Selinexor plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: a multicenter, open-label, phase 1 study.

Introduction

Myelofibrosis (MF) is a rare hematologic malignancy associated with substantial morbidity, including splenomegaly, anemia, thrombocytopenia, fatigue, cachexia, and leukemic progression. These effects are primarily driven by oncogenic mutations in JAK2 , CALR , and/or MPL in hematopoietic stem cells, resulting in mutant clonal expansion. 1 , 2 , 3 JAK inhibitors (JAKi), the current standard of care, have demonstrated efficacy in reducing splenomegaly and symptom burden. 1 , 4 , 5 , 6 , 7 However, JAKi treatment is limited by modest response rates, insufficient tolerability, and limited impact on disease modification. 2 , 8 Approximately one-third of patients treated with ruxolitinib achieve spleen volume reduction of ≥35% (SVR35) or total symptom score reduction of ≥50% (TSS50) by week 24 of treatment. 2 Among SVR35 responders, the probability of maintaining response decreases as early as week 12, 3 an important consideration given correlations between splenomegaly and reduced survival. 9 , 10 Treatment-related anemia and thrombocytopenia often necessitate ruxolitinib dose interruptions and reductions, particularly to doses of ≤5 mg twice daily where long-term efficacy is not observed. 4 , 11 , 12 Ruxolitinib also has a limited impact on meaningful disease modification assessed by bone marrow fibrosis, driver mutation allele burden, and anemia. 3 , 13 , 14 , 15 Combination treatments have emerged to address these limitations. In the MANIFEST-2 phase 3 trial of pelabresib plus ruxolitinib and the TRANSFORM-1 phase 3 trial of navitoclax plus ruxolitinib, SVR35 at week 24 was significantly higher with combination treatment than placebo/ruxolitinib (65.9% vs 35.2%, P < .001, and 63.2% vs 31.5%, P < .0001, respectively); however, symptom responses were not significantly improved (52.3% vs 46.3%, P = .216, and 39.2% vs 41.7%, respectively) and neither combination improved anemia. 16 , 17 Therefore, an unmet need remains for novel therapies targeting disease-relevant pathways beyond JAK/STAT alone.

Selinexor, an investigational, oral, selective exportin 1 (XPO1) inhibitor, inhibits XPO1-mediated nucleocytoplasmic cargo transport. 18 In addition to modulating JAK/STAT signaling, 19 , 20 , 21 , 22 XPO1 inhibition affects non-JAK/STAT pathways, including NF-κB proinflammatory signaling, 18 p53-driven cell death, 22 , 23 , 24 , 25 and cell cycle arrest. 18 , 26 , 27 Nonclinical data demonstrate that XPO1-mediated nuclear export may be a critical pathway for MF pathophysiology, with XPO1 inhibition increasing malignant cell death, reducing inflammatory markers, and inducing apoptosis of JAK2 -mutated MF CD34 + cells. 26 , 28 Synergy between selinexor and ruxolitinib or other therapeutic agents in cell lines with or without JAK2 V617F or TP53 mutations provides a strong rationale for further investigation of these combinations. 26 , 28 The ongoing SENTRY phase 1/3 study is evaluating selinexor plus ruxolitinib in JAKi treatment–naïve MF; phase 1 results are presented here.

Methods

Patients and study design

The open-label, phase 1 portion of the multicenter phase 1/3 SENTRY (XPORT-MF-034; NCT04562389 ; EudraCT: 2020-003883-19) study included a 3 + 3 dose escalation followed by dose expansion (7 additional patients at 40 mg and 11 at 60 mg) ( supplemental Figure 1 ). Preliminary safety and efficacy data across phase 1a and phase 1b informed the selection of the recommended phase 3 dose. Eligible patients were ≥18 years of age with primary or secondary MF (per 2016 World Health Organization classification of myeloproliferative neoplasms), spleen volume of ≥450 cm 3 , Dynamic International Prognostic Scoring System intermediate-1 with ≥1 constitutional symptom (eg, anemia, fatigue, weakness, or feeling unwell) or higher, 29 Eastern Cooperative Oncology Group score of ≤2, and platelet count of ≥100 × 10 9 /L. Patients with >5% peripheral blood blasts or >10% bone marrow blasts or previous JAKi treatment for MF were excluded ( supplemental Methods for additional exclusion criteria). The trial was approved and performed in accordance with the International Conference on Harmonization, Guidelines for Good Clinical Practice, appropriate regulatory requirements, and approval of institutional review boards at enrolling institutions with principles originating from the Declaration of Helsinki. All patients provided a written informed consent.

Study treatments

Patients were assigned to receive oral selinexor 40 mg or 60 mg once weekly plus ruxolitinib twice daily (per label including dose modification per package instructions) in 28-day cycles. Selinexor dose reductions or interruptions followed protocol-defined criteria ( supplemental Tables 1 and 2 ). If treatment-emergent adverse events (TEAEs) required treatment discontinuation, both selinexor and ruxolitinib were to be discontinued, regardless of the drug to which the event was attributed. All patients were to receive a single-agent 5-HT 3 antagonist as prophylaxis against nausea, unless otherwise contraindicated, during the first 2 cycles and optionally in subsequent cycles. A neurokinin-1 antagonist, olanzapine, or another antiemetic agent could be added if clinically indicated.

