Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of the Phase 3 Maia Study

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy and in combination with standard-of-care regimens for patients with relapsed/refractory multiple myeloma and in combination with standard-of-care regimens for patients with NDMM. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 months), D-Rd significantly improved progression-free survival (PFS; median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43-0.73; P<0.001) and achieved a >3-fold increase in minimal residual disease (MRD)–negativity rate (10^–5 sensitivity threshold; 24.2% vs 7.3%; P<0.001) versus Rd alone in transplant-ineligible patients with NDMM (Facon T, N Engl J Med 2019). With longer follow-up (median follow-up, 56.2 months), D-Rd significantly improved overall survival (OS) versus Rd (HR, 0.68; 95% CI, 0.53-0.86; P=0.0013; Facon T, Lancet Oncol 2021). Here, we present an updated analysis of MAIA after a median follow-up of 64.5 months.

Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplant were randomized 1:1 to receive Rd ± DARA. Randomization was stratified by International Staging System disease stage (I vs II vs III), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg PO on Days 1‑21; d: 40 mg PO on Days 1, 8, 15, and 22). In the D-Rd arm, DARA (16 mg/kg IV) was given once weekly in Cycles 1‑2, once every 2 weeks in Cycles 3-6, and once every 4 weeks thereafter. In both treatment arms, patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints included MRD‑negativity rate (10^–5 sensitivity, clonoSEQ^® version 2.0), overall response rate (ORR), OS, and safety.

Results: In total, 737 patients were randomized (D-Rd, n=368; Rd, n=369). Baseline characteristics were well balanced between treatment arms. After a median follow-up of 64.5 months, PFS was improved with D-Rd versus Rd (median, 61.9 months vs 34.4 months; HR, 0.55; 95% CI, 0.45-0.67; P<0.0001; Figure A). A 34% reduction in the risk of death was observed with D-Rd versus Rd; median OS was NR with D-Rd versus 65.5 months with Rd (HR, 0.66; 95% CI, 0.53-0.83; P=0.0003). The estimated 60-month OS rate was 66.6% with D-Rd and 53.6% with Rd (Figure B). The ORR was higher for the D-Rd arm versus the Rd arm (92.9% vs 81.6%; P<0.0001). The MRD-negativity rate was also higher for D-Rd versus Rd (32.1% vs 11.1%; P<0.0001), as was the rate of sustained MRD negativity lasting ≥12 months (18.8% vs 4.1%; P<0.0001).

The most common (occurring in ≥15% of patients in either arm) grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) were neutropenia (54.1%/37.0%), anemia (17.0%/21.6%), pneumonia (19.5%/10.7%), and lymphopenia (16.5%/11.2%); grade 3/4 infection rates were 42.6%/29.6%. The most common serious TEAE in both arms was pneumonia (18.7%/10.7%). 14.6% of patients in the D-Rd arm and 23.8% of patients in the Rd arm discontinued treatment due to TEAEs.

Conclusions: In this updated analysis of MAIA, the addition of DARA to Rd continued to demonstrate PFS and OS benefits in transplant-ineligible patients with NDMM after a median follow-up of >5 years. D-Rd also achieved a nearly 3-fold higher MRD-negativity rate and a ≥4-fold higher ≥12-month sustained MRD-negativity rate versus Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the frontline use of D-Rd in transplant-ineligible patients with NDMM. Further updated OS results based on extended follow-up will be presented at the meeting.