Background: Despite recent advances in the treatment of multiple myeloma (MM), the disease remains incurable. Agents targeting the programmed death-1 (PD-1) axis have become key treatments for many cancers; however, monotherapies with PD-1/PD-L-1 inhibitors (PD-1i) have shown a limited efficacy in MM patients. We conducted a meta-analysis to evaluate the safety and efficacy of PD-1i in combination with standard of care (SOC) therapies for MM. Methods: A systematic search identified phase II and III randomized clinical trials involving MM patients treated with PD-1i, using terms such as “Relapsed Multiple Myeloma” and “PD-1 inhibitors.” The search included trials published in English after 2016 using the PubMed, CINAHL, and Cochrane databases. Data were analyzed using RStudio v4.4.2, with survival data assessed using Kaplan–Meier methods and Cox proportional hazards analysis. Results: Our search yielded 19 total trials, of which 5 (representing 889 unique patients) met the criteria for inclusion. A total of 488 patients received PD-1i + SOC, and 401 received SOC alone. The median progression-free survival (PFS) was 6.26 months for the PD-1i + SOC group and 7.34 months for the SOC alone group (HR, 1.2; 95% CI: 0.95–1.41; p = 0.14). The median overall survival (OS) was 22.49 months for PD-1i + SOC compared to 24.38 months for SOC alone (HR, 1.11; 95% CI: 0.87–1.42, p = 0.36). The PD-1i group showed a higher incidence of all-grade pneumonia (RR = 1.44, 95% CI: 1.03–2.02, p = 0.03), grade ≥ 3 neutropenia (RR = 1.36, 95% CI: 1.00–1.85, p = 0.05), immune-mediated adverse events (RR = 10.1, 95% CI: 0.38–271.1, p = 0.17), and grade ≥ 3 irAEs (RR = 9.59, 95% CI: 0.62–148.8, p = 0.11). Conclusion: This analysis highlights the limited efficacy and increased toxicity of adding PD-1i to SOC in MM patients. Further research is needed to explore whether targeting the PD-1/PD-L1 axis in combination with novel therapies can safely enhance the therapeutic efficacy in MM patients.