End points and assessments

Primary end points were maximum tolerated dose (MTD), recommended clinical trial dose, and safety. MTD was defined as the highest dose at which ≥1 of 6 patients developed dose-limiting toxicity ( supplemental Methods ) during cycle 1. Secondary end points included SVR35 (by magnetic resonance imaging or computed tomography per International Working Group–Myeloproliferative Neoplasms Research and Treatment criteria), 30 TSS50 (modified Myelofibrosis Symptom Assessment Form version 4.0 excluding fatigue), 31 , 32 and anemia response (International Working Group–Myeloproliferative Neoplasms Research and Treatment criteria). 30 Absolute mean changes in SVR and TSS (Abs-TSS) were also assessed as exploratory end points. Duration of response was defined as the time from the first achieved SVR35/TSS50 response to the time when the patient stopped responding (SVR35, ≤35% reduction from baseline and >25% increase from nadir; TSS50, TSS equaled or exceeded the baseline value). Censoring date was defined as the last efficacy assessment date for patients who discontinued treatment or the last on-study visit date for patients still on treatment. End of treatment (EoT) was defined as treatment discontinuation, withdrawal of the patient from the study, death, or loss to follow-up, whichever occurred first. End of study was defined as completion of survival follow-up for up to 1 year after the EoT visit.

Exploratory end points included antiemetic use, weight changes, hemoglobin stabilization (hemoglobin change from baseline, ≤2 g/dL), platelet and hemoglobin levels, and efficacy by subgroups, including suboptimal ruxolitinib dosage (ruxolitinib ≤5 mg twice daily for ≥5 of the first 6 cycles). Variant allele frequency (VAF) in MF driver genes ( JAK2 , CALR , and MPL ) and other high-molecular-risk (HMR) genes ( ASXL1 , EZH2 , IDH1/IDH2 , SRSF2, and U2AF1 ) were evaluated locally. Plasma cytokine and chemokine concentrations were centrally evaluated using a Luminex 200 system human cytokine/chemokine array 71-plex panel (Eve Technologies, Calgary, Canada). Transforming growth factor β (TGF-β) and hepcidin were evaluated using the Millipore TGF-β 3-Plex Discovery Assay (MilliporeSigma, Burlington, MA) and the R&D Human Hepcidin enzyme-linked immunosorbent assays (R&D Systems, Minneapolis, MN), respectively. Bone marrow biopsies were obtained at screening and week 24. Slide pairs were stained centrally for reticulin, CD61, and CD71. Independent digital images of stained bone marrow slides were evaluated to calculate megakaryocyte density (mean number of CD61 + cells from ≤10 randomly selected fields per image) and spatial analysis (mean distance between nuclei in a field with variable number of nuclei/field and ≤10 fields per image), percentage of CD71 + erythroid cells, and area of reticulin fibers (mean number of intersections from ≤10 randomly selected 400 mm 2 fields per image). 33 , 34

PK

Exposure–response analyses were conducted using model-derived pharmacokinetic (PK) parameters (from empirical Bayes estimates) used to generate exposure models aligned with observed data for both selinexor and ruxolitinib, and association with efficacy and selected safety end points was explored. Ruxolitinib steady-state concentrations were categorized as low or high based on median exposure.

Statistical analysis

Safety and efficacy were analyzed using data cutoffs of 24 February 2023 (primary completion) and 1 August 2023 (duration of response and updated safety). Analyses included all patients who received ≥1 dose of study treatment. The efficacy-evaluable population consisted of all patients who had ≥1 dose of study drug treatment and baseline and postbaseline (12 or 24 weeks) spleen imaging or TSS evaluation, respectively. The primary TSS50 analysis population included all enrolled patients who had a nonzero baseline TSS. Nonresponder imputation was used for missing data.

Results

Patients, disposition, and drug exposure

Between June 2021 and August 2022, 24 patients were enrolled and received ≥1 dose of selinexor (40 mg or 60 mg) plus ruxolitinib ( Table 1 ; supplemental Figure 2 ). Patients were predominantly male (67%) and had a median age of 64 years (range, 44-77), and 46% had primary MF. The Dynamic International Prognostic Scoring System risk category was intermediate-1 in 29% (7/24), intermediate-2 in 46% (11/24), and high risk in 25% of patients (6/24). Five patients had received previous antineoplastic medications ( supplemental Table 3 ). Median platelet count was 257.5 × 10 9 /L (range, 101.0-746.0) and median hemoglobin was 10.0 g/dL (range, 7-14.6 g/dL). Driver mutations at baseline were JAK2 (75%; 18/24), CALR (21%; 5/24), and MPL (4%; 1/24), with concomitant HMR mutations in 46% of patients (11/24). Median baseline spleen volume was 1655 cm 3 (650-3657). Median baseline TSS (excluding fatigue) was 16 (0-54).

