ASCT Plus Isa-KRd Consolidation Does Not Boost MRD Negativity Rates in Myeloma

ASCT Plus Isa-KRd Consolidation in Myeloma

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Minimal residual disease (MRD) status–guided consolidation therapy with autologous stem cell transplant (ASCT) plus isatuximab (Sarclisa) plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) following Isa-KRd induction therapy did not improve MRD outcomes vs continued Isa-KRd alone in patients with MRD-negative, newly diagnosed multiple myeloma, according to data from the phase 3 IFM2020-02-MIDAS trial (NCT04934475) presented at the 2025 ASCO Annual Meeting that were simultaneously published in The New England Journal of Medicine.1,2

In patients who achieved MRD negativity following induction with Isa-KRd, ASCT consolidation did not significantly improve MRD negativity rates. Additionally, in patients who had MRD-positive status after induction, tandem ASCT did not provide greater benefit in MRD outcomes vs single ASCT.

“The academic MIDAS trial is the first phase 3 study to evaluate MRD-guided consolidation strategy after Isa-KRd induction in transplant-eligible myeloma,” Aurore Perrot, MD, an associate professor in hematology at the University of Toulouse in France, said in her presentation.1

As MRD is a predictor of outcomes including progression-free survival (PFS) in multiple myeloma, the MIDAS study was designed to investigate whether there is additional benefit with ASCT in patients who achieve MRD negativity after induction therapy. Tandem ASCT has demonstrated benefit in patients who are at higher risk of relapse but has primarily been investigated following triplet therapy.

The MIDAS study enrolled 791 patients to receive Isa-KRd for 6 cycles with SCT collection after cycle 3. Patients were eligible to enroll if they had newly diagnosed multiple myeloma, were younger than 66 years of age, were considered transplant eligible, and had no active cardiac disease. Of the enrolled patients, 757 completed induction, 761 had stem cells collected, and 751 were evaluated for MRD. Post induction, 499 patients, or 63% of the intent-to-treat (ITT) population, achieved MRD negativity at 10–5 sensitivity, whereas 47% of patients had MRD negativity at 10–6 sensitivity. Those with translocation 4;14 (t(4;14)) were more likely to be MRD negative (81%) vs those without this feature (62%), whereas those with t(11;14) were less likely to be MRD negative (40%) than those without this feature (71%).

Patients who were MRD negative at 10–5 were randomly assigned to receive ASCT plus 2 cycles of Isa-KRD (n = 242) vs 6 cycles of Isa-KRd (n = 243), each followed by 3 years of lenalidomide maintenance. Those who were MRD positive were randomly assigned to receive tandem ASCT (n = 124) vs single ASCT plus 2 cycles of Isa-KRD (n = 109), with both arms receiving 3 years of isatuximab plus iberdomide as maintenance. Perrot noted that approximately 15% of patients assigned to receive tandem ASCT did not complete treatment.

Perrot said the patient characteristics at the time of randomization post–Isa-KRd were well balanced besides higher frequency of t(11;14) in the MRD-positive arms vs the MRD-negative arms.

The rate of post-induction MRD negativity at 10–6 sensitivity was 76% in patients receiving consolidation Isa-KRd vs 73% in those receiving ASCT plus Isa-KRd. Following consolidation, the MRD negativity rates were 84% vs 86%, respectively, in the ITT population, showing no significant difference between the groups (P = .64). In the MRD-positive group, 40% of patients achieved MRD negativity after single ASCT plus Isa-KRd compared with 32% of those who underwent tandem transplant (P = .31).

“The subgroup analysis comparing arms A and B did not identify any specific patient populations in which transplant adds a meaningful impact on MRD negativity after consolidation. Similarly, the subgroup analysis comparing single vs tandem transplant did not reveal any patient population that appeared to benefit from a second transplant,” stated Perrot.

In patients who received consolidation Isa-KRd, the rate of MRD negativity at 10–6 increased from 76% to 90%, with 42 patients (24%) achieving MRD negativity over consolidation, whereas in those who received consolidation ASCT, the MRD negativity rate increased from 72% to 93%, with 63 patients (28%) achieving MRD negativity over consolidation.

Only 24% of patients with t(11;14) were MRD negative at 10–6 post induction, a rate which increased to 63% post consolidation regardless of treatment arm. In those without t(11;14), the post-induction MRD negativity rate was 59% and increased to 78% after consolidation.

No new safety signals appeared in the consolidation phase in the MRD-negative group, and no adverse effects (AEs) occurred with greater than 10% frequency. Patients in the ASCT arm experienced additional AEs related to melphalan including nausea, mucositis, febrile neutropenia, and sepsis. Among patients in the MRD-positive group, the only AEs with a frequency of greater than 10% were mucosal inflammation in 12% and stomatitis in 14% of the tandem ASCT arm. There was also a higher rate of vascular device infections among patients in the tandem ASCT arm.

With median follow-ups of 16.8 months in the group of patients who were MRD negative at induction and 16.3 months among those who were MRD positive at induction, PFS and sustained MRD negativity data were not yet available.

“The lack of added benefit with ASCT in MRD-negative patients may be explained by the very high MRD negativity rates already achieved after induction,” Perrot suggested.

She recommended that future strategies should combine initial cytogenetic risk and MRD-based stratification. “These findings support a more individualized induction approach based on MRD status,” she concluded.

References

1. Perrot A, Hulin C, Lambert J, et al. MRD-driven strategy following IsaKRD induction in transplant-eligible NDMM: primary endpoints of the phase 3 MIDAS trial. J Clin Oncol. 2025;43(suppl_16):7500. doi:10.1200/JCO.2025.43.16_suppl.7500
2. Perrot A, Lambert J, Hulin C, et al; MIDAS Study Group. Measurable residual disease–guided therapy in newly diagnosed myeloma. N Engl J Med. Published online June 3, 2025. doi:10.1056/NEJMoa2505133