The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma

•Significant progress has been made on the treatment of MM during past two decades.•Acquired drug-resistance continues to drive early relapse in primary refractory MM.•XPO1 over-expression and cargo mislocalization are associated with drug-resistance.•XPO1 inhibitor selinexor restores drug sensitivity to subsets of RR-MM cells. Multiple myeloma (MM) treatment regimens have vastly improved since the introduction of immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies; however, MM is considered an incurable disease due to inevitable relapse and acquired drug resistance. Understanding the molecular mechanism by which drug resistance is acquired will help create novel strategies to prevent relapse and help develop novel therapeutics to treat relapsed/refractory (RR)-MM patients. Currently, only homozygous deletion/mutation of TP53 gene due to “double-hits” on Chromosome 17p region is consistently associated with a poor prognosis. The exciting discovery of XPO1 overexpression and mislocalization of its cargos in the RR-MM cells has led to a novel treatment options. Clinical studies have demonstrated that the XPO1 inhibitor selinexor can restore sensitivity of RR-MM to PIs and dexamethasone. We will elaborate on the problems of MM treatment strategies and discuss the mechanism and challenges of using XPO1 inhibitors in RR-MM therapies while deliberating potential solutions.