As of 24 February 2023, the median duration of exposure to selinexor plus ruxolitinib was 31.5 weeks (range, 6-68) ( supplemental Table 4 ); 13 patients discontinued treatment and 18 patients remained on study ( supplemental Figure 2 ). Reasons for treatment discontinuation were TEAEs (40-mg group: 20%, 2/10; 60-mg group: 21%, 3/14), physician decision (60-mg group: 14%, 2/14), patient withdrawal (40-mg group: 20%, 2/10; 60-mg group: 7%, 1/14), progressive disease (acute myeloid leukemia; 60-mg group: 7%, 1/14), and other (40-mg group: 10%, 1/10; 60-mg group: 7%, 1/14). Two patients (60-mg group) discontinued the study and study drug to receive allogeneic stem cell transplantation. Four deaths occurred during the study, 2 (both in the 60-mg group) within 30 days of final drug administration (1 owing to leukemic transformation [accelerated phase/blast phase progression, cause of death acute myeloid leukemia]; 1 owing to uncertain cause suspected by investigator to be related to underlying chronic heart failure with fluid overload and ascites) and two >30 days after last dose (40-mg, unknown cause; 60-mg, posttransplant lymphoproliferative disorder). None of the deaths were considered related to the study drug by the study investigators.

Dose-limiting toxicities

Three patients were enrolled at each dosage (40 mg once weekly and 60 mg once weekly) in phase 1a. No dose-limiting toxicities were reported.

Safety

All 24 patients experienced ≥1 TEAE, 17 of 24 (71%) experienced ≥1 grade 3+ TEAE, and 8 of 24 (33%) experienced serious TEAEs ( Table 2 ). Common TEAEs overall were nausea (18/24; 75%), fatigue (14/24; 58%), anemia (13/24; 54%), thrombocytopenia (13/24; 54%), constipation (9/24; 38%), vomiting (9/24; 38%), and headache (9/24; 38%). Neutropenia was reported in 7 of 24 (29%) patients and leukopenia in 6 of 24 (25%). Although numerically higher in the 60-mg dose group, overall safety profiles and grades of clinically significant TEAEs were similar between dose groups.

To further support the manageability of the safety profile, exploratory analyses were performed to determine potential mitigating effects of antiemetic prophylaxis. Nausea events among all patients were predominantly grade 1 (50%) and transient in nature (median duration, ∼2 cycles); 1 patient had grade 3 nausea but had not received antiemetic prophylaxis. Among patients who received ≥1 prophylactic antiemetic (58% of all patients), nausea (grade 1 only in the 60-mg group, 1 grade 2 in the 40-mg group) was experienced by 64% of patients compared with 90% of those not receiving prophylactic antiemetics (grades 1-3). Despite the incidence of nausea, over the 10 treatment cycles, absolute weight increased (median increase of 2.5 kg at week 28 in the 60-mg group; supplemental Figure 3 ).

Efficacy

SVR and symptom improvements observed at week 12 were sustained to week 24, with numerically higher response rates in the 60-mg group ( Table 3 ; Figure 1 A-B). SVR35 was achieved at week 24 in 11 of 14 (79%) patients in the 60-mg group and 4 of 10 (40%) in the 40-mg group; most patients in the 60-mg group (10/14; 71%) achieved SVR35 at week 12 compared with 3 of 10 (30%) in the 40-mg group. All patients in the efficacy-evaluable population in the 60-mg group achieved SVR35 at any time ( supplemental Figure 4 A). Mean (standard deviation) absolute change in spleen volume from baseline at week 24 was −1201 cm 3 (592) in the 60-mg group and −433 cm 3 (223) in the 40-mg group.

TSS50 was achieved at week 24 by 7 of 12 (58%) patients in the 60-mg group and by 4 of 10 (40%) in the 40-mg group. In the efficacy-evaluable population, 9 of 10 (90%) patients treated with selinexor 60 mg and 8 of 10 (80%) treated with 40 mg achieved TSS50 at any time ( supplemental Figure 4 B). Both SVR35 and TSS50 were achieved at week 24 in 6 of 12 (50%) patients treated with 60 mg and at any time in 9 of 12 (75%) patients ( Figure 1 C). Improvements in symptom scores were observed across all domains by week 12 for both groups ( Figure 1 D). Mean (standard deviation) absolute changes from baseline in TSS were −19 (13) for the 60-mg group and −8 (8) for the 40-mg group in the efficacy-evaluable population. After the maximum 78-week follow-up, the probability estimate of maintaining SVR (median follow-up, 32 weeks) and TSS50 (median follow-up, 51 weeks) in the 60-mg group was 100% ( supplemental Figure 5 ; additional information on TEAEs, patient disposition, and dose exposure at the 1 August 2023 cutoff can be found in supplemental Tables 5-7 ).

There were no differences for SVR35 and TSS50 across key subgroups, and responses were independent of baseline hemoglobin or platelet levels ( Figure 2 ). No differences were found between subgroups who received ruxolitinib 5/10 mg twice daily vs 15/20 mg twice daily ( Figure 2 ). Seven patients received selinexor plus suboptimal ruxolitinib dose (≤5 mg twice daily for ≥5 of the first 6 cycles); of these patients, 6 of 7 (86%) achieved SVR35, and 5 of 7 (71%) achieved TSS50 at any time ( Figure 3 ). All patients receiving suboptimal ruxolitinib in the 60-mg group achieved SVR35 at any time.

