Myelofibrosis is driven by dysregulated JAK-STAT signalling that typically manifests as bone marrow fibrosis, anaemia, splenomegaly, and debilitating symptoms [1]. JAK inhibitors can decrease many symptoms of myelofibrosis but fail to address, and may even induce or worsen, anaemia. Anaemia is the most important negative prognostic factor in myelofibrosis and therefore the most important unmet need in patients with myelofibrosis. Momelotinib is a new drug inhibiting not only JAK1 and JAK2, but also ACVR1 and thus promotes iron metabolism and erythropoiesis [2]. In previous phase 3 trials, treatment with momelotinib demonstrated benefits on symptoms, spleen, and anaemia in JAK inhibitor-naïve myelofibrosis patients [3–5].
The MOMENTUM trial (NCT04173494) was designed to further evaluate the clinical benefits of momelotinib. In this phase 3 trial, momelotinib was compared with danazol, a drug in use to ameliorate anaemia in patients with myelofibrosis as recommended by NCCN and ESMO guidelines. Dr Srdan Verstovsek (University of Texas MD Anderson Cancer Center, TX, USA) presented the first results [6].
A total of 195 patients with symptomatic and anaemic (Hb <10 g/dL) myelofibrosis who were previously treated with a JAK inhibitor were (after JAK inhibitor washout of ≥21 days) 2:1 randomised to momelotinib or danazol treatment for 24 weeks. After 24 weeks, all patients were treated with momelotinib. The primary endpoint was total symptoms score (TSS) response after 24 weeks. TSS response was defined as achieving a ≥50% reduction in TSS over the 28 days immediately before the end of week 24, compared with baseline. Secondary endpoints were transfusion independence rate and splenic response rate at week 24.
TSS response for momelotinib at week 24 was 24.6% versus 9.2% for danazol (P=0.0095). Also concerning spleen response, momelotinib proved superior to danazol: 40% versus 6.2% of patients achieved a 25% reduction (P<0.00001); 23.1% versus 3.1% of patients achieved a 35% reduction (P=0.0006). Transfusion independence at week 24 was achieved by 31% of patients in the momelotinib arm versus 20% in the danazol arm, which was non-inferior due to strict definition. However, mean haemoglobin level showed a rapid, sustained, and higher increase with momelotinib: within 4 weeks mean haemoglobin increased from 8.0 to 9.5 g/dL in the momelotinib arm versus 8.5 g/dL in the danazol arm. The most common adverse events (predominantly grade 1–2) of treatment with momelotinib were diarrhoea, nausea, and asthenia.
“All prespecified primary and secondary endpoints of MOMENTUM were met,” Dr Verstovsek concluded. “These results support future use of momelotinib as an effective treatment in myelofibrosis patients, especially in those with anaemia.”