Refining the role of selinexor in multiple myeloma: strategic use in a shifting treatment landscape

The treatment landscape of multiple myeloma (MM) has been revolutionized over the past two decades, leading to unprecedented deep and durable responses, prolonged survival, and improved quality of life. Nonetheless, MM is still an incurable disease, and many patients, especially those with high-risk cytogenetics, renal impairment, or early drug resistance, continue to face poor outcomes. Selinexor, the first-in-class, orally bioavailable selective inhibitor of exportin 1 (XPO1), has shown encouraging results in combination with other agents, and selinexor-based therapy has been approved for the treatment of relapsed/refractory MM, with selinexor-bortezomib-dexamethasone approved for patients with at least one prior line of therapy and selinexor-dexamethasone approved in the later-relapse setting. Notably, selinexor-based combinations have demonstrated consistent efficacy across different subgroups of patients, including those with triple-class refractory disease, renal dysfunction, high-risk cytogenetics, and prior anti-CD38 therapy. We herein provide an overview of selinexor, by describing its mechanism of action, potential interaction with other classes of drugs, novel combinations under investigation, and its role in treatment sequencing, by discussing latest results and potential strategies to mitigate toxicities, increase efficacy, and implement treatment adherence in MM. Overall, selinexor continues to represent a valuable option, especially for patients who are ineligible to receive T-cell-redirecting therapies, or difficult-to-treat patient subgroups, where alternative strategies remain limited. Meanwhile, further data on the use of selinexor-based combinations in different settings are eagerly awaited, to help clarify its role and address persistent unmet clinical needs.