Comprehensive review on outcomes from Phase 3 clinical trials of drugs in multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by clinical heterogeneity, high relapse rates, and eventual drug resistance despite advances in therapy. Over the past two decades, phase 3 clinical trials have redefined MM management by integrating novel agents, monoclonal antibodies, and cellular therapies into frontline and relapsed/refractory settings. CD38-targeting antibodies, particularly daratumumab- and isatuximab-based regimens, have demonstrated superior depth of response, prolonged progression-free survival (PFS), and improved overall survival (OS) across transplant-eligible, transplant-ineligible, and relapsed populations. Proteasome inhibitor (PI) and immunomodulatory drug (IMiD)-based triplets and quadruplets, such as bortezomib, lenalidomide, and dexamethasone (VRd), carfilzomib, daratumumab, and dexamethasone (KdD), and pomalidomide and dexamethasone (Pd) combinations, have further enhanced treatment efficacy, while maintenance strategies primarily lenalidomide-based remain central to sustaining remission, with ongoing trials evaluating MRD-guided approaches. The emergence of B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapies, exemplified by idecabtagene vicleucel and ciltacabtagene autoleucel, has transformed outcomes in heavily pretreated, triple-class refractory patients, providing durable responses and quality of life benefits. Despite these advances, therapeutic decisions must consider patient frailty, cytogenetic risk, and prior treatment exposure. Future directions emphasize optimizing sequencing strategies, integrating bispecific antibodies, and validating MRD as a biomarker for treatment cessation. This review consolidates evidence from recent phase 3 trials to provide clinicians with an updated framework for personalized, risk-adapted management of MM.