Work

Melflufen in Multiple Myeloma: Clinical Limitations, Biological Rationale, and Future Perspectives

Year: 2026

Type: article

Abstract: 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-drug 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-drug conjugate development in MM.

Source: Cancers

DOI: 10.3390/cancers18101551

Authors: Matteo Garibotto, Debora Soncini, Roberto M. Lemoli, Antonia Cagnetta, Michele Cea

Institutions: Ospedale Policlinico San Martino, IRCCS Azienda Ospedaliera Metropolitana, University of Genoa

Language: English

Topic: Multiple Myeloma Research and Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499