Melphalan in the biologic era: A 70-year story in hematological malignancies and its legacy, evolution, and future

Melphalan, a bifunctional alkylating agent derived from nitrogen mustard, remains a cornerstone in the treatment of multiple hematological and solid malignancies – most notably multiple myeloma – and continues to serve as a key component of conditioning regimens in hematopoietic stem cell transplantation. Despite the rapid emergence of novel therapeutic classes including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and cellular therapies, melphalan remains the standard conditioning regimen for autologous stem cell transplantation due to its potent, broad-spectrum antitumor activity and predictable myeloablative properties. This review focuses on the current understanding of melphalan’s historical development, molecular mechanisms, pharmacokinetic characteristics, clinical applications across hematologic malignancies, safety considerations, and its evolving role alongside contemporary treatment modalities. We conducted systematic literature searches across major medical databases, including PubMed, Google Scholar, and the recent IMWG and Mayo Clinic Guidelines for myeloma, focusing on publications from 2000 to 2025 that provided insights into melphalan’s clinical utility, pharmacological properties, and therapeutic optimization.