First-line Therapy in Newly Diagnosed Multiple Myeloma

First-line multiple myeloma treatment has evolved from melphalan-prednisone to quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation, yielding significantly improved survival. This review summarizes current approaches to risk stratification and therapy for newly diagnosed multiple myeloma and highlights the emerging role of measurable residual disease-adaptive strategies. We also discuss recent efforts to integrate chimeric antigen receptor T cells and bispecific antibodies into up-front treatment. As biology-driven strategies advance, select patients may achieve durable treatment-free remissions. Ongoing studies will clarify how to best tailor therapy while balancing efficacy, toxicity, and survivorship toward functional cures. SIGNIFICANCE: Despite unprecedented advances, multiple myeloma therapy remains largely uniform and emphasizes indefinite treatment. Herein, although summarizing current standard-of-care therapy, we advocate for individualized approaches informed by disease biology, treatment response, and emerging biomarkers. Novel strategies incorporating immunotherapies are paving the way toward treatment-free remissions and functional cures in select patients.