Selinexor Combo Improves Spleen Volume Reduction in Myelofibrosis

The frontline combination of selinexor (Xpovio) and ruxolitinib (Jakafi) showed a statistically significant improvement in spleen volume reduction of 35% or more (SVR35) vs ruxolitinib/placebo among those with myelofibrosis, according to a press release on data from the phase 3 SENTRY trial (NCT04562389).¹

At week 24, the rate of SVR35 was 50% with the selinexor regimen vs 28% with ruxolitinib alone (P <.0001). Rapid spleen reduction at week 12 was reported in 49% vs 20% of patients in each arm. After 36 weeks, investigators continued to observe spleen volume reduction in 47% and 23% of patients, respectively.

Based on mean change in absolute total symptom score (Abs-TSS) at 24 weeks, symptom improvement from baseline was similar across the experimental and placebo arms. Data showed a 9.89-point improvement with the selinexor combination vs 10.86-point improvement with ruxolitinib alone.

Investigators noted a promising overall survival (OS) signal with the selinexor regimen and intend to follow this end point to further establish this signal (HR, 0.43; 95% CI, 0.19-1.00; P = .0222). Additionally, post hoc analyses at 12 and 24 weeks after initiating treatment showed that SVR35 may correlate with OS outcomes.

Data showed that 32% of patients who received the selinexor combination experienced a reduction of 20% or more in variant allele frequency (VAF) for JAK2, MPL, and CALR vs 24% of those in the placebo arm, suggesting evidence of possible disease modification. Investigators observed no meaningful differences between arms regarding the secondary and exploratory end points of progression-free survival, hemoglobin stabilization, and bone marrow fibrosis improvement.

Selinexor plus ruxolitinib showed a manageable safety profile that was comparable with prior reports of each individual agent. In the combination and placebo arms, respectively, the most common treatment-emergent adverse effects (TEAEs) of any grade included thrombocytopenia (59% vs 43%), anemia (57% vs 58%), nausea (57% vs 17%), constipation (32% vs 36%), and neutropenia (27% vs 9%). Grade 3 or higher TEAEs occurred in 70% vs 50% of patients in each arm, and 15% vs 9% had TEAEs associated with treatment discontinuation.

“The results from SENTRY are an important development for patients as the combination of selinexor plus ruxolitinib meaningfully improved spleen response and we observed a promising signal in [OS]. Reducing spleen volume remains one of the most important treatment goals in myelofibrosis since achieving SVR35 is associated with improvement in [OS],” John Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders, stated in the press release.¹ “While the symptom end point did not reach statistical significance, patients treated in both arms achieved similar symptom improvement relative to baseline. Importantly, while JAK inhibitors have been the backbone of therapy, continued progress requires new therapies that target additional biological pathways. Inhibition of XPO1 represents a differentiated mechanism that has the potential to address these pathways and evolve treatment beyond JAK inhibition alone.”

Developers intend to meet with the FDA to discuss findings from the SENTRY trial and support a filing plan for a supplemental new drug application. Investigators also plan to share additional results from the trial at a future medical conference.

In the phase 3 SENTRY trial, 353 patients with myelofibrosis were randomly assigned 2:1 to receive selinexor at 60 mg once weekly or matched placebo in combination with ruxolitinib at 15 mg or 20 mg orally twice daily.² The trial’s coprimary end points were SVR35 after 24 weeks and the average change in Abs-TSS at 24 weeks vs baseline. Patients 18 years and older with primary myelofibrosis, post-essential thrombocytopenia, or post-polycythemia vera myelofibrosis were eligible for enrollment on the trial.

References

1. Karyopharm's phase 3 SENTRY Trial in myelofibrosis met first co-primary endpoint, demonstrating statistically significant improvement in spleen volume reduction. News release. Karyopharm Therapeutics Inc. March 24, 2026. Accessed March 24, 2026. https://tinyurl.com/ypsue6aa
2. Study of selinexor in combination with ruxolitinib in myelofibrosis (SENTRY). ClinicalTrials.gov. Updated October 3, 2025. Accessed March 24, 2026. https://tinyurl.com/bd78nwwr