MIDAS Trial: ASCT Offers No MRD Benefit Over Isa-KRd in Myeloma

In the phase 3 MIDAS trial (NCT04934475), patients with newly diagnosed multiple myeloma who were measurable residual disease (MRD)-negative at 10⁻⁵ sensitivity after quadruplet induction therapy did not derive additional benefit from autologous stem-cell transplantation (ASCT) compared with continued therapy using isatuximab (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd), according to results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.^1–3

The study found no significant difference in the rate of MRD negativity at 10⁻⁶ sensitivity between patients who received ASCT vs those who continued the Isa-KRd regimenfollowing induction. The findings challenge the long-standing assumption that upfront ASCT provides incremental benefit in patients who achieve early deep remissions with modern induction regimens.

MRD-Negative vs MRD-Positive Outcomes

The MIDAS trial enrolled transplant-eligible patients with newly diagnosed multiple myeloma who had completed 6 cycles of Isa-KRd induction therapy. Patients were stratified based on their MRD status at 10⁻⁵ sensitivity, as measured by next-generation sequencing.

Among the 485 patients who achieved MRD negativity at 10⁻⁵ after induction, the proportion who remained MRD-negative at 10⁻⁶ sensitivity before maintenance was 86% in the ASCT group vs 84% in the Isa-KRd group (adjusted relative risk, 1.02; 95% CI, 0.95-1.10; P =.64). Among the 233 patients who were MRD-positive at 10⁻⁵, 32% of those assigned to tandem ASCT and 40% of those who received a single ASCT plus Isa-KRd achieved MRD negativity at 10⁻⁶ (adjusted relative risk, 0.82; 95% CI, 0.58-1.15; P =.31). Notably, 15% in the tandem group did not complete the second transplant.

The median follow-up was approximately 16.8 months. No new safety signals were observed, although 7 adverse events occurred during consolidation therapy, including 5 cases of disease progression and 2 unrelated deaths, with none in the single ASCT arm.

Impact on Myeloma Treatment Guidelines

Although ASCT remains a standard component of multiple myeloma treatment, the MIDAS trial suggests that it may not offer additional benefit in terms of deep molecular response for patients who are MRD-negative after induction with Isa-KRd. The lack of added efficacy from tandem ASCT in MRD-positive patients also raises questions about its routine use following potent induction regimens.

These results align with a growing body of evidence questioning the necessity of upfront ASCT in the context of newer, more effective induction regimens. While ASCT has historically demonstrated progression-free survival (PFS) benefits, those gains have not consistently translated into overall survival (OS) advantages, particularly in the era of effective salvage therapies.^4,5

Limitations and Future Directions

The trial underscores the limitations of using MRD status in isolation as a decision-making tool for consolidation strategies.

“The findings highlight the complexity of tailoring treatment on the basis of MRD status only, in the context of the underlying biologic characteristics of disease,” Aurore Perrot, MD, PhD, et al, noted in the study.¹ They emphasized that MRD kinetics vary with cytogenetic risk, and that risk-adapted strategies integrating both genomic and MRD-based stratification are likely to offer more clinically meaningful guidance.

Longer follow-up is underway to evaluate whether PFS and OS outcomes will differ across study arms. Until then, the data support a more nuanced, response-adapted approach to consolidation, particularly for patients who respond well to initial therapy with Isa-KRd.

REFERENCES:

1. Perrot A, Lambert J, Hulin C, et al. Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma. N Engl J Med. Published online June 3, 2025. doi:10.1056/NEJMoa2505133

2. 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):abstr LBA7500. doi:10.1200/JCO.2025.43.16_suppl.7500

3. Minimal residual disease adapted strategy (MIDAS). ClinicalTrials.gov. Updated November 7, 2025. Accessed July 9, 2025. https://clinicaltrials.gov/study/NCT04934475

4. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371:895–905. doi:10.1056/NEJMoa1402888

5. Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: A phase 3 study. Lancet Oncol. 2017;18(4):519–530. doi:10.1001/jamaoncol.2017.4600