Isatuximab Regimen Improves MRD Negativity in Transplant-Eligible NDMM

Combining isatuximab-irfc (Sarclisa) with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) significantly improved minimal residual disease (MRD) negativity vs KRd alone among patients with newly diagnosed multiple myeloma (NDMM) who were eligible for transplantation, according to findings from a phase 3 study (NCT04483739) published in Nature Medicine.¹

The rate of MRD negativity at a sensitivity of 10^–5 was 77% in the Isa-KRd arm and 67% in the KRd alone arm (OR, 1.67; 95% CI, 1.00-2.80; P = .049). At a sensitivity of 10^–6 the MRD-negative rates were 68% vs 48% in each respective arm (OR, 2.36; 95% CI, 1.47-3.79; P = .0004). At the 10^–5 and 10^–6 cutoffs, consistent MRD negativity benefits were observed across all patient subgroups following the autologous stem cell transplant (ASCT) full-dose consolidation period, which included those with high-risk and ultra-high-risk disease.

The 1-year sustained MRD-negative rates with Isa-KRd were sustained across all patient subgroups, with particular benefits highlighted in ultra-high-risk patients with 2+ HRCA (OR, 6.30; 95% CI, 1.11-35.66) and those with International Myeloma Society (IMS) or International Myeloma Working Group (IMWG) high-risk features (OR, 2.84; 95% CI, 1.00-8.11). Between the experimental and control arms, the rates of sustained MRD negativity at a 10^–6 threshold were comparable for patients with high-risk, ultra-high-risk, and standard-risk disease.

The 4-year progression-free survival (PFS) rate was 80% between both treatment arms. Investigators noted that a limited number of events did not permit an adequate comparison of PFS outcomes across arms.

“[P]re-ASCT induction and post-ASCT consolidation with Isa-KRd, compared with KRd, provided rapid, clinically meaningful and high-quality responses in [transplant-eligible] patients with NDMM. We believe that our data, including those regarding the control arm with KRd, can support the potential role of carfilzomib in the upfront setting, given the high efficacy in terms of MRD negativity,” lead study author Francesca Gay, MD, PhD, from the Division of Hematology of AOU Città della Salute e della Scienza di Torino and the Department of Molecular Biotechnology and Health Sciences at University of Torino, wrote with coauthors in the publication.¹ “In the rapidly evolving treatment landscape of [multiple myeloma], novel regimens based on KRd plus an anti-CD38 [monoclonal antibody] backbone upfront may represent valuable alternatives, given their different toxicity profiles, the efficacy observed both overall and in high-risk and ultra-high-risk subgroups, as well as their potential to offer different treatment plans, with or without prolonged multiagent therapy.”

In the open-label phase 3 study, transplant-eligible patients with NDMM were randomly assigned to receive Isa-KRd (n = 151) or KRd alone (n = 151). Dosing consisted of carfilzomib at 20 mg/m² intravenously on day 1 of cycle 1 followed by 56 mg/m² on days 8 and 15 of cycle 1 then 56 mg/m² on days 1, 8, and 15 of each subsequent cycle; lenalidomide at 25 mg orally on days 1 to 21; dexamethasone at 40 mg on days 1, 8, 15, and 22; and isatuximab at 10 mg/m² on days 1, 8, 15, and 22 of the first induction cycle, days 1 and 15 of induction cycles 2 to 4 and full-dose consolidation cycles 1 to 4, and on day 1 of each light-consolidation cycle.

The trial’s primary end point was the rate of MRD negativity after ASCT consolidation therapy per next-generation sequencing (NGS).² Secondary end points included PFS, overall response rate, duration of response, overall survival, and time to next therapy. Patients 18 to 70 years old with NDMM and eligibility for ASCT, a life expectancy of at least 3 months, and an ECOG performance status of 0 to 2 were permitted to enroll on the trial.

The median age was 61 years (IQR, 55-66) in the Isa-KRd arm and 60 years (IQR, 54-63) in the KRd arm, and most in each arm were male (52% vs 56%). Across each arm, most patients had an ECOG performance status of 0 (58% vs 62%), an absence oft(11;14) (79% vs 81%), standard-risk disease per IMWG guidelines (82% vs 81%), and revised International Staging System stage II disease (59% vs 58%).

During light consolidation therapy, the most common grade 3/4 adverse effects (AEs) in the Isa-KRd and KRd arms included neutropenia (17% vs 17%), infections (10% vs 7%), and gastrointestinal toxicities (4% vs 5%). In the Isa-KRd arm, second primary malignancy diagnoses included endometrial cancer (n = 2), basal cell carcinoma (n = 2), melanoma (n = 1), and myelodysplastic syndrome (n = 1).

References

1. Gay F, Roeloffzen W, Dimopoulos MA, et al. Isatuximab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma: a randomized phase 3 trial. Nat Med. Published online April 6, 2026. doi:10.1038/s41591-026-04282-0
2. Isa-KRd vs KRd in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation (IsKia TRIAL) (IsKia). ClinicalTrials.gov. Updated February 26, 2025. Accessed April 6, 2026. https://tinyurl.com/34s7a3zp