As reported at the 2024 ASCO Annual Meeting (Abstract 7500) and in The New England Journal of Medicine by Thierry Facon, MD, and colleagues, interim analysis of the phase III IMROZ trial showed significantly improved progression-free survival with the addition of isatuximab to bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma who were ineligible to receive autologous stem cell transplantation.

As stated by the investigators, “VRd is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear.”

Thierry Facon, MD

Study Details

In the open-label trial, 446 patients aged 18 to 80 years from sites in 21 countries were randomly assigned 3:2 between December 2017 and March 2019 to receive isatuximab plus VRd (n = 265) or VRd (n = 181). All patients received four 6-week induction cycles of VRd; isatuximab at 10 mg/kg was given once weekly in cycle 1 and every 2 weeks thereafter. Patients then received 4-week cycles of continuous treatment with VRd; isatuximab at 10 mg/kg was given every 2 weeks followed by every month starting at cycle 18.  During continuous treatment, patients receiving VRd alone could cross over to receive isatuximab plus VRd upon disease progression. Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoint of the trial was progression-free survival on independent review.       

Progression-Free Survival

At data cutoff for the interim analysis in September 2023, median follow-up was 59.7 months (interquartile range = 56.0–63.2 months). Estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group vs 45.2% in the VRd group (hazard ratio [HR] = 0.60, 98.5% confidence interval [CI] = 0.41–0.88, P < .001). Median progression-free survival was not reached (95% CI = not reached to not reached) vs 54.3 months (95% CI = 45.2 months to not reached).

Complete response or better was observed in 74.7% of the isatuximab group vs 64.1% of the VRd group (P = .01). Minimal residual disease (MRD)-negative status (10⁻⁵ sensitivity) was achieved in 58.1% vs 43.6% of all patients (odds ratio [OR] = 1.79, 95% CI = 1.22–2.63), and MRD-negative status and complete response or better were observed in 55.5% vs 40.9% (OR = 1.80, 95% CI = 1.23–2.65, P = .003).

At data cutoff, subsequent antimyeloma therapy had been initiated in 19.6% of the isatuximab-VRd group and 44.2% of the VRd group. At time of analysis, death had occurred in 26.0% of the isatuximab-VRd group vs 32.6% of the VRd group, with an estimated 60-month overall survival of 72.3% vs 66.3% (HR = 0.78, 99.97% CI = 0.41–1.48). Patients continue to be followed for overall survival.

Adverse Events

The most common adverse events in both groups were hematologic in nature. The most common nonhematologic grade ≥ 3 adverse events in both the isatuximab-VRd group and the VRd group included pneumonia (20.2% vs 12.7%) and cataracts (15.6% vs 11.0%). Serious adverse events occurred in 70.7% vs 67.4% of patients. Adverse events led to discontinuation of treatment in 22.8% vs 26.0% of patients. Death due to infection occurred in 6.5% vs 3.9% of patients (including COVID-19 infection in 3.0% vs 1.1%). Second primary solid cancers were observed in 8.4% vs 4.4% of patients.  

The investigators concluded, “Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation.”

Dr. Facon, of Centre Hospitalier Universitaire de Lille, Lille, France, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Sanofi. For full disclosures of the study authors, visit nejm.org.