Karyopharm Therapeutics’s flagship drug selinexor (XPOVIO) is a first-in-class, oral selective inhibitor of nuclear export (XPO1 inhibitor) with a novel mechanism of action that restores tumor suppressor function by blocking nuclear export, enabling anti-tumor activity across multiple malignancies. Approved in more than 50 countries, XPOVIO/NEXPOVIO continues to demonstrate growing global utilization in high unmet need settings, supported by its differentiated biology and expanding clinical evidence base.

In the Phase III SENTRY trial, selinexor plus ruxolitinib demonstrated clinically meaningful improvements in myelofibrosis, including rapid, deep, and sustained spleen volume reduction and a favorable overall survival trend versus ruxolitinib alone. The combination showed a manageable safety profile consistent with known toxicities of each agent, with no new safety signals observed. Supported by a strong intellectual property position extending into 2033–2035 and ongoing global regulatory interactions, selinexor continues to advance as a differentiated therapeutic option in myelofibrosis.

The results presented at ASCO 2026 were as follows:

Key Efficacy Highlights:

• Spleen Volume Reduction 35% or more (SVR35) at Week 24: 49.8% (selinexor plus ruxolitinib) vs. 28.0% (ruxolitinib alone); odds ratio 2.58; p < 0.0001

• SVR35 at Week 12: 49.4% vs. 20.3%

• SVR35 at Week 36: 46.9% vs. 23.0%

• any-time SVR35: 67.7% vs. 44.9%

• Mean spleen volume reduction: −40.0% vs. −26.7%.

• Absolute Total Symptom Score (Abs-TSS) showed no significant difference (−9.9 vs. −10.9; p = 0.825)

• Overall survival favored selinexor plus ruxolitinib (hazard ratio 0.43; nominal p = 0.022), with separation around Month 9.

• Variant Allele Frequency (VAF) ≥20% reduction: 32.0% vs. 23.9%

Key Safety Highlights:

• Treatment-emergent adverse events (TEAEs): 99.1% vs. 97.4%

• Grade ≥3: 70% vs. 50%

• Predominantly hematologic toxicities (thrombocytopenia, anemia, neutropenia) with nausea also frequent

• Treatment discontinuation due to TEAEs: 14.5% vs. 8.6%

• TEAEs leading to death: 0.9% vs. 2.6%

• Confirmed leukemic transformation: 1.7% in both arms

KOL insights

“Although Janus kinase (JAK) inhibitors remain the backbone of therapy in myelofibrosis, there is a clear need to go beyond JAK pathway inhibition to more comprehensively address disease biology. XPO1 inhibitor represents a differentiated therapeutic strategy with the potential to complement existing JAK inhibitor–based regimens and meaningfully advance current treatment paradigms.”–Expert Opinion

“The myelofibrosis community continues to await novel treatment options that can build upon the established benefits of JAK inhibitors. In the Phase III SENTRY trial, improving overall survival remains the ultimate goal for patients living with myelofibrosis, and the selinexor plus ruxolitinib results are highly encouraging, suggesting meaningful progress beyond current standards of care.”–Expert Opinion

Conclusion: 

Myelofibrosis is a rare, progressive myeloproliferative neoplasm marked by bone marrow fibrosis, splenomegaly, and cytopenias, with limited curative options and a high unmet need for disease-modifying therapies. In 2025, primary myelofibrosis accounted for ~75% of all cases in the United States. The current treatment landscape is largely anchored by JAK inhibitor–based therapies, led by ruxolitinib (JAKAFI/JAKAFI XR) as the foundational agent, alongside fedratinib (INREBIC), pacritinib (VONJO), and momelotinib (OJJAARA), each addressing distinct patient subgroups but still largely focused on symptom control and spleen response rather than survival extension. In this setting, selinexor (XPOVIO), a first-in-class selective inhibitor of nuclear export, is poised to intensify competition by extending therapeutic goals beyond JAK inhibition; in the Phase III SENTRY trial, selinexor plus ruxolitinib demonstrated improved spleen volume reduction, early overall survival signal, and potential disease-modifying activity versus ruxolitinib alone, while maintaining a manageable safety profile, collectively signaling a potential shift toward deeper and more durable disease control in myelofibrosis.