Therapeutic Potential of Venetoclax and Selinexor in Targeting Hypoxia-Induced Vulnerabilities in Multiple Myeloma.

BACKGROUND

Multiple myeloma (MM) is a blood cancer marked by the abnormal clonal growth of plasma cells. Hypoxia plays a critical role in the progression and treatment resistance of MM.

AIMS

This study investigates the expression of B-cell/CLL lymphoma 2 (BCL2) family genes. We also investigated the activity of BCL2 and exportin-1 (XPO1) inhibitors and the potential therapeutic synergy of venetoclax and selinexor under hypoxic conditions.

METHODS AND RESULTS

Analysis of publicly available datasets revealed hypoxia-induced upregulation of BCL2 and BCL2-like 11 (BCL2L11), while BCL2-associated agonist of cell death (BAD) expression was suppressed. Venetoclax, a selective BCL2 inhibitor, demonstrated enhanced cytotoxicity and increased caspase-3/7 activity under hypoxic conditions. Selinexor exhibited potent anti-myeloma effects, including dose-dependent reductions in cell viability and increased apoptotic activity. Combining selinexor with venetoclax under hypoxia produced anti-myeloma effects, significantly reducing cell viability, increasing apoptosis, and disrupting the mitochondrial membrane potential. This combination effectively overcame resistance in bortezomib-resistant MM cells and demonstrated efficacy in primary plasma cell leukemia (PCL) samples.

CONCLUSION

These findings highlight the potential of selinexor and venetoclax combination therapy to exploit hypoxia-induced vulnerabilities in MM cells.