The therapeutic landscape for relapsed/refractory multiple myeloma (RRMM) has become increasingly complex, with clinicians navigating a growing array of treatment options across sequential lines of therapy.1 Strategic sequencing becomes essential to maximize clinical benefit, preserving future treatment opportunities, and maintain quality of life.1
Historically, RRMM management centered on three foundational drug classes: immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.1 More recently, Chimeric Antigen Receptor (CAR T‑cell) therapy has provided significant advancements. While these agents have dramatically improved outcomes for patients with RRMM, the rapidly evolving treatment landscape and acquired‑drug resistance has led to limited consensus guidelines regarding therapy selection and sequencing.1,2
The introduction of selective nuclear export inhibition represents a fundamentally different strategy, targeting the XPO1 protein to restore tumor suppressor function through a novel pathway. Early incorporation of mechanistically novel agents may delay multi‑drug resistance and extend the continuum of effective therapy, having shown promise in restoring sensitivity to both proteasome inhibitors and dexamethasone.2
Treatment selection in the second‑ through fourth‑line setting requires careful consideration of disease biology, prior exposures, and patient fitness.3,4 Nuclear export inhibitors demonstrate clinically relevant activity in heavily pretreated populations.2 Their distinct toxicity profile, characterized by often manageable and reversible effects including gastrointestinal upset and hematologic disturbances (e.g., thrombocytopenia, anemia, neutropenia), allows use alongside other drug classes.2
The introduction of CAR T therapies and bispecific antibodies creates intervals requiring effective bridging therapy.4,5 Mechanistically distinct small molecules offer advantages with oral availability, predictable pharmacokinetics, and lack of interference with T‑cell function. For patients progressing after cellular immunotherapy, preserved therapeutic classes with non‑overlapping mechanisms provide critical rescue options.5
Incorporating nuclear export inhibitors into RRMM treatment offers a scientifically grounded, mechanistically diverse therapeutic approach that could establish future treatment options and improve patient outcomes through personalized, disease‑characteristic‑based management strategies.4
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