AUTHORS
Anna Maria Cafro, MD, Paola Tacchetti, MD, PhD2, Concetta Conticello, MD3, Annalisa Citro, MD4, Antonia Cagnetta, MD5, Sonia Moré, MD6, Stefania Oliva, MD, PhD7, Francesca Fazio, MD, PhD8, Arianna Zappaterra, MD9, Paola Bertazzoni, MD10, Maria Luisa Pioltelli, MD11, Davide Paolo Bernasconi, MS, PhD12, Francesca Gay, MD, PhD13, Elena Zamagni, MD, PhD14, Massimo Offidani, MD15, Maria Teresa Petrucci, MD16, Benedetto Bruno, MD, PhD17, Roberto Cairoli, MD18
AFFILIATIONS
1 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
2 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
3 Azienda Policlinico-S. Marco, University of Catania, Catania, Italy
4 Legnano General Hospital, Legnano, Italy
5 IRCCS Azienda Ospedaliera Metropolitana San Martino, Genoa, Italy
6 AOU delle Marche, Ancona, Italy
7 AOU Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
8 Azienda Ospedaliera Universitaria Policlinico Umberto I Roma, Sapienza University of Rome, Rome, Italy
9 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
10 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
11 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
12 SC Ricerca Innovazione e Trasferimento Tecnologico - Unità di Ricerca Clinica Bicocca Bioinformatics Biostatistics and Bioimaging Centre, Milan, Italy
13 AOU Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
14 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
15 AOU delle Marche, Ancona, Italy
16 Azienda Ospedaliera Universitaria Policlinico Umberto I Roma, Sapienza University of Rome, Rome, Italy
17 AOU Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
18 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
ABSTRACT
Background
Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging, particularly in advanced lines where therapeutic options are limited by prior drug exposure, refractory disease and cumulative toxicity. Agents with novel mechanisms of action may provide disease control and, in selected patients (pts), serve as a bridge to T-cell–redirecting therapies. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate with alkylating activity, clinically meaningful efficacy and a manageable safety profile in heavily pretreated RRMM, including triple-class refractory disease (Richardson PG, J Clin Oncol 2021; Schjesvold F, Future Oncol 2020). However, real-world evidence on its efficacy and safety, particularly regarding sequencing with next-generation immunotherapies, remains limited. We report preliminary results from an Italian multicenter real-world study of melf-dex in RRMM.
Methods
We retrospectively analyzed RRMM pts treated with melf-dex within an Early Access Program at 8 Italian centers between 2021 and early 2025. Melflufen was administered intravenously at 40 mg on day 1 of each 28-day cycle, with dexamethasone 40 mg (20 mg in pts >75 years) on days 1, 8, 15, and 22. Two pts started melflufen at 30 mg due to impaired renal function. Treatment continued until disease progression or unacceptable toxicity. Responses were assessed according to IMWG criteria.
Results
A total of 42 pts (27 male, 15 female) were included in the analysis, with a median age of 71 years (range, 56–84) at melf-dex initiation. Pts had received a median of 4 prior lines of therapy (range, 2–11). All pts were triple-class exposed to at least one immunomodulatory drug, proteasome inhibitor and anti-CD38 monoclonal antibody. Overall, 40% (17) were triple-class refractory, 35% (15) were penta-refractory and 23% (10) were refractory to anti-BCMA therapy. One pt had received an anti-GPRC5D antibody and 5% (2) ide-cel. At least one prior ASCT had been performed in 43% (18) and 26% (11) had non-paraskeletal extramedullary disease. FISH cytogenetics was evaluable in 71% (30), of whom 36% (11) harbored ≥1 high-risk cytogenetic abnormality according to the 2025 EHA-EMN criteria. Moderate renal impairment (creatinine clearance 45–60 mL/min) was present in 18% (8), while 5% (2) had a creatinine clearance <30 mL/min.
Patients received a median of 5 melf-dex cycles (range, 1–23). The overall response rate was 48%, including 14% (6) with deep hematologic responses (CR=2; VGPR=4). Stable disease was observed in 20% (8). Median progression-free survival was 5.02 months (IQR, 2.10–8.92), and median overall survival was 13.51 months (IQR, 5.44–23.02).
Treatment was discontinued due to disease progression in 69% (29) and adverse events (AEs) in 7% (3; 2 infections, 1 melflufen-unrelated cardiac toxicity). One pt discontinued melf-dex to receive CAR-T cell therapy. Median time to melf-dex discontinuation was 3.41 months (IQR, 1.84–7.22).
AEs were reported in 76% (32) of pts and were predominantly hematologic. Grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 36% (15), 50% (21), and 43% (18), respectively. Hematologic toxicity led to dose reductions in 26% (11), with no permanent discontinuations. Grade ≥3 infections occurred in 19% (8; 7 pneumonia, 1 urinary tract infection), while grade ≥3 gastrointestinal toxicity occurred in 7% (3).
Subsequent therapy was administered to 67% (28) of pts: 19% (8) received anti-BCMA bispecific antibodies (BsAb), 5% (2) anti-GPRC5D BsAb and 5% (2) proceeded to CAR-T cell therapy after melf-dex bridging. Twenty-nine percent (12) received other regimens. Among the 19 pts with available data, median time to next treatment following melf-dex discontinuation was 2.13 months (IQR, 1.58–3.00).
Conclusions
Although preliminary, these real-world data support the efficacy and feasibility of melf-dex in heavily pretreated RRMM, including triple- and penta-refractory pts and those previously exposed to T-cell–redirecting therapies. Melf-dex showed a manageable safety profile and provided disease control in this challenging population, while allowing selected pts to proceed to subsequent novel therapies, including BsAbs and CAR-T cell therapy. Larger cohorts and longer follow-up are needed to better define the role of melflufen in advanced RRMM.
DISCLOSURES
Anna Maria Cafro, MD: No relevant conflicts of interest to declare.