Targeting Nuclear Export in Multiple Myeloma: Selinexor, Emerging XPO1 Inhibitors, and Future Therapeutic Strategies

Background and Aim: Exportin 1 (XPO1) is the principal nuclear export receptor for numerous tumor-suppressor proteins, regulatory factors, and selected oncogenic mRNAs and has emerged as a therapeutically relevant vulnerability in multiple myeloma (MM). Selinexor, a first-in-class oral selective inhibitor of nuclear export (SINE), targets XPO1 and has demonstrated antimyeloma activity both as a doublet and in combination with established therapeutic agents. This review summarizes the biological rationale and molecular mechanisms of XPO1 inhibition, clinical evidence supporting selinexor-based therapy, mechanisms of resistance and potential predictive biomarkers, and practical considerations regarding toxicity management. Materials and Methods: A narrative review of the published literature on XPO1 biology and selinexor in MM was performed, with emphasis on preclinical mechanistic studies, prospective clinical trials, and studies addressing resistance, biomarkers, pharmacology, and treatment-related toxicity. Particular attention was given to pivotal and clinically relevant studies evaluating selinexor-based regimens, including Selinexor Treatment of Refractory Myeloma (STORM), BOSTON, and combination cohorts from the STOMP program, together with recent translational studies expanding the molecular framework of XPO1 inhibition. Results: XPO1 inhibition exerts pleiotropic antimyeloma effects through nuclear retention and reactivation of tumor-suppressor proteins, suppression of NF-κB-dependent signaling and oncogenic mRNA translation, enhancement of glucocorticoid signaling, and disruption of cellular protein homeostasis. More recent findings implicate treatment-induced XPO1 degradation through ubiquitin-regulatory mechanisms and suppression of lipid biosynthesis through the Lipin1–SREBP axis. Clinically, selinexor demonstrated activity in heavily pretreated triple-class refractory MM and subsequently showed improved efficacy when incorporated into once-weekly combination regimens, particularly with bortezomib and dexamethasone. Additional combinations with carfilzomib, pomalidomide, lenalidomide, and daratumumab have demonstrated clinically meaningful activity in selected relapsed/refractory multiple myeloma (RRMM) populations. Candidate determinants of response and resistance include XPO1 Cys528 alterations, hnRNPU, USP7-dependent regulation of XPO1 stability, and Lipin1–SREBP signaling, although none is currently prospectively validated for patient selection. Treatment-related cytopenias, gastrointestinal toxicity, fatigue, and hyponatremia remain important but can frequently be addressed through proactive supportive care and dose optimization. Conclusion: XPO1 inhibition represents a mechanistically distinct therapeutic strategy in MM, and selinexor has established clinical activity across multiple relapsed/refractory settings. Increasing use of lower-dose, once-weekly combination strategies has improved its therapeutic feasibility, while emerging insights into XPO1 degradation, metabolic regulation, and molecular determinants of response are broadening the biological framework of this drug class. Prospective biomarker validation and optimization of treatment sequencing will be important for defining the future role of XPO1-directed therapy in the evolving MM treatment landscape.