A three gene signature predicts response to selinexor in multiple myeloma

Selinexor is the first selective inhibitor of nuclear export (SINE) to be approved for treatment of relapsed or refractory multiple myeloma (MM). There are currently no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aim to characterize transcriptomic correlates of response to selinexor-based therapy, and present a novel, three-gene expression signature that predicts selinexor response in MM. We analyzed RNA sequencing of CD138+ tumor cells from bone marrow of 100 MM patients who participated in the BOSTON study and identified three genes upregulated in responders. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM, and additionally in an external cohort of 35 patients treated in a real world setting outside of clinical trials. We also found that the signature tracked with response in a cohort of 57 patients with recurrent glioblastoma treated with selinexor. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. This signature has important clinical relevance as it could identify cancer patients that are most likely to benefit from treatment with selinexor-based therapy.