Venetoclax vs Placebo in Combination with Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma

The phase 3 BELLINI trial was designed to investigate the efficacy and safety of venetoclax/bortezomib/dexamethasone versus bortezomib/dexamethasone in patients with relapsed/refractory multiple myeloma. This randomized, double-blind, multicenter study randomized 291 pretreated patients with relapsed/refractory multiple myeloma who were sensitive or naïve to treatment with proteasome inhibitors in a 2:1 ratio 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 demonstrated in patients with t(11; 14) or BCL2^high gene expression. This year, poster authors shared updated safety and efficacy data from the second interim overall survival (OS) analysis.

Baseline patient characteristics were consistent among study arms. In the venetoclax arm, median age was 66 years (65 in the placebo arm), 17% had high-risk cytogenetics, 10% had t(11;14), and 34% had BCL2^high gene expression. As of data cutoff (September 13, 2019), 45 (23%) patients in the venetoclax arm and 14 (14%) patients in the placebo arm were still on study. By median follow-up (28.6 months), 64 (33%) patients in the venetoclax arm and 24 (25%) patients in the placebo arm had died. As of this analysis, median PFS for all patients (N = 291) in the venetoclax arm was 23.2 months versus 11.4 months in the placebo arm (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.43-0.82), and median OS for all patients in the venetoclax arm was 33.5 months and not reached for the placebo arm (HR, 1.46; 95% CI, 0.91-2.34).

For those with t(11;14) translocation (N = 35), median PFS was not reached for the venetoclax arm and was 9.3 months for 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 those with t(11;14) or BCL2^high gene expression (N = 114), median PFS was not reached for the venetoclax arm, but was 9.9 months for 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 those who are non-t(11;14), BCL2^low (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 was 32.8 months in the venetoclax arm and not reported for the placebo arm (HR, 1.74; 95% CI, 0.93-3.25). For patients with either t(11;14) or BCL2^high regardless of cytogenetic status, trends in PFS and OS favored the venetoclax arm. In contrast, patients with high-risk cytogenetics and BCL2^low expression in the absence of t(11;14) favored the placebo arm and were most at risk when treated with venetoclax.

In the venetoclax arm, the most common treatment-emergent adverse events were diarrhea (59% vs 50% in placebo), nausea (37% vs 23% in placebo), and constipation (35% vs 31% in placebo). 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 due to adverse events was higher in the venetoclax arm (24%) than the placebo arm (12%). Treatment-emergent deaths were also higher in the venetoclax arm (12) than the placebo arm (1).

The authors concluded that adding venetoclax to bortezomib/dexamethasone treatment improves PFS, but it does so at the cost of a higher mortality rate. For the population of patients with t(11;14) or BCL2^high, the risk–benefit profile is favorable, as this population experiences the greatest PFS improvement. This study is still under way for final OS analysis.

Reference

• 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.