Melphalan (DB01042): A Comprehensive Clinical and Pharmacological Monograph

Executive Summary

Melphalan (DrugBank ID: DB01042), a bifunctional nitrogen mustard alkylating agent, represents a cornerstone of cancer chemotherapy with a clinical legacy spanning six decades since its initial U.S. approval in 1964. Structurally a derivative of L-phenylalanine, it was rationally designed to leverage amino acid transport systems for preferential entry into malignant cells. Its primary mechanism involves the induction of extensive DNA damage, particularly inter-strand cross-links, leading to cell cycle arrest and apoptosis in both dividing and quiescent cells. This broad cytotoxicity has established melphalan as an indispensable therapeutic agent for several malignancies. Its most prominent and enduring role is in the treatment of multiple myeloma (MM), where high-dose intravenous (IV) melphalan followed by autologous stem cell transplantation (ASCT) remains the undisputed standard of care for consolidation therapy in transplant-eligible patients. It also holds approved indications for the palliative treatment of ovarian cancer and, in a highly specialized formulation, for the liver-directed treatment of uveal melanoma with hepatic metastases.

Despite its proven efficacy, the clinical use of melphalan is complicated by significant challenges. Its oral formulation is plagued by highly variable and incomplete absorption, leading to unpredictable systemic exposure and a tenuous balance between efficacy and toxicity. The principal dose-limiting toxicity across all formulations is profound and prolonged myelosuppression, which necessitates ASCT rescue at high doses and careful hematologic monitoring in all settings. Furthermore, as a direct-acting mutagen, melphalan carries an inherent risk of inducing secondary malignancies, such as myelodysplastic syndrome and acute myeloid leukemia.