Current Treatment Strategies for Multiple Myeloma at First Relapse.

Multiple myeloma (MM), the second most common hematologic cancer, remains an incurable malignancy, characterized by an initial response to therapy followed by successive relapses. The upfront treatment typically involves induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance therapy. It is important to note that the anticipated duration of myeloma response diminishes with each subsequent relapse. Therefore, the first relapse represents a critical juncture in treatment, where refractoriness to key drug classes emerges as a significant challenge. Addressing the optimal management in this setting requires careful consideration of disease biology, prior therapies, and patient-specific factors to optimize outcomes. Cilta-cel, a chimeric antigen receptor T-cell construct, has emerged as the most promising therapeutic option at first relapse, resulting in long-term remissions with a significant treatment-free interval. However, availability and accessibility are not universal and treatment logistics are complex. Triplet regimens based on carfilzomib, pomalidomide or selinexor, remain the cornerstone of treatment at first relapse, whereas the optimal combination is based on refractoriness to prior drugs, especially anti-CD38 monoclonal antibodies and lenalidomide, and patient comorbidities. With the rapidly expanding therapeutic landscape, clinicians face increasing complexity in selecting the most appropriate regimens for individual patients. This review aims to guide clinicians through these evolving options by consolidating evidence-based strategies and highlighting emerging therapies, ensuring a personalized approach to managing first-relapse MM.