Revisiting the role of alkylating agents in multiple myeloma: Up-to-date evidence and future perspectives

From the 1960s to the early 2000s, alkylating agents (e.g., melphalan, cyclophosphamide, and bendamustine) remained a key component of standard therapy for newly-diagnosed or relapsed/refractory multiple myeloma (MM). Later on, their associated toxicities (including second primary malignancies) and the unprecedented efficacy of novel therapies have led clinicians to increasingly consider alkylator-free approaches. Meanwhile, new alkylating agents (e.g., melflufen) and new applications of old alkylators (e.g., lymphodepletion before chimeric antigen receptor T-cell [CAR-T] therapy) have emerged in recent years. Given the expanding use of antigen-directed modalities (e.g., monoclonal antibodies, bispecific antibodies, and CAR-T therapy), this review explores the current and future role of alkylating agents in different treatment settings (e.g., induction, consolidation, stem cell mobilization, pre-transplant conditioning, salvage, bridging, and lymphodepleting chemotherapy) to ellucidate the role of alkylator-based regimens in modern-day MM management.