Early-line immunotherapy in multiple myeloma: reshaping the treatment paradigm

Multiple myeloma (MM) has traditionally been considered to be incurable, despite increasingly effective induction, transplantation, and maintenance strategies. Chimeric antigen receptor (CAR) T-cell therapies and T-cell–redirecting bispecific antibodies have produced deep and durable responses in heavily pretreated disease and are now moving into earlier lines of therapy. The biologic rationale for earlier use includes the potential for greater T-cell fitness, a more permissive bone marrow immune microenvironment, a lower burden of treatment-resistant disease, and the need to deliver effective therapy before attrition prevents patients from receiving effective treatments. Randomized trials have established the superiority of B-cell maturation antigen (BCMA)-directed CAR T-cell therapy and BCMA- or G protein–coupled receptor class C group 5 member D (GPRC5D)-directed bispecific regimens over conventional therapies in early relapse. In contrast, frontline use remains investigational, with predominantly small, nonrandomized studies and limited follow-up. Ongoing studies are evaluating these approaches as induction, consolidation, maintenance, and measurable residual disease (MRD)–directed therapy, as well as potential alternatives to autologous stem cell transplantation. However, moving T-cell–redirecting immunotherapy earlier introduces important biological and clinical challenges, including sustained immune and antigen engagement, antigen escape and distinct toxicities. Optimal sequencing across targets and treatment modalities, as well as the optimal duration of therapy, remain areas of active investigation. The high efficacy of modern anti-CD38–based quadruplets and transplantation also establishes a demanding benchmark against which early-line immunotherapy must be assessed. In this review, we examine the immunological and clinical rationale for earlier treatment, summarize emerging evidence for CAR T-cell therapies and bispecific antibodies in early-relapsed and newly diagnosed myeloma, and discuss their evolving relationship with autologous transplantation. We further highlight the need for prospective sequencing studies, sustained MRD endpoints and fixed-duration/response-adapted strategies to determine whether earlier immunotherapy can provide durable disease control while reducing cumulative treatment exposure.