Predictors of Response to Venetoclax and Therapeutic Potential of CDK7 Inhibition in Multiple Myeloma

Venetoclax, a selective BCL2 inhibitor, has emerged as a promising therapeutic agent for multiple myeloma (MM), particularly in patients harboring the t(11;14) translocation. In this study, we set out to identify markers of sensitivity and resistance to venetoclax in a real-world patient population, aiming to facilitate the development of personalized therapeutic strategies. Through the analysis of RNA-seq data from relapsed/refractory patients treated with venetoclax, either as a single agent or in combination with other drugs, we unveiled a novel six-gene signature that significantly stratified patients into risk groups for relapse and further validated its clinical relevance in two independent clinical and ex vivo datasets. In our cohort, we explored Cyclin-Dependent Kinase 7 (CDK7) inhibition as a potential strategy to overcome venetoclax resistance. In vitro experiments demonstrated that CRISPR-Cas9-mediated CDK7 depletion led to decreased MCL1 levels, enhancing the sensitivity of MM cells to venetoclax.