Novel treatments: Momelotinib and luspatercept

During the MPN Hub Steering Committee meeting, Ruben Mesa discussed the use of momelotinib and luspatercept for the treatment of patients with myelofibrosis and anemia, featuring John Mascarenhas, Steffen Koschmieder, Laura Michaelis, and Tiziano Barbui.

Mesa first discusses current and emerging therapies for patients with myelofibrosis (MF)-related anemia, including momelotinib and luspatercept, and highlights that both of these treatments are included in the British Society of Haematology (BSH) and the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with MF and anemia.^1,2 

Momelotinib

• Momelotinib inhibits both the BMP/ACVR1/SMAD pathway and the IL-6/JAK/STAT3 pathway, resulting in a decrease in hepcidin, which may improve anemia in patients with MF.³

• Three key phase III trials have assessed the efficacy and safety of momelotinib in patients with MF: SIMPLIFY-1⁴ (NCT01969838), SIMPLIFY-2⁵ (NCT02101268), and MOMENTUM⁶ (NCT04173494).

• In the SIMPLIFY-1 trial, momelotinib demonstrated noninferiority vs ruxolitinib in terms of 35% reduction in spleen volume (SVR35) response (26.5% vs 29.0%; p = 0.011), while transfusion independence (TI) rates were improved (Figure 1).⁴

  • Anemia was observed more frequently in the ruxolitinib arm (38.0%) vs the momelotinib arm (13.6%).⁴

• In the SIMPLIFY-2 trial, although SVR35 response rates were similar, momelotinib improved TI rates vs best available therapy (43% vs 21%; p = 0.012).⁵

• A pooled survival analysis from the SIMPLIFY trials suggested that momelotinib was associated with a survival benefit in patients who became TI.⁸

• Results from the MOMENTUM trial suggested that momelotinib was associated with durable symptom, TI, and SVR35 responses vs danazol (Figure 2).⁹

Luspatercept

• Luspatercept is an activin receptor ligand trap that is approved for the treatment of patients with myelodysplastic syndromes.¹⁰

  • Luspatercept binds tumor growth factor β superfamily ligands to diminish SMAD2/3 signaling and enhance late-stage erythropoiesis.¹¹

• The phase II ACE-536-MF-001 trial (NCT03194542) assessed the efficacy and safety of luspatercept in patients with MF and anemia, with and without both transfusion dependence (TD) and concomitant ruxolitinib treatment.¹¹

• Results from the ACE-536-MF-001 trial demonstrated that luspatercept was associated with anemia response in both TD and non-TD patients (Figure 3).¹¹

  • Luspatercept also improved mean hemoglobin rates in non-TD patients, and the transfusion burden in TD patients.¹¹

  • The safety profile of luspatercept was consistent with previous studies.¹¹ 

• The ongoing phase III INDEPENDENCE trial (NCT04717414) is assessing the efficacy and safety of luspatercept in combination with ruxolitinib in patients with MF.¹²

• Momelotinib and luspatercept have a complementary mechanism of action, which may improve anemia by promoting both early- and late-stage erythropoiesis, suggesting a potential additive and possibly synergistic benefit.¹³

• The phase II ODYSSEY trial (NCT06517875) will assess the combination of momelotinib and luspatercept in TD patients with MF (Figure 4).¹³

Discussion 

Key discussion points: 

• The panel discussed the pooled survival analysis from the SIMPLIFY trials, highlighting the impact of achieving TI on survival in patients treated with momelotinib, the potentially increased TD rates in patients who responded to ruxolitinib, the impact of dose levels, and iron overload.

• Responses based on luspatercept dose were discussed, and it was suggested that patients tend to have a better response at a dose of 1.75 mg compared with lower doses.

• The impact of concomitant leukopenia and thrombocytopenia was raised, and it was highlighted that momelotinib showed relative equivalence in terms of response in patients with platelet counts <50 × 10⁹/L.

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