Hemoglobin and platelet change

Anemia response (≥2 g/dL increase in hemoglobin level in patients with baseline hemoglobin <10 g/dL) was achieved at any time in 2 patients (1 in each dose group); 6 of 13 patients (46%) in the 60-mg group and 5 of 10 (50%) in the 40-mg group achieved hemoglobin stabilization. Median hemoglobin levels remained stable through the 10 treatment cycles ( Figure 4 A). Median platelet counts initially decreased in the 60-mg group and then stabilized at >100×10 3 /μL throughout the study; platelet counts in the 40-mg group remained consistently at >100×10 3 /μL ( Figure 4 B).

Exploratory biomarkers

Baseline and post-treatment VAFs were available for 13 patients. Mutations were observed across all 3 driver genes, with mutations in JAK2 in 9 patients, CALR in 3 patients, and MPL in 1 patient ( supplemental Figure 6 ). Reduction in VAF at week 24 was observed in 6 of 8 evaluable patients (75%) in the 60-mg group and in 5 of 5 (100%) in the 40-mg group. Reduction in VAF of ≥20% was observed in 4 of 13 patients (31%); 2 patients with the highest VAF reduction at week 24 (∼30%) were also characterized to have ≥50% VAF at baseline and to be at HMR of ASXL1 and IDH2 mutations. SVR35 was achieved at any time in 11 of 13 patients (85%) with available VAF values.

At baseline, 76% of the 75 cytokines and chemokines analyzed were elevated in MF samples compared with healthy donor samples (data not shown). In most patients (pooled data), early decreases in proinflammatory MF-relevant cytokines were observed by week 4 and maintained at least until EoT ( supplemental Figure 7 ). Affected cytokines included TGF-β1, interferon ɣ, tumor necrosis factor α, interleukin-7 (IL-7), IL-1RA, and IL-16. Early reductions (week 4) in some cytokines, including tumor necrosis factor α, IL-1RA, IL-7, TGF-β1, and IL-18, were associated with week 24 SVR ( supplemental Figure 8 ). Patients in the 60-mg group were generally characterized by a greater, although not statistically significant, reduction in cytokine plasma levels compared with the 40-mg group.

Bone marrow biopsy pairs were available from 14 patients (4 from the 40-mg group; 10 from the 60-mg group). At screening, 1 sample was grade MF-0, 3 were MF-1, 5 were MF-2, 3 were MF-3, and 2 were undetermined. Local MF grade was available for 11 patients, with poor concordance between centrally and locally reviewed data sets; the patient graded MF-0 centrally was graded MF-2 by local review, and only 1 of the 3 patients graded MF-1 centrally was similarly graded locally. In this small cohort of patients, there was no correlation between baseline JAK2 V617F VAF and baseline bone marrow MF grade. Based on the central pathologist review of reticulin-stained slides, MF grade was stable at week 24 in most patients, and only 2 worsened (1 from MF-1 to MF-2, 1 from MF-0 to MF-3). However, whole-slide analysis of 8 pairs (screening and week 24) of biopsies showed decreased reticulin fiber density in 3 patients (37%), decreased CD61 + megakaryocytic progenitor density in 3 (37%) patients, increased megakaryocyte nuclei distance in 4 (50%) patients, and increased CD71 + erythroid progenitors in 2 (25%) patients.

PK

Noncompartmental analysis results are presented in supplemental Table 8 . There was a clear trend of increasing exposure with increasing dose for both selinexor and ruxolitinib ( supplemental Figure 9 ). Simulations using population PK models suggested no impact of ruxolitinib on selinexor exposure or vice versa (data not shown). Patients with model-derived week 1 area under the concentration–time curve (AUC W1 ) of >2500 h × ng/mL had a 100% (9/9) response rate for SVR35 at any point in the study, whereas patients with an AUC W1 of <2500 h × ng/mL had an SVR35 of 56% (5/9) ( supplemental Figure 10 ). Based on a population PK model simulation, ∼30% of patients achieved the AUC W1 target of 2500 h × ng/mL with 40 mg once weekly, and ∼80% achieved this target with 60 mg once weekly. Overall mean ruxolitinib steady-state concentration for all patients was 225nM (134nM in the AUC W1 of <2500 h × ng/mL group and 326nM in the AUC W1 >2500 h × ng/mL group; supplemental Figure 11 ). Given the ruxolitinib exposures observed, the SVR35 response rate in this study was higher than expected with ruxolitinib alone based on historical exposure–response analysis, 35 particularly in patients with exposures of ≤185nM (7/10 responders; 70%), with a 30% expected response rate (3/10). There was no clear exposure–response relationship with selinexor exposure for safety end points (data not shown).

Recommended phase 3 dose

Selinexor at 60 mg once weekly in combination with ruxolitinib offered a manageable safety profile and a substantially improved clinical benefit over the 40-mg dose, which was further supported by the clinical pharmacology analysis. Thus, 60 mg once weekly in combination with ruxolitinib was identified as the recommended phase 3 dosage.

Discussion

This phase 1 component of SENTRY evaluated safety and tolerability of selinexor plus ruxolitinib in JAKi-naïve patients with MF. No dose-limiting toxicities were identified, and thus, no MTD was determined. Notably, 60 mg once weekly was selected as the recommended phase 3 dosage based on substantially higher efficacy (SVR35 at week 24 of 79% vs 40%) without meaningful differences in safety profiles, supported by PK exposure–response analyses.

