BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Abstract

Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.

Keywords:

• multiple myeloma
• BCL2 family inhibitors
• venetoclax

Author Contributions

V.A.G. and J.A. prepared the manuscript. V.A.G., J.A., J.L.K., and L.H.B. assisted with the review and editing of the manuscript. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

J.L.K. receives honoraria from Tecnofarma; research support from BMS, Janssen, Bluebird, Sutro Biopharma, Amgen, Abbvie, Fortis Therapeutics, GSK, Genentech, and Celgene; reports consultancy for BMS, Janssen, Genentech, and Celgene; and data safety monitoring board for TG therapeutics. L.H.B. performs consultancy for Genentech and Abbvie: and reports research funding, consultancy, and honoraria from AstraZeneca. The authors report no other potential conflicts of interest for this work.