ABSTRACT: Quadruplet regimens (anti-CD38 monoclonal antibodies [mAbs] with proteasome inhibitor [PI] and immunomodulatory drugs [IMiDs]) are increasingly being investigated in newly diagnosed multiple myeloma (NDMM). The objective of our study was to conduct a systematic review and meta-analysis to measure the efficacy and toxicity of quadruplet regimens used in NDMM. Embase, MEDLINE, Web of Science, Cochrane Library, clinical trial registries, and meeting libraries from inception to 24 January 2024, in addition to American Society of Clinical Oncology conference abstracts 2024, were searched using terms reflecting multiple myeloma and components of the quadruplet regimen. Included studies were randomized controlled trials (RCTs) that compared backbone regimens consisting of a PI and IMiD vs the same regimen plus an anti-CD38 mAb in NDMM. We identified 7 RCTs including 3716 patients. Compared with triplets, quadruplets increase the overall response rate (ORR; relative risk [RR], 1.03; 95% confidence interval [CI], 1.01-1.05) and progression-free survival (PFS; hazard ratio [HR], 0.55; 95% CI, 0.46-0.66). Quadruplets increase the rates of minimal residual disease (MRD) negativity at 10-5 (RR, 1.39; 95% CI, 1.23-1.58) and 10-6 (RR, 1.62; 95% CI, 1.36-1.94). Quadruplets improve overall survival (OS; HR, 0.65; 95% CI, 0.53-0.79). There was a slight increase in the rates of grade 3 to 4 infections (RR, 1.22; 95% CI, 1.07-1.39) noted with quadruplets compared with triplets. Overall, in this meta-analysis, quadruplets were associated with improved efficacy including ORR, MRD negativity, PFS, and OS, with a slight increase in infection rates. Quadruplet regimens represent a new standard of care, particularly in transplant-eligible NDMM.