Overall, selinexor plus ruxolitinib demonstrated a generally tolerable safety profile without major end-organ toxicities. Most TEAEs were grade 1/2, nonserious, and managed with supportive care or dose modifications. Common TEAEs were anemia, nausea, fatigue, thrombocytopenia, constipation, vomiting, and headache with no apparent safety trends when comparing dose levels, acknowledging small numbers and possible confounding effects of ruxolitinib and disease status. Nausea and vomiting rates were consistent with the known selinexor toxicity profile, potentially owing to centrally induced nausea and vomiting after crossing the blood-brain barrier. Meaningful weight gain was observed, suggesting no detrimental effect of nausea on patient weight. Previous experience with selinexor in multiple myeloma has shown a direct correlation between selinexor dose and nausea, 36 which tends to be limited to the first 2 cycles, with improvement as tolerance develops. 37 For patients who received recommended single prophylactic antiemetics, nausea and vomiting were transient and limited to grade 1. Retrospective analyses have shown no apparent superiority in efficacy for any agent/antiemetic class on selinexor-related nausea and have shown that dual antiemetic prophylaxis is superior to single antiemetic prophylaxis, with substantially lower rates of grade 3+ nausea and vomiting. 38 , 39 Accordingly, dual antiemetic prophylaxis is mandated for the first 2 cycles of SENTRY phase 3. 40

Thrombocytopenia and neutropenia were generally asymptomatic laboratory abnormalities without clinical sequelae. Initial platelet and hemoglobin decreases, similar to those reported for ruxolitinib monotherapy, 10 , 32 increased again before stabilizing around week 8, suggesting no clear detrimental or even potentially beneficial effect of selinexor. The patient who discontinued treatment owing to progressive disease had increasing blast counts before study drug initiation, so acute myeloid leukemia transformation was likely unrelated to treatment.

Splenomegaly is associated with worsening of disease symptoms and, although not included in prognostic scores, may decrease survival and limit treatment outcomes. 41 , 42 , 43 Selinexor 60 mg plus ruxolitinib resulted in rapid, deep, and sustained SVR and robust symptom improvement. Symptom reductions were observed across all TSS domains, including fatigue, which has the greatest impact on patient quality of life. 44 , 45 SVR35 or TSS50 rates in the 60-mg group exceeded those expected with JAKi monotherapy, 2 although no direct comparison with other trials can be drawn. The exposure–response analysis provides strong support for SVR35 response rates beyond what would be expected with ruxolitinib monotherapy based on historical exposure–response analysis, 35 particularly in patients with below-average ruxolitinib exposures (≤185 nM), where 70% of patients achieved SVR35 compared with an expected response rate of 30%. SVR35 and TSS50 responses at low or reduced ruxolitinib doses commonly used in clinical practice in response to reduced platelet counts or anemia 46 , 47 , 48 have been reported as limited, 49 , 50 and responses have not been observed with long-term maintenance at 5 mg twice daily. 4 In patients receiving selinexor plus suboptimal ruxolitinib doses, spleen and symptom responses were maintained, with 86% of patients achieving SVR35 and 71% achieving TSS50 at any time. This evidence for the efficacy of selinexor in the absence of an effective ruxolitinib dose may indicate a fundamental role of XPO1 in MF pathogenesis. Two studies are investigating the potential for selinexor monotherapy in patients with MF: ESSENTIAL ( NCT03627403 ) in patients refractory or intolerant to JAKi 51 and the currently ongoing and recruiting SENTRY-2 (XPORT-MF-044; NCT05980806 ) in JAKi-naïve patients with MF and moderate thrombocytopenia. 52

In nonclinical studies, selinexor selectively induced apoptosis in malignant MF CD34 + cells and inhibited CD34+ cell proliferation through p53-dependent and p53-independent pathways. 27 Underscoring the potential of selinexor to act in synergy with multiple therapeutic agents, depletion of malignant cells is more pronounced when combined with ruxolitinib or other MF therapeutic agents than when either drug is used alone. 27 Reductions of VAF seen in the current trial, a feature not typically observed with ruxolitinib alone, 2 align with selective targeting of malignant clones, 26 possibly through antiproliferative activity of nuclear accumulation of proapoptotic p53 in affected cells. 53 Although higher JAK2 VAF is sometimes associated with more advanced fibrosis, 54 reductions in VAF do not consistently translate into immediate or concordant histopathologic improvement, and bone marrow fibrosis changes may not parallel clinical responses after JAKi therapy in MF. 55 In addition, NF-κB transcriptional activity is inhibited by selinexor-induced nuclear localization of IκBα that is enhanced by the ruxolitinib combination. 28 , 56 Changes in cytokine levels showed correlative trends with week 24 SVR, supporting the hypothesis that XPO1 inhibition decreases NF-κB activity and synthesis of specific cytokines. 18 NF-κB, a central transcriptional regulator of inflammation, has a fundamental role in MF pathogenesis, contributing to both symptoms and proliferation of malignant MF clones. 8 , 54 Although the exploratory analysis of biomarkers affecting biological MF hallmarks was suggestive of disease modification, this preliminary proof of concept will need to be corroborated by a longitudinal evaluation in a larger cohort of patients.

