Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved in combination with standard of care in patients (pts) with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard of care for pts with relapsed/refractory multiple myeloma. In the randomized, phase 3 MAIA study (NCT02252172), DARA plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone was evaluated in transplant-ineligible pts with NDMM. In the primary analysis of MAIA (median follow-up, 28.0 months), D-Rd significantly improved progression-free survival (PFS) versus Rd alone (Facon T, N Engl J Med 2019). Additionally, D-Rd significantly prolonged PFS versus Rd for pts aged ≥75 years (median, not reached [NR] vs 31.9 months; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.44-0.92; P = 0.0146; Usmani SZ, ASCO 2019). In an analysis of overall survival (OS; median follow-up, 56.2 months), D-Rd showed a significant reduction in the risk of death versus Rd alone (HR, 0.68; 95% CI, 0.53-0.86; P = 0.0013; Facon T, Lancet Oncol 2021). Here, we present a subgroup analysis of MAIA pts aged <75 years, <70 years, and ≥70 to <75 years. Methods: Pts with NDMM ineligible for high-dose chemotherapy with autologous stem cell transplant were randomized 1:1 to receive D-Rd or Rd alone. All pts received 28-day cycles of lenalidomide (R: 25 mg orally on Days 1-21) and dexamethasone (d: 40 mg orally on Days 1, 8, 15, and 22) with or without DARA (16 mg/kg intravenously once weekly in Cycles 1-2, once every 2 weeks in Cycles 3-6, and once every 4 weeks thereafter) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), OS, and minimal residual disease (MRD)-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0). Results: Of 737 randomized pts (D-Rd, n = 368; Rd, n = 369), 416 (56%) pts were aged <75 years (D-Rd, n = 208; Rd, n = 208), 155 (21%) pts were aged <70 years (D-Rd, n = 78; Rd, n = 77), and 261 (35%) pts were aged ≥70 to <75 years (D-Rd, n = 130; Rd, n = 131). At a median follow-up of 64.5 months, PFS was improved for pts receiving D-Rd versus Rd who were aged <75 years (median, NR vs 37.5 months; HR, 0.52; 95% CI, 0.39-0.68; P <0.0001; Figure A), <70 years (median, NR vs 39.2 months; HR, 0.35; 95% CI, 0.21-0.56; P <0.0001), and ≥70 to <75 years (median, 61.9 vs 37.5 months; HR, 0.64; 95% CI, 0.45-0.89; P = 0.0079; Figure B). The estimated 60-month PFS rates were higher for pts receiving D-Rd versus Rd across all subgroups: <75 years (57.4% vs 33.6%), <70 years (67.2% vs 28.7%), and ≥70 to <75 years (51.6% vs 36.6%). OS was also improved for pts receiving D-Rd versus Rd who were aged <75 years (HR, 0.59; 95% CI, 0.43-0.83; P = 0.0017), <70 years (HR, 0.50; 95% CI, 0.27-0.90; P = 0.0179), and ≥70 to <75 years (HR, 0.64; 95% CI, 0.43-0.96; P = 0.0274). The estimated 60-month OS rates were higher for pts receiving D-Rd versus Rd across all subgroups: <75 years (73.9% vs 58.8%), <70 years (79.9% vs 61.7%), and ≥70 to <75 years (70.3% vs 57.0%). The ORR was higher for D-Rd versus Rd in pts aged <75 years (95.2% vs 81.7%; P <0.0001), <70 years (93.6% vs 80.5%; P = 0.0156), and ≥70 to <75 years (96.2% vs 82.4%; P = 0.0004). Increased rates of MRD negativity (10-5) were observed with D-Rd versus Rd in pts aged <75 years (36.1% vs 12.0%; odds ratio [OR], 4.13; 95% CI, 2.49-6.84; P <0.0001), <70 years (35.9% vs 11.7%; OR, 4.23; 95% CI, 1.84-9.75; P = 0.0006), and ≥70 to <75 years (36.2% vs 12.2%; OR, 4.07; 95% CI, 2.16-7.67; P <0.0001). Conclusions: At a median follow-up of 64.5 months, D-Rd improved efficacy versus Rd alone in subgroups of pts aged <75, <70, and ≥70 to <75 years. D-Rd demonstrated clinically meaningful benefit across all endpoints, including PFS, OS, ORR, and MRD negativity. These results, along with those presented previously (Usmani SZ, ASCO 2019), support the frontline use of DARA-based combination regimens in pts aged <75 years and ≥75 years with transplant-ineligible NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal