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The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.