The SVR observed with selinexor plus ruxolitinib compares favorably with that seen with ruxolitinib monotherapy in recent studies, with more than doubling of SVR35 at week 24. 10 , 57 These results are comparable with those of navitoclax plus ruxolitinib and pelabresib plus ruxolitinib, with more favorable TSS50 responses in response to selinexor. 17 , 58 Although these differences may be caused in part by the exclusion of intermediate-1-risk MF from the COMFORT studies, resulting in a higher-risk patient population compared with SENTRY phase 1, MANIFEST-2 and TRANSFORM-1 also evaluated treatment-naïve patients and included patients with intermediate-1-risk MF. Limited real-world evidence has demonstrated that ruxolitinib monotherapy achieves SVR35 in ∼27% to 55% of patients with intermediate-1-risk MF at 6 months, which is still numerically less than the SVR35 shown with the combination of selinexor plus ruxolitinib in the present phase 1 study. 59 , 60 Despite the rates of nausea and vomiting in SENTRY phase 1, there was still a reduction in Abs-TSS, which is important, given that chronic patient-based symptoms and clinical side effects are key considerations in oral long-term frontline settings. Thus, the SENTRY phase 3 study, in which 1 goal is to demonstrate long-term tolerability of an all-oral combination, will include Abs-TSS as a coprimary end point and requires a dual antiemetic for the first 2 cycles to help manage time-limited nausea symptoms.

In conclusion, this study provided proof of concept for XPO1 inhibition with selinexor plus ruxolitinib as a treatment strategy in MF. Selinexor plus ruxolitinib exhibited a suitable safety profile without adverse impact on hematologic parameters and with promising clinical activity associated with changes in biomarkers suggestive of disease modification, a feature not observed with ruxolitinib monotherapy. Selinexor’s multifaceted mechanism of action could synergize with ruxolitinib efficacy in the context of a heterogeneous disease such as MF. Selinexor 60 mg once weekly was selected for the phase 3 portion of this study to further evaluate this all-oral combination as a potential first-line treatment for JAKi-naïve patients with MF.

Conflict-of-interest disclosure: H.A. has participated in a speakers’ bureau for and received research support from Incyte Corporation. S.M. has received research funding from Incyte Corporation, Ichnos Sciences, Kartos Therapeutics, Karyopharm Therapeutics, and Taiho Pharmaceutical. A.K. has taken part in advisory boards for Geron, MorphoSys, Servier Laboratories, and Swedish Orphan Biovitrum AB. Y.C., G.G., P.T., and T.M. are employees/stockholders of Karyopharm Therapeutics. S.K.T. has received research funding from Karyopharm Therapeutics and has acted as a consultant, taken part in advisory boards, or received honoraria from AbbVie, Genentech, GlaxoSmithKline, Karyopharm Therapeutics, MorphoSys, and Novartis. The remaining authors declare no competing financial interests.

Acknowledgments

The authors acknowledge Kathleen Martyn and Chris Walker from the Karyopharm Therapeutics Inc Translational Medicine Department for processing clinical samples and biomarker data analysis. The authors thank all patients, caregivers, physicians, and staff at the study sites. Medical writing and editorial support were provided by Yvette Edmonds, PhD, and Matthew Weddig of Peloton Advantage, an OPEN Health company, and were funded by Karyopharm.

This study was sponsored by Karyopharm.

Authorship

Contribution: H.A., S.M., A.K., J.T.P., K.M., Y.C., G.G., P.T., and S.K.T. designed the study; H.A., S.M., A.K., J.T.P., K.M., and S.K.T. performed the study investigation; H.A., S.M., A.K., J.T.P., K.M., and S.K.T. provided the patients or study materials; Y.C. and P.T. collected and assembled the data; Y.C. analyzed the data; H.A., S.M., A.K., J.T.P., K.M., Y.C., G.G., P.T., T.M., and S.K.T. interpreted the data; H.A., S.M., A.K., J.T.P., K.M., Y.C., G.G., P.T., T.M., and S.K.T. prepared the manuscript; and all authors participated in the critical review and revision of this manuscript and provided approval of the manuscript for submission.

Footnotes

Karyopharm Therapeutics is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research, consistent with the European Federation of Pharmaceutical Industries and Associations (EFPIA)/Pharmaceutical Research and Manufacturers of America (PhRMA) Principles for Responsible Clinical Trial Data Sharing. Karyopharm is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. Interested researchers can send their requests to medicalinformation@karyopharm.com .

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Methods, Tables, and Figures

References

1. Tefferi A. Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(5):801–821. doi: 10.1002/ajh.26857.

2. Levavi H, Hoffman R, Marcellino BK. JAK inhibitors in the treatment of myelofibrosis. Clin Adv Hematol Oncol. 2022;20(7):456–467.

3. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi: 10.1186/s13045-017-0417-z.

4. United States Food and Drug Administration . Incyte Corporation; 2021. JAKAFI® (ruxolitinib). Prescribing information.

5. United States Food and Drug Administration . Celgene Corporation; 2021. INREBIC® (fedratinib). Prescribing information.

