BELLINI was a phase 3, randomized, double-blind, multicenter study designed to investigate the efficacy and safety of venetoclax + bortezomib + dexamethasone versus bortezomib + dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).
A total of 291 pretreated patients who were sensitive or naïve to treatment with proteasome inhibitors in a 2:1 ratio were randomized to receive venetoclax (194 patients) or placebo (97 patients). The addition of venetoclax was associated with significant improvements in response rate and progression-free survival (PFS) compared with placebo. Significant efficacy was shown in patients with t(11; 14) or BCL2high gene expression. Poster authors this year shared updated safety and efficacy data from the second interim overall survival (OS) analysis.
Baseline patient characteristics were consistent among study arms. Median age was 66 years in the venetoclax arm and 65 years in the placebo arm; 17% had high-risk cytogenetics, 10% had t(11;14), and 34% had BCL2high gene expression. As of September 13, 2019 (data cutoff), 45 (23%) patients in the venetoclax arm and 14 (14%) patients in the placebo arm were still on study. A total of 64 (33%) patients in the venetoclax arm and 24 (25%) patients in the placebo arm had died by median follow-up (28.6 months). As of this analysis, median PFS for all patients (N = 291) in the venetoclax arm was 23.2 months versus 11.4 months for those in the placebo arm (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.43-0.82), and median OS rates for all patients in the venetoclax arm were 33.5 months and not reached for those in the placebo arm (HR, 1.46; 95% CI, 0.91-2.34).
For those patients with t(11;14) translocation (N = 35), median PFS rates were not reached for the venetoclax arm and 9.3 months for those in the placebo arm (HR, 0.09; 95% CI, 0.02-0.41); median OS was not reached for either arm (HR, 0.72; 95% CI, 0.14-3.6). For patients with t(11;14) or BCL2high gene expression (N = 114), median PFS rates were not reached for the venetoclax arm but 9.9 months for those in the placebo arm (HR, 0.31; 95% CI, 0.18-0.53); median OS was not reached for either arm (HR, 0.97; 95% CI, 0.43-2.17). For patients who are non-t(11;14), BCL2low (N = 164), median PFS was 15.3 months in the venetoclax arm versus 11.5 months in the placebo arm (HR, 0.84; 95% CI, 0.55-1.28); median OS rates were 32.8 months in the venetoclax arm and not reported for those in the placebo arm (HR, 1.74; 95% CI, 0.93-3.25). Trends in PFS and OS favored the venetoclax arm for patients with either t(11;14) or BCL2high regardless of cytogenetic status. In contrast, patients with high-risk cytogenetics and BCL2low expression in the absence of t(11;14) were most at risk when treated with venetoclax and favored the placebo arm.
The most common treatment-emergent adverse events in the venetoclax arm were diarrhea (59%), nausea (37%), and constipation (35%) versus placebo (50%, 23%, and 31%, respectively). The number of patients experiencing serious adverse events was similar in each arm (venetoclax arm, 54%; placebo arm, 52%). The most common grade 3 or 4 adverse events were neutropenia (venetoclax arm, 21%; placebo arm, 8%), thrombocytopenia (venetoclax arm, 15%; placebo arm, 30%), anemia (venetoclax arm, 16%; placebo arm, 15%), diarrhea (venetoclax arm, 15%; placebo arm, 12%), and pneumonia (venetoclax arm, 18%; placebo arm, 13%). Discontinuation rates due to adverse events were higher in the venetoclax arm (24%) than in the placebo arm (12%). Treatment-emergent deaths were also higher in the venetoclax arm (12) than in the placebo arm (1).
The authors concluded that adding venetoclax to treatment with bortezomib + dexamethasone improves PFS, but it does so at the cost of a higher mortality rate. The risk–benefit profile is favorable for the population of patients with t(11;14) or BCL2high, because this population experiences the greatest improvement in PFS. This study is still ongoing, evaluating patients for final OS analysis.
Abstract and Poster EP939. EHA 2020. June 12, 2020. Updated results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.