Background
Phase 3, double-blind, placebo-controlled RCT; N=353; JAK inhibitor-naïve myelofibrosis; randomized 2:1 (selinexor + ruxolitinib vs placebo + ruxolitinib). Rationale: ruxolitinib improves splenomegaly/symptoms but lacks reliable clonal burden reduction. Selinexor = oral exportin-1 (XPO1) inhibitor with single-agent activity in myelofibrosis.
Results
Interventions and follow up: Arm A: Selinexor 60 mg PO once weekly + ruxolitinib
Arm B: Placebo + ruxolitinib
Co-primary endpoints: SVR35 (spleen volume reduction ≥35%) and absolute mean change in Total Symptom Score (AbsTSS, excluding fatigue) at Week 24
mFollow up: ~12 mo
Results: SVR35 (Wk 24): 49.8% vs 28.0%; OR 2.58 (95% CI 1.60–4.17); P<.0001 (met)
AbsTSS (Wk 24): −9.9 vs −10.9; not significant (co-primary NOT met)
OS (interim, ~12 mo): HR 0.43 (95% CI 0.19–1.00); nominal P=.022
Arm B: Placebo + ruxolitinib
Co-primary endpoints: SVR35 (spleen volume reduction ≥35%) and absolute mean change in Total Symptom Score (AbsTSS, excluding fatigue) at Week 24
mFollow up: ~12 mo
Results: SVR35 (Wk 24): 49.8% vs 28.0%; OR 2.58 (95% CI 1.60–4.17); P<.0001 (met)
AbsTSS (Wk 24): −9.9 vs −10.9; not significant (co-primary NOT met)
OS (interim, ~12 mo): HR 0.43 (95% CI 0.19–1.00); nominal P=.022
Adverse events
Grade ≥3 (any): 70.1% vs 50.0%
Hematologic: anemia, thrombocytopenia, neutropenia (most common)
GI: nausea more frequent with selinexor, predominantly low-grade and early
Discontinuation (TEAE): 15% vs 9%
Hematologic: anemia, thrombocytopenia, neutropenia (most common)
GI: nausea more frequent with selinexor, predominantly low-grade and early
Discontinuation (TEAE): 15% vs 9%
Conclusions
In JAK inhibitor-naïve myelofibrosis, selinexor + ruxolitinib met the SVR35 co-primary endpoint (~50% vs 28%) but did NOT meet the symptom (AbsTSS) co-primary. An early, nominal OS signal favored the combination. Adds an oral XPO1 inhibitor to the frontline ruxolitinib backbone with improved spleen responses but added hematologic toxicity; symptom benefit unproven.
Key Limitations
One of two co-primary endpoints (AbsTSS) NOT met, undermining a clean win and complicating the value proposition; OS immature (CI upper bound 1.00, nominal P only); higher grade ≥3 hematologic toxicity and more discontinuations; short (~12-mo) follow-up; patient-reported symptom score may be insensitive; risk-stratified subgroup and transfusion-independence data not in the primary report.
Clinical Context
Ruxolitinib is the longstanding frontline JAK inhibitor for intermediate/high-risk myelofibrosis (alternatives: fedratinib, pacritinib, momelotinib). Selinexor (Xpovio) is FDA-approved in multiple myeloma and DLBCL but not in MPNs; on the basis of SENTRY, Karyopharm plans to discuss an sNDA filing with the FDA. Given the missed symptom co-primary, NCCN/ESMO positioning is uncertain pending regulatory review and mature OS. Presented as a late-breaking oral at ASCO 2026 with simultaneous JCO publication.