Isatuximab Combo Increases MRD Negativity in MRD-Positive Multiple Myeloma

Isatuximab-irfc (Sarclisa) plus iberdomide (Zenbexus; Isa-Iber) maintenance increased measurable residual disease (MRD)–negativity rates during the first year in patients with newly diagnosed multiple myeloma (NDMM) who remained MRD positive after induction and transplant, according to first-year results from Arms C and D of the phase 3 MIDAS trial (NCT04934475) presented at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition.¹

What were the MRD negativity outcomes with isatuximab/iberdomide maintenance?

MRD negativity rates improved from post-consolidation to 1 year of Isa-Iber maintenance in both arms and at both sensitivity thresholds. At 10⁻⁵, rates increased from 67% to 76% in Arm C and from 62% to 70% in Arm D. At the deeper 10⁻⁶ threshold, rates increased from 40% to 58% in Arm C and from 32% to 48% in Arm D.

Among 146 patients who remained MRD positive at 10⁻⁶ at the end of consolidation, 55 converted to MRD negativity during the first year of maintenance. In an analysis by cytogenetic subgroup, 45% of 62 patients with t(11;14) who were MRD positive after consolidation converted to MRD negativity, compared with 32% of 84 patients without t(11;14). Among 47 patients with high-risk cytogenetics by the IMS/IMWG definition, MRD negativity improved to 34% after 1 year of maintenance, although 19% of this subgroup had progressed or died. Overall, 5 progressions and 1 death occurred in each arm during the first year.

What was the safety profile of the combination?

Among 203 patients evaluable for safety, neutropenia was the most common hematologic adverse event (AE), occurring in 46% of patients (grade 3 or higher, 42%); of 102 patients who experienced neutropenia, 72 received granulocyte colony-stimulating factor. The most common nonhematologic AEs were infections (72%; grade 3 or higher, 18%), diarrhea (19%; grade 3 or higher, 1%), peripheral neuropathy (18%; grade 3 or higher, 0%), and rash (16%; grade 3 or higher, 2%).

A total of 52 patients had an iberdomide dose reduction to 0.75 mg, primarily for neutropenia (n = 31) or skin disorders (n = 10). A safety run-in was reviewed by an independent data monitoring committee, and no significant differences in safety were observed between Arms C and D, with no unexpected toxicity signals and no evidence of additive toxicity when isatuximab and iberdomide were combined.

“Maintenance with isatuximab plus iberdomide after isatuximab plus carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone [Isa-KRd] induction and single or tandem autologous stem cell transplant [ASCT] is feasible and shows a manageable safety profile. This combination induced substantial MRD conversion rates during the first year of maintenance in patients who remained MRD positive after consolidation,” lead study investigator Aurore Perrot, MD, PhD, a professor in Toulouse University and Hospital and head of the clinical research program on myeloma in the Toulouse Cancer Institute Oncopole, stated in the presentation.¹ “These findings support further evaluation of anti-CD38 plus CELMoD-based maintenance strategies in [patients with] high-risk NDMM. Longer follow-up is needed to determine the impact of MRD conversion on progression-free survival [PFS] and overall survival [OS].”

What is the MIDAS trial design, and what was the Arm C/D population?

MIDAS (Minimal Residual Disease Adapted Strategy) is an MRD-adapted, phase 3 trial conducted by the Intergroupe Francophone du Myélome. All patients with NDMM received 6 cycles of Isa-KRd induction, with MRD assessed to guide risk-adapted consolidation and maintenance. Patients who remained MRD positive after induction were randomly assigned to Arm C (single ASCT plus 2 cycles of Isa-KRd consolidation) or Arm D (tandem ASCT), after which both arms received Isa-Iber maintenance for up to 3 years.

Maintenance consisted of isatuximab at 10 mg/kg every 4 weeks (initially intravenous, then subcutaneous) plus iberdomide at 1 mg daily on days 1 to 21 of each 28-day cycle. A total of 233 patients were randomly assigned to Arms C and D (Arm C, n = 109; Arm D, n = 124); 219 initiated maintenance and 203 (94%) completed the first year. The median age was 57.5 (range, 36-65) and 58.3 years (range, 33-65) in Arms C and D, respectively, and high-risk cytogenetics were present in 17% and 23% of patients.

The primary end point was MRD negativity.² Secondary end points included sustained MRD rate, OS, PFS, and safety.

What is the significance of these findings, and what comes next?

The investigators concluded that Isa-Iber maintenance is feasible with a manageable safety profile and induced substantial MRD conversion during the first year in a population that had already failed to clear MRD after intensive induction and consolidation, supporting anti-CD38 antibody plus CELMoD therapy as an intensification strategy for patients with MRD-positive, higher-risk disease. The results add to a growing body of evidence for antibody-based maintenance after transplant, including daratumumab (Darzalex) plus lenalidomide in the PERSEUS (NCT03710603) and AURIGA trials (NCT03901963) and isatuximab plus lenalidomide in GMMG-HD7 (NCT03617731).

References

1. Perrot A, Lambert J, Hulin C, et al. First-year results of isatuximab-iberdomide maintenance in MRD-positive newly diagnosed multiple myeloma patients included in the phase 3 MIDAS trial. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Abstract OA-29.
2. Minimal residual disease adapted strategy (MIDAS). ClinicalTrials.gov. Updated November 7, 2024. Accessed September 25, 2026. https://tinyurl.com/48z7reu9