Preliminary experience from the ODYSSEY trial: Efficacy and safety of momelotinib in combination with luspatercept in patients with transfusion-dependent myelofibrosis

Abstract Introduction: The management of patients with transfusion-dependent (TD) anemia represents an area of high medical need in myelofibrosis (MF). Nearly 50% of patients with primary MF become TD by 1 year after diagnosis, which is associated with negative health-related quality of life and survival impacts. While JAK inhibitors are the current standard of care in transplant-ineligible patients with intermediate- or high-risk MF, some such as ruxolitinib cause or worsen anemia. In contrast, the JAK1/JAK2/ACVR1 inhibitor momelotinib is approved for the treatment of adult patients who have JAK inhibitor–naive or –experienced, intermediate- or high-risk MF and anemia, after demonstrating comprehensive spleen, symptom, and anemia-related benefits in phase 3 trials. Luspatercept is a TGF-β superfamily ligand trap approved for the treatment of anemia in β-thalassemia and lower-risk myelodysplastic syndromes. In a phase 2 trial of patients with MF and either TD or non-TD anemia, luspatercept alone or in combination with ruxolitinib was associated with anemia improvements (Gerds A, et al. Blood Adv. 2024); the phase 3 INDEPENDENCE trial is evaluating luspatercept in patients with MF who are receiving a stable dose of a JAK2 inhibitor and require red blood cell (RBC) transfusions. Through respective inhibition of SMAD1/5 and SMAD2/3 phosphorylation, momelotinib and luspatercept offer complementary mechanisms of action promoting both early- and late-stage erythropoiesis. We report an early analysis of the ongoing ODYSSEY trial, which is evaluating the hypothesis that combining momelotinib and luspatercept may provide transfusion burden reductions in more patients with TD MF. Methods: ODYSSEY (NCT06517875) is an open-label, multicenter, global, phase 2 study of patients with TD (≥4 units transfused or a hemoglobin [Hb] level <8 g/dL in the 8 weeks before enrollment) primary or secondary MF and intermediate-1–, intermediate-2–, or high-risk disease per Dynamic International Prognostic Scoring System (DIPSS)/DIPSS-plus. Patients are enrolling in 2 cohorts of approximately 28 patients each: JAK inhibitor naive (cohort 1) or experienced (cohort 2). In cohort 2, previous or current ruxolitinib or fedratinib is permitted (no washout required), while discontinuation of other MF-directed therapy is required ≥28 days before enrollment in both cohorts. Key exclusion criteria include platelet counts <50×109/L and prior treatment with any ACVR1 inhibitor or TGF-β ligand trap. Patients will receive momelotinib 200 mg orally once daily plus a luspatercept starting dose of 1 mg/kg subcutaneously every 3 weeks through week 24. In the absence of safety concerns, luspatercept may be uptitrated not more frequently than every 6 weeks to 1.33 mg/kg and up to a maximum of 1.75 mg/kg. Results: The first patient was enrolled in ODYSSEY in February 2025. As of July 22, 2025, 14 patients (7 JAK inhibitor naive, 7 JAK inhibitor experienced) have been enrolled. Mean age is 71.6 years, 86% are male, and 64% have primary MF; 14%, 64%, and 21% have intermediate-1–, intermediate-2–, and high-risk disease per DIPSS, respectively. Median (range) Hb levels at screening were 8.9 (7.8-9.9) and 8.2 (5.6-9.7) g/dL in the JAK inhibitor–naive and –experienced cohorts, respectively; respective median (range) platelet counts were 170 (69-302) and 136 (60-856) ×109/L. Mean Total Symptom Scores per MF Symptom Assessment Form v4.0 were 18.4 and 26.8 in each cohort. In the JAK inhibitor–naive cohort, spleen size data were available for 5 of 7 patients (71%) enrolled to date, with a mean length of 7.6 cm; in the JAK inhibitor–experienced cohort, spleen size was available for all 7 patients, with a mean length of 12.1 cm. The primary endpoint is transfusion independence (TI) rate by week 24, defined as no RBC transfusions for any ≥12-week period through the end of week 24. Secondary endpoints include safety, pharmacokinetics, and TI rate at week 24 (no RBC transfusions and no Hb levels <8 g/dL for ≥12 weeks immediately preceding week 24). Preliminary efficacy and safety results from an ad hoc analysis of patients enrolled as of early September 2025 will be presented at the ASH Annual Meeting 2025.Conclusions:ODYSSEY builds on the established anemia-related benefits of momelotinib and luspatercept in patients with MF and may highlight momelotinib as a potentially optimal JAK inhibitor backbone for combination with emerging agents in patients with MF and anemia.