BACKGROUND: The treatment landscape for relapsed/refractory multiple myeloma (RRMM) is rapidly evolving, particularly for patients exposed or refractory to lenalidomide. With the aim of evaluating the relative efficacy of lenalidomide-free regimens as second-line treatment options, an updated network meta-analysis, incorporating phase II/III randomized controlled trials, has been conducted. MATERIALS AND METHODS: A systematic literature search identified eight eligible trials comprising 3952 patients. The primary outcome was progression-free survival (PFS), analyzed through Bayesian and frequentist approaches. RESULTS: Our findings indicate that belantamab mafodotin, bortezomib, and dexamethasone (BVd) combination is the most effective regimen for both lenalidomide-exposed and lenalidomide-refractory MM patients at first relapse, achieving the highest surface under the cumulative ranking curve for PFS. BVd outperformed other triplet regimens, including daratumumab, bortezomib, and dexamethasone, isatuximab, carfilzomib, and dexamethasone, and bortezomib, pomalidomide, and dexamethasone. CONCLUSIONS: Emerging therapies, including chimeric antigen receptor T-cell (CAR-T-cell) therapy and bispecific antibodies, are set to reshape RRMM treatment paradigms. Trials such as CARTITUDE-4 and MajesTEC-3 are exploring these agents in earlier treatment lines, particularly for lenalidomide- and daratumumab-refractory patients. Our analysis provides an evidence-based hierarchy of lenalidomide-free regimens, supporting BVd as a preferred second-line treatment. Future studies should refine treatment sequencing strategies and evaluate novel agents in earlier disease stages to optimize outcomes for RRMM patients.