Background
IMROZ was a phase III randomized open-label trial evaluating isatuximab (anti-CD38 monoclonal antibody) plus bortezomib-lenalidomide-dexamethasone (VRd) versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). While MAIA established DRd (daratumumab-Rd) as standard of care for transplant-ineligible NDMM, VRd had not been tested as the backbone for CD38-antibody augmentation in this setting. IMROZ directly addressed whether adding isatuximab to the VRd triplet could further improve outcomes over the doublet-backbone standard.
Interventions and follow up
Arm A (VRd): Bortezomib 1.3 mg/m² + lenalidomide 25 mg + dexamethasone (induction × 4 cycles, then continuous Rd until progression)
Arm B (Isa-VRd): Isatuximab 10 mg/kg + VRd × 4 induction cycles → isatuximab + Rd until progression
Primary endpoint: Progression-free survival (PFS) per IMWG criteria assessed by IRC
Secondary: complete response (CR) rate, MRD negativity, OS
mFollow-up: 59.7 months
Arm B (Isa-VRd): Isatuximab 10 mg/kg + VRd × 4 induction cycles → isatuximab + Rd until progression
Primary endpoint: Progression-free survival (PFS) per IMWG criteria assessed by IRC
Secondary: complete response (CR) rate, MRD negativity, OS
mFollow-up: 59.7 months
Results
4-yr PFS: 63.2% vs 45.2% (HR 0.596, 95% CI 0.44–0.81, P<.001)
CR or better: 74.7% vs 59.1%
MRD negativity (10⁻⁵): 55.5% vs 26.5%
Sustained MRD negativity (≥12 mo): 46.8% vs 14.9%
OS: data immature at time of primary analysis
CR or better: 74.7% vs 59.1%
MRD negativity (10⁻⁵): 55.5% vs 26.5%
Sustained MRD negativity (≥12 mo): 46.8% vs 14.9%
OS: data immature at time of primary analysis
Adverse events
Overall: Grade ≥3 AEs 93.6% vs 87.2%; second primary malignancies 9.1% vs 5.0%; no new unexpected safety signals for isatuximab
Hematologic: neutropenia 84.2% vs 54.0%
Infectious: infections Grade ≥3 39.1% vs 27.4%
Infusion-related/neurologic: infusion reactions 23.2% (Grade ≥3: 0.8%); peripheral neuropathy Grade ≥3 9.1% vs 8.8%
Hematologic: neutropenia 84.2% vs 54.0%
Infectious: infections Grade ≥3 39.1% vs 27.4%
Infusion-related/neurologic: infusion reactions 23.2% (Grade ≥3: 0.8%); peripheral neuropathy Grade ≥3 9.1% vs 8.8%
Conclusions
Isatuximab added to VRd (Isa-VRd) significantly prolonged PFS with a 40% reduction in risk of progression or death, and achieved substantially higher CR and MRD-negativity rates compared to VRd alone in transplant-ineligible NDMM, establishing Isa-VRd as a new standard of care for this population and extending the quadruplet paradigm from transplant-eligible to transplant-ineligible myeloma.
Key Limitations
Open-label design; VRd control arm (not DRd) — IMROZ cannot be directly compared to MAIA (DRd vs Rd) since different backbones used; unequal randomization (3:2) limits some statistical comparisons; OS data immature; isatuximab is IV (no SC formulation approved as of 2024); higher neutropenia rates with Isa-VRd warrant G-CSF prophylaxis planning; patients ≤80 years — generalizability to oldest/frailer myeloma patients limited; no biomarker-driven enrollment; head-to-head comparison with DRd not available.
Clinical Context
IMROZ published in NEJM 2024 and led to FDA approval of Isa-VRd for transplant-ineligible NDMM in 2024. Together with MAIA (DRd) and CEPHEUS (D-VRd, another Phase III, 2024), IMROZ establishes the quadruplet anti-CD38 antibody + PI/IMiD combination as the new standard of care for transplant-ineligible NDMM. The comparison across trials is challenging due to different backbones (VRd vs Rd) and patient populations, but the magnitude of PFS benefit and depth of MRD negativity with Isa-VRd are compelling. Isa-VRd is now a preferred option for transplant-ineligible NDMM alongside DRd and D-VRd-based regimens per ASCO/ESMO guidance.