EHA 2019: BELLINI Trial Evaluates Addition of Venetoclax to Bortezomib/Dexamethasone in Relapsed or Refractory Multiple Myeloma
The phase III BELLINI trial—reported by Kumar et al at the 24th Annual Congress of the European Hematology Association (EHA; Abstract LB2601) investigated the efficacy and safety of venetoclax/bortezomib/dexamethasone vs bortezomib/dexamethasone in patients with relapsed or refractory multiple myeloma.
BELLINI was a randomized, double-blind multicenter trial, focused on 291 pretreated patients with relapsed or refractory multiple myeloma who were sensitive or naive to treatment with proteasome inhibitors. Patients were randomly assigned 2:1 to receive venetoclax (800 mg/d) or placebo. Both cohorts received treatment with bortezomib/dexamethasone. Cycles 1 through 8 were administered over 21 days, with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, plus dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Cycles 9 and later were given over 35 days, with bortezomib at 1.3 mg/m2 on days 1, 8, 15, and 22 plus dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23.
Median age was 66 years; 53% had International Staging System (ISS) stage II/III disease; 54% had received two or three prior lines of therapy; 59% had prior stem cell transplant; 70% had prior treatment with a proteasome inhibitor, 68% had prior treatment with an immunomodulatory drug, and 41% had been treated with both; 18% had high-risk cytogenetics; 13% were t(11;14); and 79% were BCL-2–high.
The primary endpoint was progression-free survival.
Findings
The median progression-free survival was 22.4 months in patients treated with the venetoclax combination vs 11.5 months in patients treated with only bortezomib/dexamethasone (hazard ratio [HR] = 0.630, P = .01). The overall response rate was 82% in the venetoclax combination group vs 68% in bortezomib/dexamethasone–only group; very good partial or better response rate was 59% vs 36%; and undetectable minimal residual disease rate was 13% vs 1%.
Median duration of response was 12.8 months in the bortezomib/dexamethasone–only group; it was not yet reached in the venetoclax combination group. Median overall survival was not reached in either arm but favored the bortezomib/dexamethasone–only group. Subgroup analyses indicated that low BCL-2 expression, high-risk cytogenetics, or ISS III disease were associated with decreased progression-free survival and overall survival in the venetoclax combination group.
Safety
The most common treatment-emergent adverse events were diarrhea (58% in the venetoclax combination group, 48% in the bortezomib/dexamethasone–only group), nausea (36%/22%), constipation (34%/31%), and fatigue (31%/32%). The most common grade 3/4 treatment-emergent adverse events were neutropenia (18%/7%), pneumonia (16%/9%), thrombocytopenia (15%/30%), and anemia (15%/15%). The rates of serious adverse events and serious infections were comparable between arms.
There were 51 deaths in the total study population—40 in the venetoclax combination group and 11 in the bortezomib/dexamethasone–only group, mostly due to progressive disease. There were 13 treatment-emergent deaths in the venetoclax combination group and 1 in the bortezomib/dexamethasone–only group.
The study authors concluded, “Although the addition of venetoclax to bortezomib/dexamethasone significantly improved progression-free survival, overall response rate, very good partial or better response, and undetectable minimal residual disease rates, the increased risk of death results in an unfavorable benefit-risk profile in a broad population. In t(11;14) patients, in addition to improvements in progression-free survival, a positive trend in overall survival with venetoclax was observed, suggesting that a biomarker-driven approach with venetoclax may be most appropriate in multiple myeloma.”
Disclosure: For full disclosures of the study authors, visit library.ehaweb.org.
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