Isatuximab combinations are emerging as promising treatments for newly diagnosed multiple myeloma, demonstrating significant improvements in progression-free survival (PFS) and minimal residual disease (MRD) negativity. Recent data from the IMROZ and GMMG-HD7 trials highlight the potential of isatuximab-based regimens in both transplant-ineligible and transplant-eligible patients. These findings suggest a shift towards quadruplet therapies as a new standard of care in the frontline treatment of multiple myeloma.
IMROZ Trial: Isatuximab Plus VRd in Transplant-Ineligible Patients
The phase 3 IMROZ trial (NCT03319667) evaluated the efficacy of isatuximab (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) in adult patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant (ASCT). The results, presented at the 2024 ASCO Annual Meeting and published in the New England Journal of Medicine, demonstrated a significant reduction in the risk of disease progression or death.
At a median follow-up of 59.7 months, isatuximab plus VRd reduced the risk of disease progression or death by 40.4% compared with VRd alone (HR, 0.596; 98.5% CI, 0.406-0.876; log-rank P = .0005). Patients treated with isatuximab plus VRd (n = 265) achieved a median PFS that was not reached (NR) and a 60-month PFS rate of 63.2%, while those in the VRd arm (n = 181) experienced a median PFS of 54.34 months (95% CI, 45.207-NR) and a 60-month PFS rate of 45.2%.
Dietmar Berger, MD, PhD, chief medical officer and global head of development at Sanofi, stated, "The positive CHMP opinion is an important step forward for people with transplant-ineligible newly diagnosed multiple myeloma for whom effective frontline therapy may improve long-term outcomes. If approved, this [isatuximab]-based combination could establish a new standard-of-care treatment approach for patients in the European Union, helping to address a critical care gap in multiple myeloma treatment, and reinforcing [isatuximab’s] potential as the anti-CD38 therapy of choice."
In September 2024, the FDA approved isatuximab-irfc in combination with VRd for adult patients with newly diagnosed multiple myeloma who are not eligible for ASCT, based on data from the IMROZ trial.
GMMG-HD7 Trial: Isatuximab-RVd in Transplant-Eligible Patients
The phase 3 GMMG-HD7 trial (NCT03617731) investigated the addition of isatuximab to lenalidomide, bortezomib, and dexamethasone (RVd) as induction therapy, followed by autologous stem cell transplant (ASCT), in patients with transplant-eligible newly diagnosed multiple myeloma. The analysis of part 1 of the trial, presented at the 2024 ASH Annual Meeting, showed a significant improvement in progression-free survival (PFS) with the addition of isatuximab.
At a median follow-up of 48 months, Isa-RVd (n = 331) given as induction treatment for 18 weeks without consolidation led to a 30% reduction in the risk of disease progression or death vs RVd (n = 329), irrespective of the maintenance therapy received (HR, 0.70; 95% CI, 0.52-0.95; stratified log-rank P = .0184).
Elias K. Mai, MD, hematologist and myeloma specialist in the Department of Internal Medicine V (Hematology, Oncology and Rheumatology) at Heidelberg University Hospital in Germany, noted, "GMMG-HD7 is the first phase 3 study to show that an 18-week initial quadruplet regimen with isatuximab, without consolidation, allows for significant long-term benefits regardless of subsequent maintenance therapy."
Impact on Minimal Residual Disease (MRD)
Both trials demonstrated that isatuximab-based regimens led to higher rates of minimal residual disease (MRD) negativity, indicating deeper responses. In the GMMG-HD7 trial, MRD negativity rates after induction were 50.1% in the Isa-RVd arm and 35.6% in the RVd arm (OR, 1.83; 95% CI, 1.34-2.51; P < .0001). Isa-RVd also led to a deeper MRD-negative response post-transplant vs RVd in the ITT population, at 66.2% vs 47.7% (OR, 2.13; 95% CI, 1.56-2.92; P < .0001).
These findings underscore the importance of achieving MRD negativity as a key treatment goal in multiple myeloma, with isatuximab-based regimens offering a promising approach to achieve this goal.
Safety and Tolerability
In the IMROZ trial, safety and tolerability data for the isatuximab regimen were consistent with previously reported data for the combination. Grade 5 treatment-emergent adverse effects (TEAEs) occurred in 11.0% of patients in the isatuximab arm vs 5.5% of patients in the VRd arm. The rates of grade 3 or higher TEAEs were 91.6% and 84.0%, respectively. The respective rates of serious TEAEs were 70.7% and 67.4%. TEAEs led to definitive treatment discontinuation in 22.8% of patients in the experimental arm vs 26.0% of patients in the control arm.
