HORIZON and LocoMMotion: a descriptive cross-study comparison of outcomes in triple-class refractory multiple myeloma

Background Multiple myeloma (MM) is a relapsing plasma cell malignancy. Patients’ refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies (triple-class refractory) and, more recently, to T-cell-redirected (TCR) therapies have limited treatment options and a poor prognosis. Melphalan flufenamide (melflufen), a first-in-class peptide–drug conjugate, delivers intracellular alkylators independently of prior resistance mechanisms. Objective This was a descriptive cross-study comparison to indirectly compare efficacy and safety of melflufen plus dexamethasone (HORIZON trial) versus real-world standard of care (LocoMMotion study) in relapsed/refractory MM, focusing on TCRMM and high-risk subgroups. Methods Data were analyzed from the single-arm, phase II HORIZON study and the prospective, observational LocoMMotion study. Endpoints included overall response rate, progression-free survival, overall survival, duration of response, and treatment-emergent adverse events. Subgroup analyses considered ≥3 prior therapy lines, prior autologous stem cell transplant, time to progression post-autologous stem cell transplant, extramedullary disease, and high-risk cytogenetics. Results HORIZON enrolled 157 patients (median 5 prior lines; 76% TCR), LocoMMotion 248 patients (median 4 lines; 74% TCR). In the initial analyses of the TCR subgroups, overall response rate was 26% in HORIZON and 25.1% in LocoMMotion; median progression free survival was 3.9 months in both studies, and median overall survival was 11.2 and 11.1 months, respectively. Responses were also observed in patients with high-risk cytogenetics and extramedullary disease, but response rates were low and survival remained limited in these subgroups. Treatment-emergent adverse events were mostly hematologic and manageable; safety was consistent in elderly and heavily pretreated patients. Conclusion This descriptive cross-study comparison provides contextual information on outcomes reported with melflufen plus dexamethasone and real-world standard-of-care regimens in heavily pretreated TCRMM. Given the absence of adjustment for baseline differences and the historical nature of the LocoMMotion comparator, these findings should be considered hypothesis-generating and do not establish comparative efficacy or a specific role for melflufen in contemporary treatment sequencing.