Background
MAIA was a phase III randomized open-label trial evaluating the addition of daratumumab (anti-CD38 monoclonal antibody) to lenalidomide plus dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem cell transplantation (ASCT). Rd had been established as a standard of care for transplant-ineligible NDMM (FIRST trial), and MAIA asked whether adding a CD38-directed antibody to this backbone could further improve outcomes in this predominantly elderly, comorbid population.
Interventions and follow up
Arm A (Rd): Lenalidomide 25 mg PO days 1–21 + dexamethasone 40 mg weekly (28-day cycles) until progression
Arm B (DRd): Daratumumab 16 mg/kg IV (weekly × 8, q2w × 16, then q4w) + lenalidomide 25 mg PO days 1–21 + dexamethasone 40 mg weekly until progression
Primary endpoint: Progression-free survival (PFS) by IRC per IMWG criteria
Secondary: OS, ORR, MRD negativity, safety
mFollow-up: 56.2 months
Arm B (DRd): Daratumumab 16 mg/kg IV (weekly × 8, q2w × 16, then q4w) + lenalidomide 25 mg PO days 1–21 + dexamethasone 40 mg weekly until progression
Primary endpoint: Progression-free survival (PFS) by IRC per IMWG criteria
Secondary: OS, ORR, MRD negativity, safety
mFollow-up: 56.2 months
Results
mPFS: not reached vs 31.9 months (HR 0.56, 95% CI 0.43–0.73, P<.0001); 48-mo PFS 66.3% vs 53.0%
ORR: 92.9% vs 81.3%
sCR: 30.4% vs 9.5%
MRD negativity (10⁻⁵): 24.2% vs 7.3%
OS: HR 0.68 (95% CI 0.53–0.86, P=.0013) at updated analysis
ORR: 92.9% vs 81.3%
sCR: 30.4% vs 9.5%
MRD negativity (10⁻⁵): 24.2% vs 7.3%
OS: HR 0.68 (95% CI 0.53–0.86, P=.0013) at updated analysis
Adverse events
Overall: Grade ≥3 AEs 86.3% vs 78.6%; second primary malignancies 4.8% vs 3.8%
Hematologic: neutropenia 50.0% vs 35.3%
Infectious: pneumonia 18.0% vs 10.0%; infections higher with daratumumab
Infusion-related: reactions 40.8% (Grade ≥3: 2.7%)
Hematologic: neutropenia 50.0% vs 35.3%
Infectious: pneumonia 18.0% vs 10.0%; infections higher with daratumumab
Infusion-related: reactions 40.8% (Grade ≥3: 2.7%)
Conclusions
Daratumumab added to Rd (DRd) significantly prolonged PFS and OS versus Rd alone in transplant-ineligible NDMM, with markedly higher sCR and MRD-negativity rates, establishing DRd as a new standard of care in this population and demonstrating that CD38 antibody augmentation of IMiD-based regimens improves survival in non-transplant myeloma.
Key Limitations
Open-label design; transplant ineligibility not strictly defined (age ≤80, ECOG 0–2) — some younger patients who declined transplant included; no quadruplet comparison arm; daratumumab was IV in this trial (SC formulation available since 2020 with equivalent efficacy per COLUMBA); Rd is now largely superseded by triplet/quadruplet regimens making Rd-only control arm less relevant; MRD thresholds (10⁻⁵) lower than current NGS-based 10⁻⁶ standards; crossover not permitted limiting OS interpretation.
Clinical Context
MAIA established DRd as the foundational CD38-based triplet for transplant-ineligible NDMM, leading to FDA approval in 2019. The IMROZ trial (2024) later demonstrated isatuximab-VRd superiority over VRd in a similar non-transplant population, representing the next iteration of quadruplet therapy. DRd remains a preferred regimen for transplant-ineligible NDMM, particularly where bortezomib-based regimens are less suitable (neuropathy, renal impairment favoring lenalidomide). The MRD data from MAIA contributed to growing evidence for MRD as a surrogate endpoint in myeloma trials (ASCO/ESMO endorsed).