6. United States Food and Drug Administration . CTI BioPharma Corp; 2022. VONJO™ (pacritinib). Prescribing information.

7. United States Food and Drug Administration . GlaxoSmithKline; 2023. OJJAARA (momelotinib). Prescribing information.

8. Fisher DAC, Miner CA, Engle EK, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFkappaB signaling. Leukemia. 2019;33(8):1978–1995. doi: 10.1038/s41375-019-0379-y.

9. Song MK, Chung JS, Lim SN, et al. Usefulness of spleen volume measured by computed tomography for predicting clinical outcome in primary myelofibrosis. Int J Hematol. 2016;104(4):476–484. doi: 10.1007/s12185-016-2050-y.

10. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. doi: 10.1056/NEJMoa1110557.

11. Copher R, Kee A, Gerds A. Treatment patterns, health care resource utilization, and cost in patients with myelofibrosis in the United States. Oncologist. 2022;27(3):228–235. doi: 10.1093/oncolo/oyab058.

12. Harrison CN, Schaap N, Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann Hematol. 2020;99(6):1177–1191. doi: 10.1007/s00277-020-04002-9.

13. Vachhani P, Verstovsek S, Bose P. Disease modification in myelofibrosis: an elusive goal? J Clin Oncol. 2022;40(11):1147–1154. doi: 10.1200/JCO.21.02246.

14. Maffioli M. Making a case for disease-modifying agents in myelofibrosis. Lancet Haematol. 2022;9(6):e391–e392. doi: 10.1016/S2352-3026(22)00140-5.

15. Pemmaraju N, Verstovsek S, Mesa R, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128(13):2420–2432. doi: 10.1002/cncr.34205.

16. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study [abstract] Blood. 2023;142(suppl 1):628.

17. Pemmaraju N, Mead AJ, Somervaille TCP, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis [abstract] Blood. 2023;142(suppl 1):620.

18. Kashyap T, Argueta C, Aboukameel A, et al. Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death. Oncotarget. 2016;7(48):78883–78895. doi: 10.18632/oncotarget.12428.

19. Walker CJ, Oaks JJ, Santhanam R, et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013;122(17):3034–3044. doi: 10.1182/blood-2013-04-495374.

20. Cheng Y, Holloway MP, Nguyen K, et al. XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer. Mol Cancer Ther. 2014;13(3):675–686. doi: 10.1158/1535-7163.MCT-13-0416.

21. Argueta C, Kashyap T, Klebanov B, et al. Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death. Oncotarget. 2018;9(39):25529–25544. doi: 10.18632/oncotarget.25368.

22. Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335–345. doi: 10.1016/j.clml.2018.03.003.

23. Gravina GL, Mancini A, Sanita P, et al. KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models. BMC Cancer. 2015;15:941. doi: 10.1186/s12885-015-1936-z.

24. Garg M, Kanojia D, Mayakonda A, et al. Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma. Oncotarget. 2017;8(5):7521–7532. doi: 10.18632/oncotarget.13485.

25. Tan M, Wettersten HI, Chu K, et al. Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels. Am J Physiol Ren Physiol. 2014;307(11):F1179–F1186. doi: 10.1152/ajprenal.00406.2014.

26. Yan D, Pomicter AD, Tantravahi S, et al. Nuclear-cytoplasmic transport is a therapeutic target in myelofibrosis. Clin Cancer Res. 2019;25(7):2323–2335. doi: 10.1158/1078-0432.CCR-18-0959.

27. Lu M, Xia L, Hoffman R. Use of combination therapies including the XPO1 inhibitor selinexor in is a potential effective therapeutic strategy to treat myelofibrosis patients. Blood. 2023;142(suppl 1):1792.

28. Maloof ME, Wu S, Ellero A, et al. Paper presented at: 15th International Congress for Myeloproliferative Neoplasms; 3 November 2023. Activity of selinexor as a single agent and synergistic activity with approved/investigational myelofibrosis therapies in vitro. Brooklyn, NY.

29. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment) Blood. 2010;115(9):1703–1708. doi: 10.1182/blood-2009-09-245837.

30. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395–1398. doi: 10.1182/blood-2013-03-488098.

31. Gwaltney C, Paty J, Kwitkowski VE, et al. Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res. 2017;59:26–31. doi: 10.1016/j.leukres.2017.05.012.

32. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I. Haematologica. 2013;98(12):1865–1871. doi: 10.3324/haematol.2013.092155. (Supplementary Materials)

33. Teman CJ, Wilson AR, Perkins SL, Hickman K, Prchal JT, Salama ME. Quantification of fibrosis and osteosclerosis in myeloproliferative neoplasms: a computer-assisted image study. Leuk Res. 2010;34(7):871–876. doi: 10.1016/j.leukres.2010.01.005.

34. Sangle N, Cook J, Perkins S, et al. Myelofibrotic transformations of polycythemia vera and essential thrombocythemia are morphologically, biologically, and prognostically indistinguishable from primary myelofibrosis. Appl Immunohistochem Mol Morphol. 2014;22(9):663–668. doi: 10.1097/PAI.0000000000000000.

35. Center for Drug Evaluation and Research Application Number: 202192Orig1s000 – Clinical Pharmacology and Biopharmaceutis Review(s) 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202192Orig1s000ClinPharmR.pdf

36. Baljevic M, Schiller G, Mark TM, Van Domelen DR, Gasparetto C. Lower dose and weekly schedules of selinexor in multiple myeloma - updated evidence on safety and efficacy. Front Oncol. 2025;15 doi: 10.3389/fonc.2025.1649493.

