The United States (US) Food and Drug Administration (FDA) has approved the anti-CD38 monoclonal antibody, isatuximab-irfc, in combination with standard-of-care treatment for adult patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for transplant.^1,2 The approval was based on results from the phase 3 IMROZ study which showed that isatuximab combined with bortezomib, lenalidomide, and dexamethasone (VRd) significantly enhanced progression-free survival (PFS) compared to standard-of-care in newly diagnosed adult patients ineligible for autologous stem cell transplant (ASCT).¹

Triplet therapy with bortezomib, lenalidomide, and dexamethasone (VRd) is the preferred first-line treatment for myeloma patients and is commonly used in clinical practice, regardless of eligibility for transplantation.² Isatuximab, a CD38-targeting monoclonal antibody which can induce myeloma-cell death via multiple mechanisms, has been previously approved for use in patients with relapsed or refractory MM in combination with other regimens such as pomalidomide–dexamethasone and carfilzomib–dexamethasone.² In the phase 3 IMROZ trial, the efficacy and safety of isatuximab- VRd was compared with standard-of-care VRd in patients with NDMM who were ineligible to undergo transplantation.²

IMROZ was an international, randomized, open-label, phase 3 trial, which enrolled patients ≥18 years of age with symptomatic previously untreated myeloma and measurable disease who were ineligible to undergo transplantation due to being ≥ 65 years of age or having co-existing conditions.² Patients who were aged >80 years, had an Eastern Cooperative Oncology Group (ECOG) performance status >2, or an estimated glomerular filtration rate (GFR) <30mL/min/1.73m² were excluded from the trial.² In total, 446 patients were randomized 3:2 to receive isatuximab-VRd (n=256) or VRd (n=181), stratified by country (not China vs. China), age (<70 vs. ≥70 years), and disease stage.² All participants first underwent 4 induction cycles (6 weeks per cycle), during which all patients received the VRd regimen.2 Additionally, patients in the isatuximab-VRd group received intravenous isatuximab (10mg/kg body weight) once weekly in cycle 1, then every 2 weeks in subsequent cycles.² After the induction period, patients received 4-week cycles of continuous treatment with either isatuximab-Rd (10mg/kg isatuximab administered every 2 weeks/once a month from cycle 18), or the Rd regimen alone, until disease progression, an unacceptable adverse event, or other discontinuation criteria.2

The primary efficacy endpoint of the trial was progression-free survival (PFS), and key secondary endpoints included a complete response or better, and minimal residual disease (MRD)-negative status in patients with a complete response (assessed at 10-5 sensitivity by next generation sequencing), a very good partial response or better, and overall survival.²

At a median follow-up of 59.7 months (interquartile range: 56.0-63.2), disease progression or death had occurred in 31.7% of patients in the isatuximab-VRd group and 43.1% in the VRd group.² PFS assessed by the independent review committee was 63.2% in the isatuximab-VRd arm compared with 45.2% in the VRd arm (HR=0.60; 98.5% CI: 0.41-0.88; p<0.001).² While most subgroups showed a PFS benefit with the addition of isatuximab, the HR was 0.97 (95% CI: 0.48-1.96) in patients with high-risk cytogenetic features.²

The isatuximab-VRd group demonstrated a significantly higher percentage of patients achieving a complete response or better compared to the VRd group (74.7% vs. 64.1%; p=0.01), as well as a greater proportion of patients attaining MRD-negative status and a complete response (55.5% vs. 40.9%; p=0.003).² A sustained MRD-negative status lasting at least 12 months was also achieved by 46.8% of patients in the isatuximab-VRd group, compared to 24.3% in the VRd group.2 At 60 months, the estimated overall survival was 72.3% in the isatuximab-VRd group and 66.3% in the VRd group (HR=0.78; 99.97% CI: 0.41-1.48) and follow-up is ongoing.²

No new safety signals were observed with the isatuximab-VRd regimen, which had similar toxicity to current standard regimens.² The incidence of adverse events leading to definitive discontinuation was 22.8% with isatuximab-VRd and 26.0% with VRd.2 Serious adverse events occurred in 70.7% of the patients who received isatuximab-VRd and in 67.4% of those who received VRd.² The incidence of grade ≥3 infection was also similar between the two arms (44.9% with isatuximab-VRd and 38.1% with VRd).²

In summary, the addition of isatuximab to VRd led to a 40% reduction in the risk of progression or death in NDMM patients who were ineligible for transplantation.² The FDA’s approval of this combination offers an alternative first-line treatment option that could slow disease progression for longer compared to the current standard of care.¹