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ABSTRACT

Multiple myeloma (MM), a clonal plasma cell malignancy, presents a therapeutic challenge, especially in selecting therapy for patients with relapsed/refractory MM (RRMM). Up to 1-3 prior lines of therapy in this population are considered early relapse. This review provides clinicians with a guide for personalized, evidence-based strategies for treatment of early RRMM. Factors influencing treatment selection, including patient-related factors (e.g., frailty and comorbidities), disease characteristics (e.g., high-risk cytogenetics), prior therapy response, and toxicity profiles, are highlighted. We outline current and emerging transformative novel therapeutics, including anti-CD38 and anti-SLAMF7 monoclonal antibodies, BCMA-directed immunotherapies, such as CAR T-cells, and bispecific antibodies. The review highlights key clinical trials on efficacy (response rates, progression-free survival, overall survival) and safety profiles (e.g., cytokine release syndrome, neurotoxicity, and infections). Crucially, it provides a practical framework for clinical decision-making, including guidance on selecting between different combination regimens, immunotherapy platforms, and considering meaningful therapeutic endpoints and survival. Relapse management following BCMA-directed therapy and potential salvage strategies are outlined. Future directions include next-generation cellular therapies, novel antibody constructs, CELMoDs, and strategies to enhance immunotherapy outcomes.

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