Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies

Venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in myeloma patients harboring the t(11:14) translocation. However, despite the high response rates and prolonged PFS, a significant proportion of patients eventually relapse. Here, we aimed to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells’ sensitivity to other treatments. Our data suggests that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in BCL-2 family proteins’ expression in MM cells, conferring broad resistance to standard-of-care anti-myeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments following venetoclax-based regimens. We modeled in vitro the development of an acquired venetoclax-tolerant/resistant phenotype in MM cells. We exposed t(11;14) venetoclax-sensitive myeloma cell lines (KMS12PE and KMS27) to high-dose venetoclax treatment and generated monoclonal DTEP clones from single cells (4-5 single cell clones for each cell line), To determine whether venetoclax resistance in DTEP clones is mediated by genomic or transcriptional adaptation, we conducted whole-genome sequencing (WGS) and RNA-seq analysis of the clones and compared them with the parental cell line.