Background
Phase 3, open-label, randomized controlled trial with adaptive MRD-guided design (MIDAS; IFM 2020-02). N=718 transplant-eligible NDMM patients randomized after induction. All patients received Isa-KRd induction (isatuximab + carfilzomib + lenalidomide + dexamethasone, 6 cycles). After induction, MRD was assessed by next-generation sequencing (10⁻⁵ sensitivity). MRD-negative patients were randomized to ASCT + Isa-KRd consolidation vs continued Isa-KRd consolidation (ASCT omitted); MRD-positive patients were randomized to tandem ASCT vs single ASCT. All patients received lenalidomide-based maintenance.
Interventions and follow up
Common induction: Isa-KRd × 6 cycles, then MRD-stratified randomization
MRD-negative randomization: ASCT + Isa-KRd consolidation vs Isa-KRd consolidation (ASCT omitted)
MRD-positive randomization: Tandem ASCT vs single ASCT, then Isa-KRd consolidation
Primary endpoint: MRD-negativity rate (10⁻⁶) before maintenance, within each stratified randomization
Median follow-up: ~16.8 months
MRD-negative randomization: ASCT + Isa-KRd consolidation vs Isa-KRd consolidation (ASCT omitted)
MRD-positive randomization: Tandem ASCT vs single ASCT, then Isa-KRd consolidation
Primary endpoint: MRD-negativity rate (10⁻⁶) before maintenance, within each stratified randomization
Median follow-up: ~16.8 months
Results
MRD-neg (10⁻⁶) post-induction: highest pretransplant MRD-negativity rate yet reported with Isa-KRd
MRD-neg stratum (10⁻⁶): ASCT + Isa-KRd vs Isa-KRd consolidation alone — no significant difference in MRD-negativity
MRD-pos stratum: tandem ASCT vs single ASCT — no significant difference in MRD-negativity
PFS: immature at this follow-up; long-term data pending
MRD-neg stratum (10⁻⁶): ASCT + Isa-KRd vs Isa-KRd consolidation alone — no significant difference in MRD-negativity
MRD-pos stratum: tandem ASCT vs single ASCT — no significant difference in MRD-negativity
PFS: immature at this follow-up; long-term data pending
Adverse events
Hematologic/transplant: Hematologic grade ≥3 toxicity (neutropenia, thrombocytopenia) more common in ASCT arms; transplant-related mortality <1%
Carfilzomib/isatuximab: Carfilzomib-related hypertension grade ≥3 ~6% and cardiac events ~3%; isatuximab infusion-related reactions any grade ~46%, grade ≥3 <1%
Carfilzomib/isatuximab: Carfilzomib-related hypertension grade ≥3 ~6% and cardiac events ~3%; isatuximab infusion-related reactions any grade ~46%, grade ≥3 <1%
Conclusions
In MRD-negative TE NDMM patients after quadruplet Isa-KRd induction, adding ASCT did not improve MRD-negativity over continued Isa-KRd consolidation, suggesting MRD-guided ASCT omission may be feasible. Tandem ASCT was not superior to single ASCT in MRD-positive patients, supporting single ASCT as the standard in the modern quadruplet era. Longer follow-up for PFS/OS is required.
Key Limitations
The primary endpoint is MRD-negativity, a surrogate; PFS and OS remain immature, so whether ASCT omission is safe over the long term is not yet established. Short median follow-up (~17 months) precludes durability conclusions. The MRD-guided design with multiple randomizations reduces statistical power within each stratum. Findings apply specifically to patients receiving quadruplet Isa-KRd induction and may not generalize to other backbones. NGS MRD assessment at a single timepoint may not capture late molecular relapse.
Clinical Context
MIDAS is among the first large trials to prospectively test MRD-adapted ASCT decisions in TE NDMM, addressing whether transplant can be safely omitted in deep responders to quadruplet induction. ASCT remains a standard consolidation in TE NDMM per ESMO and ASCO frameworks pending mature survival data. In the US, daratumumab-based quadruplets (D-VRd from PERSEUS) are the more established induction standard; isatuximab quadruplets are an alternative backbone under active investigation. ESMO-MCBS: not assigned.
References