OBJECTIVES:  To examine the comparative effectiveness of different first-line strategies currently used for patients with multiple myeloma (MM) > 65 years who are ineligible for stem cell transplantation, for the outcomes overall survival (OS) and progression-free survival (PFS). Treatment alternatives include multidrug regimens combining 2-5 drugs of different classes: prednisone (P), high-dose dexamethasone (D), low-dose dexamethasone (d), thalidomide (T), lenalidomide (R), bortezomib (V), cyclophosphamide (C), and melphalan (M). METHODS:  We performed a systematic literature search in MEDLINE, Embase, Cochrane Library, and CRD databases. We used a random-effects network meta-analysis (NMA) to estimate pooled hazard ratios with 95% confidence intervals for all treatment comparisons and outcomes. We ranked treatments using cumulative ranking probabilities. RESULTS:  The NMA comprised thirteen randomized controlled trials including 5573 patients comparing eleven treatment strategies. Treatment with VMPT-VT showed a statistically significant OS benefit compared to MPR and MP regimens. VTD showed a significant survival benefit compared to MP. Regarding PFS, the VMPT-VT strategy was superior to most of the other treatments. The NMA showed significantly better PFS for MPR-R compared to CTD, Rd, MPR, MPT, and MP. Comparison of Rd-Rd against Rd, MPT, and MP showed a significant benefit of Rd-Rd. The analysis showed VTD, MPV, and MPT to be favorable compared to MP regarding PFS. Based on the cumulative ranking probabilities, VMPT-VT, VTD, and Rd-Rd might be more effective than other treatment strategies in terms of OS. With respect to PFS, VMPT-VT, MPR-R, and Rd-Rd might be more effective. CONCLUSIONS:  The NMA suggests that VMPT-VT, Rd-Rd, MPR-R, and VTD are more effective in terms of OS and PFS than other multidrug regimens for the first-line treatment of elderly patients with MM. However, further research should be considered to provide information on toxicity, quality of life, and cost-effectiveness for the different therapy approaches to consider all trade-offs.