Venetoclax Resistance Results in Broad Resistance to Majority of Anti-MM Agents Due to the Suppression of Apoptosis but Can be Overcome By BCMA-Targeted Immunotherapy

Venetoclax represents the first example of personalized medicine in multiple myeloma (MM), as it has meaningful clinical activity in patients harboring the t(11;14) translocation. This subgroup of patients generally displays upregulated BCL-2 expression and/or a higher BCL-2/BCL-X Lratio, reflecting an imbalance between cell survival (promoted by BCL-2) and cell death (promoted by BCL-X L). The Bellini study demonstrated significantly superior response rate and progression-free survival (PFS) with combination of Venetoclax and Bortezomib in relapsed myeloma, however, the overall survival in the arm with venetoclax was inferior. Part of the decrease in overall survival (OS) was considered to be related with increased incidence of infections, however, OS is also significantly impacted by response to subsequent therapies. Here, we investigated whether acquired venetoclax resistance could lead to global resistance to multiple subsequent anti-MM therapies and in turn can explain the decreased OS.