37. Nooka AK, Costa LJ, Gasparetto CJ, et al. Guidance for use and dosing of selinexor in multiple myeloma in 2021: consensus from International Myeloma Foundation Expert Roundtable. Clin Lymphoma Myeloma Leuk. 2022;22(7):e526–e531. doi: 10.1016/j.clml.2022.01.014.

38. Chari A, Florendo E, Mancia IS, et al. Optimal supportive care with selinexor improves outcomes in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2021;21(12):e975–e984. doi: 10.1016/j.clml.2021.07.014.

39. Gavriatopoulou M, Chari A, Chen C, et al. Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials. Leukemia. 2020;34(9):2430–2440. doi: 10.1038/s41375-020-0756-6.

40. Mascarenhas J, Maher K, Rampal R, et al. Selinexor plus ruxolitinib in JAK inhibitor treatment-naïve myelofibrosis: SENTRY phase 3 study design. Future Oncol. 2025;21(7):807–813. doi: 10.1080/14796694.2025.2461393.

41. Mitra D, Kaye JA, Piecoro LT, et al. Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review. Cancer Med. 2013;2(6):889–898. doi: 10.1002/cam4.136.

42. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120(6):1202–1209. doi: 10.1182/blood-2012-02-414631.

43. Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855–1864. doi: 10.1182/bloodadvances.2021006889.

44. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098–4103. doi: 10.1200/JCO.2012.42.3863.

45. Anderson LA, James G, Duncombe AS, et al. Myeloproliferative neoplasm patient symptom burden and quality of life: evidence of significant impairment compared to controls. Am J Hematol. 2015;90(10):864–870. doi: 10.1002/ajh.24098.

46. Passamonti F, Heidel FH, Parikh RC, et al. Real-world clinical outcomes of patients with myelofibrosis treated with ruxolitinib: a medical record review. Future Oncol. 2022;18(18):2217–2231. doi: 10.2217/fon-2021-1358.

47. Barraco F, Greil R, Herbrecht R, et al. Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis. Br J Haematol. 2020;191(5):764–774. doi: 10.1111/bjh.16729.

48. Coltro G, Sant'Antonio E, Palumbo GA, et al. Assessment of the efficacy and tolerability of ruxolitinib for the treatment of myelofibrosis patients in a real-life setting: an Italian MYNERVA Project. Cancer Med. 2023;12(7):8166–8171. doi: 10.1002/cam4.5618.

49. Talpaz M, Erickson-Viitanen S, Hou K, Hamburg S, Baer MR. Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study. J Hematol Oncol. 2018;11(1):101. doi: 10.1186/s13045-018-0642-0.

50. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13–21. doi: 10.2147/OTT.S53348.

51. Tantravahi S, Patel A, Yap J, et al. Long-term response to selinexor in patients with myelofibrosis and refractory or intolerant to JAK inhibitors: follow-up results of a single-center, phase II, investigator-initiated trial (IIT) [abstract MPN-652] Clin Lymphoma Myeloma Leuk. 2024;24(suppl 1)

52. Scandura JM, Gerds AT, Ritchie EK, Wang X, Kye S, Rampal RK. A phase 2 study to evaluate the efficacy and safety of selinexor monotherapy in patients with JAK inhibitor-naïve myelofibrosis and moderate thrombocytopenia (XPORT-MF-044) [abstract] Blood. 2023;142(suppl 1):3211.

53. Subhash VV, Yeo MS, Wang L, et al. Anti-tumor efficacy of selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor. Sci Rep. 2018;8(1) doi: 10.1038/s41598-018-30686-1.

54. Mascarenhas J, Gleitz HFE, Chifotides HT, et al. Biological drivers of clinical phenotype in myelofibrosis. Leukemia. 2023;37(2):255–264. doi: 10.1038/s41375-022-01767-y.

55. Oh ST, Verstovsek S, Gupta V, et al. Changes in bone marrow fibrosis during momelotinib or ruxolitinib therapy do not correlate with efficacy outcomes in patients with myelofibrosis. EJHaem. 2024;5(1):105–116. doi: 10.1002/jha2.854.

56. Tantravahi SK, Kishtagari A, Maher K, et al. MPN-527 selinexor and ruxolitinib impact on symptom burden in patients with myelofibrosis is potentially driven by inhibition of NF-κB and activation of P53 pathways. Clin Lymphoma Myeloma. 2024;24(suppl 1):S437–S438.

57. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. doi: 10.1056/NEJMoa1110556.

58. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025;31(5):1531–1538. doi: 10.1038/s41591-025-03572-3.

59. Palandri F, Elli EM, Morsia E, et al. Clinical outcomes of ruxolitinib treatment in 595 intermediate-1 risk patients with myelofibrosis: the RUX-MF Real-World Study. Cancer. 2024;130(24):4257–4266. doi: 10.1002/cncr.35489.

60. Davis KL, Côté I, Kaye JA, Mendelson E, Gao H, Perez Ronco J. Real-world assessment of clinical outcomes in patients with lower-risk myelofibrosis receiving treatment with ruxolitinib. Adv Hematol. 2015;2015 doi: 10.1155/2015/848473.

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