/21%). Grade 3/4 AEs were seen in 63%/54% of pts. The most common Grade 3/4 AEs in pts receiving VenDd were neutropenia (13%), fatigue, hyperglycemia, and hypertension (8% each); in pts receiving VenDVd, the most common were insomnia (17%), diarrhea, and thrombocytopenia (8% each). There were 6 pts with infection-related Grade 3/4 AEs (3 VenDd, 3 VenDVd). No AEs of tumor lysis syndrome were observed. Eleven pts had a serious AE (5 VenDd, 6 VenDVd), the most common being pyrexia in 3 pts. One pt treated with VenDd had a DLT of febrile neutropenia, and 1 pt treated with VenDVd died due to progressive disease. No infection-related deaths were seen. Pharmacokinetic analyses demonstrated that addition of D and V did not impact Ven exposure.

Median time on study is 3.6 months (m; 8.1 m escalation, 2.8 m expansion) in the VenDd arm and 3.1 m (5.8 m escalation, 2.4 m expansion) in the VenDVd arm. The objective response rate (ORR) was 92% and 88% in pts receiving VenDd and VenDVd, respectively (Table).

Conclusions: This first analysis of pts treated with VenDd +/- V demonstrate a tolerable safety profile with encouraging efficacy, notably among t(11;14) pts treated with VenDd who had an ORR of 92%. No new safety signals were observed. Although the study is currently on partial clinical hold, enrolled pts continue to be followed. Analysis will be updated at presentation.

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