ASH 2021 | BCL2 family changes associated with venetoclax resistance in multiple myeloma

Rafael Fonseca, MD, Mayo Clinic, Phoenix, AZ, outlines a series of investigations looking into the underlying mechanisms of resistance to venetoclax. Using venetoclax-resistant and venetoclax-sensitive human myeloma cell lines, whole exome sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays were conducted to investigate acquired resistance mechanisms. Patient samples collected before and after venetoclax-resistance development were also examined. Most notably, the investigations revealed changes in BCL2 family regulation. For example, downregulation of BIM and upregulation of BCLXL and MCL-1 were seen in resistant cell lines and patient cells. Furthermore, MCL-1 inhibition substantially enhanced venetoclax sensitivity, even more so when BCLXL was co-inhibited, suggestive of co-dependence in these cells. Dr Fonseca comments on the potential of venetoclax for certain patients subgroups and outlines ongoing investigations of its use as part of combination therapies. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.