Updates in the Use of BCL-2-Family Small Molecule Inhibitors for the Treatment of Relapsed/Refractory Multiple Myeloma

SIMPLE SUMMARY: Monumental therapeutic advances have been made over the past two decades for the treatment of multiple myeloma. Anti-apoptotic proteins, such as Bcl-2, Bcl-xL, and Mcl-1, have been found to be upregulated in multiple myeloma cell lines, and small molecule inhibitors that target these proteins are in clinical development with the goal of enhancing apoptosis, reversing drug resistance, and improving the survival outcomes of patients with relapsed/refractory multiple myeloma. In this paper, we review the available clinical data for the Bcl-2-family protein inhibitors currently in clinical development for relapsed/refractory multiple myeloma. ABSTRACT: Despite considerable advances in the treatment of multiple myeloma over the past decade, progression of disease is inevitable, and patients ultimately succumb to relapsed and refractory disease. Efficacious therapeutic regimens that target the key biological pathways that are essential for malignant plasma cell survival are necessary in the efforts to improve patient survival outcomes. The Bcl-2 family of proteins comprise oncogenes that promote myeloma cell survival by conferring resistance to apoptosis. These proteins are frequently upregulated in myeloma cells, thus making them attractive therapeutic targets. Several small molecule inhibitors of Bcl-2-family proteins are currently in clinical development for the treatment of relapsed/refractory multiple myeloma. Venetoclax, a Bcl-2-specific inhibitor, has generated the most clinical data and has shown promising results in patients with multiple myeloma harboring the t (11;14) translocation. Venetoclax has shown efficacy when combined with anti-CD38 monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors. Several other Bcl-2 inhibitors are in clinical development, as are inhibitors of Mcl-1, a Bcl-2-family oncoprotein that is perhaps more critical for myeloma cell survival than Bcl-2. This review will summarize the latest clinical data regarding the clinical development of Bcl-2-family protein inhibitors in the treatment of relapsed/refractory multiple myeloma.