Isatuximab Combo Approved in EU for Transplant-Ineligible NDMM

Patients who received the isatuximab combination in the IMROZ trial experienced prolonged MRD-negativity, which correlated with improved PFS.

Isatuximab-irfc (Sarclisa), a CD38 monoclonal antibody, in combination with standard of care—bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd)—has been approved in the EU as a treatment option for adult patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT), a press release from the developer, Sanofi, reported.¹

The drug combination was recommended for approval in this patient population by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) in November 2024.² In September 2024, the FDA approved the drug combination for patients with NDMM who are not eligible for ASCT.³

Supporting data for the approval came from the open-label, randomized phase 3 IMROZ study (NCT03319667). Updated findings were presented at the 2024 American Society of Hematology Annual Meeting & Exposition.⁴

“While there have been many important advancements in multiple myeloma treatment over the past decade, there remains a significant unmet need in the front-line setting, particularly for [patients who are] transplant-ineligible,” Olivier Nataf, global head of Oncology at Sanofi, stated in the press release.¹ “With today’s decision, the 27 countries in the EU will have access to a potentially transformative new combination regimen, marking a significant step forward in our mission to make a meaningful difference in multiple myeloma treatment.”

In the IMROZ trial, the median time from first dose to initial minimal residual disease (MRD) negativity, at 10^–5, was 6.5 months in both the group that received isatuximab and the group that did not; a significant majority of patients had sustained MRD negativity at later timepoints when isatuximab was added. Furthermore, patients who had an MRD-negative assessment at 6 months demonstrated an improved progression-free survival (PFS) benefit in the isatuximab group (HR, 0.562; 95% CI, 0.296-1.068; P = .0784).

At the following timepoints, patients who received isatuximab maintained a higher proportion of MRD negativity compared with those who did not: 6 months (49.7% vs 41.1%, respectively), 12 months (54.0% vs 39.2%), 18 months (58.0% vs 35.3%), 24 months (64.1% vs 41.0%), 36 months (68.0% vs 50.8%), 48 months (67.6% vs 41.7%), and 60 months (76.1% vs 40.0%).

Based on a landmark analysis, fewer patients who received isatuximab converted from MRD-negative status at the initiation phase (6 months) to MRD-positive status during the maintenance phase (beyond 6 months). Additionally, of patients who converted to MRD positivity after an MRD-negative assessment, those in the isatuximab group experienced an increased time to progression.

At 12 months or more (46.8% vs 24.3%), 24 months or more (35.8% vs 13.3%), and 36 months or more (25.7% vs 7.2%), sustained MRD-negative rates were 2- to 3- times greater in the isatuximab group vs the group that did not receive isatuximab.

In both treatment arms, PFS was similar once patients achieved MRD negativity for 12 months or longer (HR, 0.818; 95% CI, 0.376-1.777; P = .6117) and 24 months or longer (HR, 0.973; 95% CI, 0.275-3.450; P =.9665).

A total of 446 patients with transplant-ineligible NDMM who were 80 years or younger were randomly assigned, in a 3:2 ratio, to either receive isatuximab plus VRd (n = 265) or VRd alone (n = 181). Patients received intravenous isatuximab at 10 mg/kg, subcutaneous bortezomib at 1.3 mg/m², oral lenalidomide at 25 mg, and intravenous or oral dexamethasone at 20 mg.

Treatment continued until progressive disease, unacceptable toxicity, or patient withdrawal. Those in the group without isatuximab who experienced progressive disease during the maintenance phase were permitted to cross over to the isatuximab group.

MRD negativity was assessed via clonoSEQ^® next-generation sequencing.

The trial’s primary end point was PFS, with secondary end points including complete response (CR) rate, MRD-negative CR rate, and overall survival rate.

Lead investigator Robert Z. Orlowski, MD, PhD, director of Myeloma and professor of medicine in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, stated in the presentation, “These data support the benefit of [isatuximab] in addition to VRd as initiation therapy, as well as the addition of [isatuximab] to [lenalidomide and dexamethasone] during maintenance in [patients who are] transplant-ineligible with NDMM.”⁴

References

1. Sarclisa approved in the EU as the first anti-CD38 therapy in combination with standard-of-care VRd to treat transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. January 22, 2025. Accessed January 22, 2025. https://tinyurl.com/yez9rtk2
2. Sarclisa recommended for EU approval by the CHMP to treat transplant-ineligible newly diagnosed multiple myeloma. News release. Sanofi. November 14, 2024. Accessed January 22, 2025. https://tinyurl.com/snjbc5jc
3. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. September 20, 2024. Accessed January 22, 2025. https://shorturl.at/B8d3c
4. Orlowski RZ, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) in patients with newly diagnosed multiple myeloma (NDMM): analyses of minimal residual disease (MRD) negativity dynamics in the phase 3 IMROZ study. Blood. 2024;144(suppl 1):770. doi:10.1182/blood-2024-203818