Abstract: Chimeric antigen receptor T-cell (CAR-T) therapy targeting the B-cell maturation antigen (BCMA) has revolutionized the management of relapsed/refractory multiple myeloma (RRMM) by achieving unprecedented initial response rates. Despite this promising outlook, disease relapse remains a critical barrier to long-term remission, underscoring the urgent need to identify resistance mechanisms and optimize therapeutic strategies. This review synthesizes current evidence on the multifactorial drivers of relapse post-BCMA CAR-T therapy, including antigen escape via BCMA loss or trogocytosis, diminished CAR-T cell persistence, immunosuppressive tumor microenvironment remodeling, and T-cell exhaustion. Furthermore, it critically evaluates innovative approaches to overcome relapse, involving next-generation multi-antigen CAR-T constructs, γ-secretase inhibitors to augment BCMA expression, allogeneic CAR-T platforms, and synergistic combinations with immune checkpoint blockade or tumor microenvironment-modulating agents. By integrating preclinical insights with clinical trial data, this work highlights the emerging strategies to enhance CAR-T durability and provides a roadmap for the advancement of therapeutic outcomes in MM. Future directions include biomarker-driven personalization, earlier intervention in treatment sequencing, and combinatorial regimens to holistically address resistance mechanisms. The insights provided by this paper aim to guide translational research and clinical practice, ultimately improving the survival of patients with RRMM.