IMROZ: Adding Isatuximab to SOC in Transplant-Ineligible Newly Diagnosed Multiple Myeloma Cut Risk of Disease Progression or Death 40%

Adding isatuxmab (Sarclisa, Sanofi), an anti-CD38 monoclonal antibody, to both phases of the standard regimen for patients newly diagnosed with multiple myeloma not eligible for transplant cut the risk of disease progression or death by 40%, according to results presented Monday at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Thierry Facon, MD | Image credit: ASCO

Results for IMROZ, presented in an oral session by Thierry Facon, MD, professor of hematology, Department of Hematology at Lille University Hospital in France, were simultaneously published in the New England Journal of Medicine (NEJM).²

Facon described IMROZ as the first worldwide phase 3 study of an anti-CD38 monoclonal antibody combined with the standard-of-care combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone to show significant improvements in progression-free survival (PFS), along with deep responses based on measures of minimal residual disease (MRD), in transplant-ineligible patients newly diagnosed with multiple myeloma.

The triplet therapy that is the current standard regimen for these patients, known as VRd, is followed by maintenance with lenalidomide and dexamethasone only (Rd). In his presentation, Facon noted that several phase 3 trials are building off this triplet background therapy to seek even better results with quadruplet therapy.

In an interview with The American Journal of Managed Care^® prior to ASCO, Facon said that the results for isatuximab in IMROZ were highly significant, in part because of the results in the comparator arm were so strong—a point also noted in the NEJM paper.

“The PFS benefit, to be honest, is very significant, both from a clinical and a statistical point of view,” Facon said. “One thing is that the VRd control arm did very well—you will not see so many VRd regimens doing so well.”

He compared not only PFS but also the number of cycles of therapy between the 2 arms: “It’s totally true to say that the median duration on therapy is 31 months for VRd and 53 months for isatuximab. So, the median number of cycles is 29 vs 52. That’s a big difference.”

In IMROZ, 446 patients aged 18 to 80 years were randomized 3:2 to receive either isatuximab plus VRd or VRd alone; 4 induction cycles (6 weeks per cycle) were followed by 4-week cycles of continuous treatment of isatuximab-Rd for patients in the isatuximab-VRd group, vs Rd for patients in the VRd group. Patients were treated until disease progression or an unacceptable adverse event (AE).

Results are as follows:

• The primary endpoint was PFS. At a median follow-up of 59.7 months, the median PFS with the isatuximab-VRd combination was not reached vs 54.3 months with VRd.
• The estimated PFS at 60 months was 63.2% in the isatuximab-VRd group vs 45.2% in the VRd group, for an HR of 0.60 for disease progression or death (98.5% CI, 0.41-0.88; P < .001).
• For the secondary endpoint of complete response (CR), 74.7% of patients receiving isatuximab-VRd achieved a CR or better vs 64.1% among those who received VRd alone (P = .01).
• For the secondary end point of MRD-negative status among those with a CR, the percentage of patients with MRD-negative status and a CR favored the isatuximab group (55.5% vs 40.9%; P = .003).
• No new safety signals were reported among patients taking the isatuximab-VRd regimen. Grade 3 or higher treatment-emergent AEs were seen in 91.6% of patients taking isatuximab-VRd and 84% of those taking VRd.
• The incidence of serious AEs leading to discontinuation was similar between the 2 groups; 22.8% of patients in the isatuximab-VRd group and 26% taking VRd.

At the time of data cut-off, 47.2% of patients (125/263) receiving isatuximab-VRd and 24.3% of patients (44/181) treated with VRd were still on treatment. The median treatment duration for the isatuximab-VRd combination was 53.2 months compared with 31.3 months for VRd.

“The improved efficacy of [isatuximab] VRd, combined with a consistent safety profile, provides an important treatment option for frontline treatment in this population, establishing isa-VRd as a new standard of care for patients less than 80 years of age with transplant ineligible multiple myeloma,” Facon concluded Monday.

In a commentary on 3 related presentations, Carl Ola Landgren, MD, PhD, of the University of Miami/Sylvester Comprehensive Cancer Center, agreed that isatuximab-VRd should be the standard of care, although he asked whether the lines between “transplant eligible” and “transplant ineligible” are still needed in the era of anti-CD38 therapy.

MRD status. The FDA is deciding whether to make MRD negativity a surrogate end point following a recent unanimous endorsement from the Oncologic Drugs Advisory Committee. The NEJM paper noted that 46.8% of those in isatuximab-VRd group and 24.3% of the VRd group had sustained MRD negative status for at least 12 months, based on a sensitivity of 10^-5. IMROZ also had an exploratory analysis of the share of patients with both MRD-negative status and CR at a sensitivity of 10^-6 and results were consistent (40.0% vs 22.7%; with an OR of 2.27; 95% CI, 1.48-3.48).²

In addition, a PFS benefit was seen in the isatuximab-VRd group among MRD-negative patients compared with MRD-positive patients (HR, 0.22; 95% CI, 0.14-0.35), and this benefit was larger than what was seen among the VRd patients who were MRD-negative (HR, 0.31; 95% CI, 0.19-0.52).

During the interview, Facon was asked if the results provide evidence that MRD is a valid surrogate end point. “I think I could tell you that FDA would be happy with the study results,” he replied. “They will not complain.”

Ahead of his ASCO presentation, Facon said he anticipated questions about results that show patients with high-risk cytogenetic features did not receive additional benefits from isatuximab vs VRd (HR, 0.97; 95% CI, 0.48-1.96). The NEJM paper said this area warrants “further analyses and longer follow-up.”

References

1. Facon T, Dimopoulous MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol 2024;42(suppl 16):Abstract 7500. doi:10.1200/JCO.2024.42.16_suppl.7500

2. Facon T, Dimopoulous MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712