Background
Phase 3 EMN24 IsKia. N=302 transplant-eligible newly diagnosed MM, age ≤70, randomized 1:1. Tests whether adding CD38 mAb isatuximab to carfilzomib-lenalidomide-dexamethasone deepens response in the quadruplet-induction era.
Results
Interventions and follow up: Arm A: Isa-KRd pretransplant induction → ASCT → Isa-KRd post-transplant consolidation
Arm B: KRd induction → ASCT → KRd consolidation
Primary endpoint: post-consolidation MRD negativity (NGS, 10⁻⁵)
mFollow up: NR (PFS immature at current analysis)
Results: Post-consolidation MRD neg 10⁻⁵: 77% vs 67% (OR 1.67, P=.049)
Post-consolidation MRD neg 10⁻⁶: 68% vs 48% (OR 2.36, P=.0004)
Post-induction MRD neg 10⁻⁵: 46% vs 27% (OR 2.32, P=.0007)
1-yr sustained MRD neg 10⁻⁶: 52% vs 38% (OR 1.82, P=.012)
PFS: NR (immature)
Arm B: KRd induction → ASCT → KRd consolidation
Primary endpoint: post-consolidation MRD negativity (NGS, 10⁻⁵)
mFollow up: NR (PFS immature at current analysis)
Results: Post-consolidation MRD neg 10⁻⁵: 77% vs 67% (OR 1.67, P=.049)
Post-consolidation MRD neg 10⁻⁶: 68% vs 48% (OR 2.36, P=.0004)
Post-induction MRD neg 10⁻⁵: 46% vs 27% (OR 2.32, P=.0007)
1-yr sustained MRD neg 10⁻⁶: 52% vs 38% (OR 1.82, P=.012)
PFS: NR (immature)
Adverse events
Grade 3–4 non-hematologic: similar between arms (rates NR)
Discontinuation for AEs: similar between arms
Deaths due to AEs: similar between arms
Discontinuation for AEs: similar between arms
Deaths due to AEs: similar between arms
Conclusions
Adding isatuximab to KRd produced faster, deeper, and more durable MRD negativity in transplant-eligible NDMM with no added toxicity signal. Reinforces CD38-mAb quadruplet induction/consolidation as standard for this population.
Key Limitations
MRD negativity is a surrogate primary endpoint; PFS immature (long follow-up required, projected years away). 10⁻⁵ difference was borderline (P=.049); deeper 10⁻⁶ threshold was exploratory-tier. No comparison vs D-VRd (PERSEUS), the prevailing quadruplet standard. Restricted to age ≤70.
Clinical Context
D-VRd is the FDA-backed TE-NDMM quadruplet standard (PERSEUS); Isa-KRd is not FDA-approved in this setting. IsKia supports carfilzomib-based CD38 quadruplets as an alternative and strengthens MRD as a registrational endpoint (FDA ODAC 2024 endorsed MRD for accelerated approval in MM).