Background
Phase 3, open-label, randomized controlled trial (IsKia; EMN/GIMEMA). N=302 transplant-eligible NDMM patients randomized 1:1 to Isa-KRd vs KRd induction (4 cycles each arm) → ASCT → consolidation (4 cycles of assigned regimen) → lenalidomide maintenance. Primary endpoint: MRD negativity at 10⁻⁵ sensitivity by next-generation sequencing after consolidation. Final analysis published Nat Med 2026; key efficacy data from ASH 2023 presentation used here.
Interventions and follow up
Arm A: Isatuximab 10 mg/kg IV qwk × 4 (cycle 1) then q2wk + carfilzomib 36 mg/m² IV days 1, 2, 8, 9, 15, 16 + lenalidomide 25 mg days 1–21 + dexamethasone 40 mg weekly (Isa-KRd); 4 cycles induction → ASCT → 4 cycles consolidation → lenalidomide maintenance
Arm B: Carfilzomib + lenalidomide + dexamethasone (KRd; same schedule without isatuximab); 4 cycles → ASCT → 4 cycles consolidation → lenalidomide maintenance
Primary endpoint: MRD negativity at 10⁻⁵ threshold (NGS) after consolidation
Median follow-up: ~30 months (ASH 2023 preliminary)
Arm B: Carfilzomib + lenalidomide + dexamethasone (KRd; same schedule without isatuximab); 4 cycles → ASCT → 4 cycles consolidation → lenalidomide maintenance
Primary endpoint: MRD negativity at 10⁻⁵ threshold (NGS) after consolidation
Median follow-up: ~30 months (ASH 2023 preliminary)
Results
MRD-neg (10⁻⁵) post-consolidation: ~77% vs ~67% (Isa-KRd vs KRd; preliminary ASH 2023 data)
MRD-neg (10⁻⁶): deeper responses favoring Isa-KRd
Sustained MRD-neg: higher rate in Isa-KRd arm at 12 months post-consolidation
PFS (preliminary): HR favoring Isa-KRd; final data in Nat Med 2026
MRD-neg (10⁻⁶): deeper responses favoring Isa-KRd
Sustained MRD-neg: higher rate in Isa-KRd arm at 12 months post-consolidation
PFS (preliminary): HR favoring Isa-KRd; final data in Nat Med 2026
Adverse events
Isatuximab/carfilzomib: Isatuximab infusion-related reactions any grade ~50%, grade ≥3 <1%; carfilzomib-related hypertension grade ≥3 ~7% and cardiac events ~3%
Hematologic: Grade ≥3 neutropenia and thrombocytopenia balanced between arms; no unexpected safety signals with the quadruplet combination
Hematologic: Grade ≥3 neutropenia and thrombocytopenia balanced between arms; no unexpected safety signals with the quadruplet combination
Conclusions
Isa-KRd increased MRD negativity rates compared with KRd in TE NDMM, with a higher proportion of patients achieving MRD negativity at 10⁻⁵ after consolidation, supporting isatuximab's role in quadruplet induction regimens for transplant-eligible patients. Final OS and long-term PFS data are reported in the Nat Med 2026 publication.
Key Limitations
MRD negativity rate is a surrogate endpoint; long-term PFS and OS data are needed to confirm clinical benefit. Preliminary data (ASH 2023) may differ from the final Nat Med 2026 publication. IsKia and MIDAS both use Isa-KRd but with different designs, limiting direct comparison. Isa-KRd is not FDA-approved as a standard induction regimen; KRd (without isatuximab) has limited use in the US where daratumumab-based quadruplets (D-VRd, D-KRd) are more established.
Clinical Context
IsKia is one of several trials (alongside MIDAS, GMMG-CONCEPT) demonstrating that adding a CD38 antibody to a carfilzomib backbone improves MRD negativity rates in TE NDMM. In the US, daratumumab-based quadruplets (D-VRd from GRIFFIN/PERSEUS, D-KRd) are the more established standard given FDA approvals. Isatuximab quadruplets (Isa-KRd, Isa-VRd) represent an alternative backbone under active investigation per ESMO/ASCO frameworks. ESMO-MCBS: not yet assigned.
References