Reassessing the clinical value of momelotinib in myelofibrosis: An ESMO-MCBS:H-based appraisal of SIMPLIFY-1 and...

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, systemic symptoms, and anemia, the latter being strongly associated with poor survival and reduced quality of life. Current Janus kinase (JAK) inhibitors improve symptoms and spleen size but often exacerbate anemia, leaving a significant unmet clinical need. Momelotinib, a JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor, has been proposed to address both splenomegaly and anemia through hepcidin suppression. This study critically evaluates the clinical benefit of momelotinib using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H), focusing on the phase 3 trials SIMPLIFY-1 and MOMENTUM. In SIMPLIFY-1, momelotinib demonstrated non-inferiority to ruxolitinib in terms of spleen volume reduction (SVR35 26.5% vs 29.0%) and did not evaluated quality of life as a prespecified outcome, resulting in an ESMO-MCBS:H score indicating no evaluable benefit (NEB). In contrast, in MOMENTUM, conducted in symptomatic, anemic patients previously treated with JAK inhibitors, momelotinib was superior to danazol for MFSAF total symptom score response (≥50% reduction from baseline 25% vs 9%). As no improvement in global health status was observed, MOMENTUM was scored as Grade 1. Interpretation of hematologic benefits remains limited by trial design, as the anemia related outcomes were not primary endpoints and studies were not powered to robustly assess them. Furthermore, the negative SIMPLIFY-2 trial underscores uncertainty in pretreated populations. In conclusion, momelotinib demonstrates a differentiated clinical profile with consistent spleen control and potential hematologic benefits, particularly in anemic patients. However, superiority over other improved JAK inhibitors has not been demonstrated in the pivotal phase 3 trials evaluated. Future trials incorporating anemia-focused primary endpoints and biomarker stratification are warranted to better define its role in myelofibrosis management.