{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:09:27Z","timestamp":1790179767875,"version":"4.1.0"},"reference-count":77,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite transformative therapeutic advances, multiple myeloma (MM) remains an incurable malignancy characterized by sequential relapses and progressive treatment resistance. Patients with heavily pretreated relapsed or refractory MM continue to face limited therapeutic options and poor outcomes. Melflufen (melphalan flufenamide) is a peptide\u2013drug conjugate that enhances intracellular delivery of alkylating agents via aminopeptidase-mediated activation. Early clinical studies demonstrated encouraging activity in advanced MM, leading to accelerated approval by the U.S. Food and Drug Administration in 2021. However, results from the phase III OCEAN trial raised concerns regarding overall survival, ultimately resulting in withdrawal of the drug from the U.S. market. In this review, we examine the biological rationale, clinical development, and regulatory trajectory of melflufen, and critically reassess its role within the evolving therapeutic landscape of MM. While the negative survival findings observed in the phase III OCEAN trial substantially limited the clinical development of melflufen, the biological principles underlying enzyme-targeted intracellular drug delivery may still provide relevant insights for biomarker-driven therapeutic strategies and future peptide\u2013drug conjugate development in MM.<\/jats:p>","DOI":"10.3390\/cancers18101551","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"1551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Melflufen in Multiple Myeloma: Clinical Limitations, Biological Rationale, and Future Perspectives"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3477-7958","authenticated-orcid":false,"given":"Matteo","family":"Garibotto","sequence":"first","affiliation":[{"name":"Clinic of Hematology, IRCCS Azienda Ospedaliera Metropolitana, Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Soncini","sequence":"additional","affiliation":[{"name":"Clinic of Hematology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Massimo","family":"Lemoli","sequence":"additional","affiliation":[{"name":"Clinic of Hematology, IRCCS Azienda Ospedaliera Metropolitana, Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Clinic of Hematology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Cagnetta","sequence":"additional","affiliation":[{"name":"Clinic of Hematology, IRCCS Azienda Ospedaliera Metropolitana, Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1530-6729","authenticated-orcid":false,"given":"Michele","family":"Cea","sequence":"additional","affiliation":[{"name":"Clinic of Hematology, IRCCS Azienda Ospedaliera Metropolitana, Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Clinic of Hematology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMra1011442","article-title":"Multiple myeloma","volume":"364","author":"Palumbo","year":"2011","journal-title":"N. 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