Positioning of Melflufen in Heavily Pretreated <scp>RRMM</scp> Patients: Real‐World Evidence in a Rapidly Evolving Therapeutic Landscape

Modern therapies have clearly marked the history of multiple myeloma (MM), leading to undisputed advantages in terms of sustained responses and prolonged survival, while progressively improving patients' quality of life. Nonetheless, disease recurrence and resistance to available therapies underscore the importance of identifying additional treatment options, especially in hard-to-treat patients, or when access to cutting-edge immunotherapies is limited. Melflufen (melphalan-flufenamide) plus dexamethasone has been approved by the European Medicines Agency for triple-class-refractory MM patients after ≥ 3 prior therapies, but current data from real-world settings are scarce. We herein report data from a single-center experience of 17 relapsed/refractory MM patients treated with melflufen-dexamethasone outside clinical trials between December 2021 and July 2025 in Bologna (Italy). The overall response rate was 41%. At a median follow-up (mFU) of 8 months, mPFS was 3.7 months (95% CI 1.8-NR) in the overall population, being 9.0 months (95% CI 7.8-NR) in responders (mFU 10 months), while mOS has not been reached (95% CI 13.5-NR) either in the total population or in subgroups. Notably, 11/17 patients received subsequent therapies (seven receiving novel immunotherapeutic approaches), achieving deeper and more durable responses than those receiving conventional regimens. Grade ≥ 3 hematologic toxicities were common (35% anemia, 53% neutropenia, 53% thrombocytopenia), while grade ≥ 3 nonhematologic events were less frequent (mainly fatigue: 6%, and infections: 23.5%). No secondary primary malignancies were recorded. Collectively, our data confirmed the efficacy previously reported with melflufen-dexamethasone and its manageable safety profile, even in elderly patients likely more fragile and more heavily pretreated than those included in the trials. Overall, melflufen-dexamethasone may represent a treatment option, especially for patients refractory to novel immunotherapies or those who are not ideal candidates to receive such treatments while still preserving access to subsequent T-cell redirecting therapies, thereby addressing a significant unmet need in this hard-to-treat patient population.