Multiple myeloma (MM) remains incurable despite advances in treatment, driving interest in novel therapies for relapsed/refractory cases. This large retrospective study evaluated venetoclax-based regimens in 232 heavily pretreated patients with MM, most of whom were triple-class refractory. Patients with the t(11;14) translocation—linked to BCL-2 dependence—had significantly better response rates (64%) and longer median progression-free survival (11.8 months) compared to patients who were non-t(11;14). Among non-t(11;14) patients, BCL-2 expression by immunohistochemistry (IHC) did not reliably predict benefit. Importantly, high-risk cytogenetic abnormalities such as del(17p) and 1q gain/amplification reduced the efficacy of venetoclax even in patients who were t(11;14)-positive.

The best outcomes were observed with venetoclax-daratumumab combinations, supporting their synergistic potential. Overall, venetoclax was well tolerated, with low discontinuation due to adverse events, though infection risks remained notable. These findings reinforce venetoclax’s role in t(11;14)-positive MM, particularly in combination regimens, and suggest limited benefit in non-t(11;14) cases despite BCL-2 IHC positivity. Future research should focus on earlier-line use and refined biomarker-based patient selection to optimize outcomes.

Reference: Bolarinwa A, Nagaraj M, Zanwar S, et al. Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes. Blood Cancer J. 2025;15(1):57. doi: 10.1038/s41408-025-01264-2