The Evolving Role of Alkylating Agents in Multiple Myeloma: From the Past and Present to Next-Generation Peptide Drug Conjugates

Despite significant recent advances in treatment with small molecules, inhibitor, antibodies and immunotherapy, multiple myeloma (MM) remains an incurable malignancy characterized by high rates of relapse. Alkylating agents, a cornerstone of MM treatment, function by inducing DNA cross-linking, disrupting the cell cycle and promoting apoptosis. Melflufen, a novel peptide-drug conjugate, exploits the elevated aminopeptidase activity in MM cells to deliver the melphalan “warhead” intracellularly, thus enhancing efficacy and reducing systemic toxicity by sparing non-malignant tissue. Clinical trials have demonstrated the promising therapeutic potential of melflufen, with combination regimens enhancing response rates and clinical benefit compared with standard therapies including absence of alopecia, decreased mucositis and reduced rates on infection. Melflufen has shown efficacy in relapsed/refractory MM, including in patients resistant to conventional alkylating agents. Ongoing research is focused on optimizing the use of melflufen in personalized and combination as part of treatment strategies in relapsed/refractory disease, underscoring its potential to address critical gaps in the current management of MM. This review explores therapeutic strategies for MM, with a particular emphasis on the evolving role of alkylating agents and the emerging role of melflufen, including its mechanisms of action, preclinical efficacy and outcomes from clinical trials. Peer reviewers: Prof. Dr María-Victoria Mateos, University Hospital Salamanca/IBSAL/CIC/Ciberonc, Salamanca, Spain Prof. Dr Heinz Ludwig, Wilhelminen Cancer Research Institute, Department of Medicine I, Center for Oncology, Hematology with Outpatient Department, and Palliative Care, Clinic Ottakring, Vienna, Austria. Erik Aerts, Hematology Nurses & Healthcare Professionals Group, University Hospital Zurich, Zurich, Switzerland. This article was received on March 15, 2025; accepted after peer review on June 15, 2025; published online on June 27, 2025.