Venetoclax, Carfilzomib, Dexamethasone Combo Appears Well Tolerated in Relapsed/Refractory MM

In an ongoing phase II study, the addition of the BCL2 inhibitor venetoclax to the combination of carfilzomib and dexamethasone did not raise any new safety concerns and demonstrated preliminary efficacy among a small cohort of patients with relapsed/refractory multiple myeloma (MM). Luciano J. Costa, MD, of the University of Alabama at Birmingham, and colleagues presented their findings at the 2018 ASCO Annual Meeting.

As of April 18, 2018 (data cutoff), 42 patients were enrolled in the trial; 30 were evaluable for efficacy. This dose-escalation study evaluated the venetoclax combination in 28-day cycles in four dosing cohorts:

  • cohort 1: venetoclax 400 mg/day plus carfilzomib 27 mg/m2 plus dexamethasone 40 mg (n=4)
  • cohort 2: venetoclax 800 mg/day plus carfilzomib 27 mg/m2 plus dexamethasone 40 mg (n=3)
  • cohort 3: venetoclax 800 mg/day plus carfilzomib 70 mg/m2 plus dexamethasone 40 mg (n=6)
  • cohort 4: venetoclax 800 mg/day plus carfilzomib 56 mg/m2 plus dexamethasone 20 mg (n=4)

The cohort 4 dose was selected for the dose-expansion phase of the study (n=14), based on patient convenience, the authors noted. Per study protocol, patients were allowed to remain on combination therapy for up to 18 cycles, with the option to continue on venetoclax monotherapy.

Median age for the entire cohort was 67 years (range = 37-79 years) and 68 years (range = 40-79 years) in the efficacy cohort. In both groups, 63 and 66 percent of patients had International Staging System II/III disease, and 20 and 23 percent had t(11;14) mutation, respectively.

Participants had received a median of two prior therapies (range = 1-3 therapies). Approximately two-thirds of patients had disease that was refractory to an immunomodulatory (IMiD) agent (n=26/42; 62%), and one-third had disease that was refractory to both a proteasome inhibitor and an IMiD agent (n=14).

By data cutoff, 30 patients were still on therapy for a median of 4.9 months (range = 0.9-14.5 months); discontinuations were related to disease progression (n=3; 7%), adverse events (AEs; n=1; 2%), consent withdrawal (n=2; 5%), and lack of efficacy (n=3; 7%). In the efficacy-evaluable population, patients were treated for a median of 5.3 months (range = 0.9-14.5 months) and 20 (67%) were still on treatment. Again, discontinuation was most commonly related to disease progression and lack of efficacy (n=3; 7% for each).

In the entire population, 40 of the 42 patients (95%) experienced an AE, and 29 (69%) experienced grade 3/4 AEs. The most common AEs included diarrhea, fatigue, and neutropenia; the most common grade 3/4 AEs included lymphopenia and neutropenia (see TABLE). Twelve serious AEs occurred, but the researchers noted that these were resolved with treatment.

The objective response rate in the efficacy-evaluable patients was 83 percent, including:

  • 7% stringent complete responses (sCRs)
  • 17% CRs
  • 33% very good partial responses (VGPRs)
  • 27% partial responses (PRs)

Response rates were similar regardless of disease refractoriness, but appeared to be lowest among those with IMiD-refractory disease (overall response rate [ORR]=79%). Dr. Costa also noted that ORRs were similar independent of cytogenetic risk status, ranging from 78 to 100 percent. “While responses in the small subset of t(11;14) patients were highest [100%], high-risk and standard-risk patients had comparable responses with [the venetoclax combination],” he said.

Although the study is limited by its small patient population, the investigators concluded that the venetoclax and carfilzomib plus dexamethasone combination showed “promising preliminary efficacy, [which] supports its investigation in patients with relapsed/refractory MM.”

The authors report financial relationships with Genentech, Roche, and Amgen.

Reference

Costa LJ, Stadtmauer EA, Morgan GJ, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Abstract #8004. Presented at the 2018 American Society of Clinical Oncology Annual Meeting, June 1, 2018; Chicago, IL.

TABLE. Summary of Adverse Events
Any-grade Grade 3/4
Any adverse event 40 (95%) 29 (69%)
Diarrhea 24 (57%) 0
Fatigue 17 (41%) 3 (7%)
Thrombocytopenia 15 (36%) 3 (7%)
Nausea 14 (33%) 1 (2%)
Lymphopenia 13 (3%) 10 (24%)
Dyspnea 10 (24%) 2 (5%)
Insomnia 10 (24%) 1 (2%)
Leukopenia 9 (21%) 4 (10%)
Hypertension 4 (10%) 3 (7%)

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