Background: The addition of Daratumumab (D) to backbone multiple myeloma (MM) regimens leads to improved response rates and progression free survival (PFS). Whether improved outcomes are also seen among patients with high-risk cytogenetics (HRC) remains unclear, particularly in first-line (FL) setting. Methods: We conducted a systematic search of bibliographic databases, clinical trials registries and meeting libraries from inception to December 2019, for phase III randomized trials that compared backbone MM regimens vs. same regimen plus D either in FL or relapsed/refractory (R/R) setting and reported outcomes by cytogenetic risk (HRC vs standard risk cytogenetics, SRC). We defined HRC as presence of t(4;14), t(14;16) or del(17p). The primary endpoint was PFS. We pooled relative log-hazard ratios using DerSimonian-Laird random-effects model. We assessed heterogeneity using Cochran’s Q and the I² statistic. Results: Of 3,070 studies screened, 6 phase III trials were included. This included 3 trials in FL setting (Alcyone, Maia and Cassiopeia, 2,528 patients, 358 HRC) and 3 trials in R/R setting (Castor, Pollux and Candor, 1,533 patients, 222 HRC). The addition of D to FL backbone regimens among patients with HRC led to improved PFS (pooled HR 0.67; 95% CI 0.47-0.95, p = 0.02) with little heterogeneity (Cochran’s Q p = 0.77, I²= 0), similar to R/R setting (pooled HR 0.45; 95% CI 0.30-0.67, p < 0.01, Cochran’s Q = 0.63, p < 0.01, I²= 0). Similar results were seen in SRC MM patients in FL setting (pooled HR 0.45; 95% CI 0.37-0.54, p < 0.01, Cochran’s Q p = 0.49, I²= 0) and R/R setting (pooled HR 0.38; 95% CI 0.25-0.56; p < 0.01, Cochran’s Q p = 0.04, I²= 70%). Conclusions: Incorporating D to backbone regimens led to improved PFS among patients with HRC MM in both FL and R/R setting. Lack of substantial heterogeneity suggests benefit of D regardless of backbone regimen. D based regimens are appropriate choices in FL and R/R setting for both SRC and HRC patients. Longer follow up with mature overall survival data is needed to validate these findings.