INTRODUCTION: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. AREAS COVERED: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. EXPERT OPINION: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.

Azienda Ospedaliero Universitaria Città Della Salute E Della Scienza Di Torino University of Torino Torino Italy

Department of Hemato Oncology University of Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology Clínica Universidad De Navarra Pamplona Spain

Department of Hematology Hôpital De La Milétrie CHU De Poitiers Poitiers France

Department of Medical Sciences Division of Clinical Pharmacology Uppsala University Uppsala Sweden

Division of Hematology Oncology and Stem Cell Transplant Rush University Medical Center Chicago IL USA

Institut Josep Carreras and Institut Català d'Oncologia Hospital Germans Trias 1 Pujol Badalona Spain

Jerome Lipper Multiple Myeloma Center Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Oslo Myeloma Center Oslo University Hospital and K G Jebsen Centre for B Cell Malignancies University of Oslo Oslo Norway

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