Venetoclax with bortezomib and dexamethasone improves response rates for patients with relapsed or refractory multiple myeloma, particularly in patients with a specific genetic profile, according to research published in The Lancet Oncology.
Many patients with multiple myeloma experience long-term remission, but relapse rates remain high. The randomized, phase 3, double-blind BELLINI trial (ClinicalTrials.gov Identifier: NCT02755597) compared venetoclax, an oral BCL-2 inhibitor, combined with bortezomib and dexamethasone to placebo with bortezomib and dexamethasone. In the study, 291 patients were randomly assigned 2:1 to each group with 194 in the venetoclax group and 97 in the placebo group.
The venetoclax group had a median progression-free survival (PFS) of 22.4 months compared with 11.5 months in the placebo group. A larger proportion of patients in the venetoclax group achieved a complete response or better with minimal residual disease negativity compared with those in the placebo group. Median overall survival (OS) was not reached in either treatment group.
Both treatment groups experienced adverse events, and the venetoclax group had a higher rate of mortality; 99% of patients in each group experienced treatment-related adverse events, and approximately half of patients in each group (48% in the venetoclax group vs 50% in the placebo group) experienced serious treatment-emergent events. More fatal infections occurred in the venetoclax group, and 13 treatment-emergent deaths were reported in the venetoclax group compared with 1 in the placebo group.
Multiple myeloma has a range of disease characteristics, with clinical features driven by underlying genetic abnormalities. The authors noted that previous research has found patients with BCL-2 dependent disease respond better to venetoclax. BCL-2 dependency differs between patients and is affected by the expression and presence of BCL-2 protein family abnormalities; one such abnormality is t(11;14) translocation.
In a subset of 35 patients with t(11;14) translocation, median PFS was not reached in the venetoclax group, compared to 9.5 months in the placebo group. Patients with high BCL2 expression (66 in venetoclax and 32 in placebo) had a PFS of 22.4 months with venetoclax compared with 9.9 months with placebo.
In the trial, approximately 26% of patients in the venetoclax group had a complete response or better. However, venetoclax has a higher risk of death and should be considered in biologically selected patients who have t(11;14) translocation and high BCL2 expression. The limitations of this study include a small sample size and small subset of patients with t(11;14) translocation.
“The finding that patients with t(11;14) and those with high BCL2 expression appear to have a more [favorable] risk-benefit profile than patients without t(11;14) and with low BCL2 expression suggests that a biomarker-driven approach might be appropriate for the use of venetoclax in multiple myeloma,” the authors wrote.
“This concept is being explored in an ongoing phase 3 trial (ClinicalTrials.gov Identifier: NCT03539744) that is comparing venetoclax and dexamethasone or pomalidomide and dexamethasone in patients with t(11;14)-positive relapsed or refractory multiple myeloma,” concluded the investigators.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. Published online October 29, 2020. doi:10.1016/S1470-2045(20)30525-8