Isa-VRd as a new standard of care for patients with transplant-ineligible newly-diagnosed multiple myeloma
Patients with transplant-ineligible newly-diagnosed multiple myeloma (NDMM) still require therapies which prolong survival and improve quality of life. Recent results from the global, phase III IMROZ study demonstrated a significant improvement in progression-free survival in patients with transplant-ineligible NDMM when treated with isatuximab added to bortezomib, lenalidomide and dexamethasone (Isa-VRd), as compared to the standard VRd treatment.
The triplet combination of bortezomib-lenalidomide-dexamethasone (VRd) is a standard frontline treatment for patients with transplant-eligible and -ineligible multiple myeloma (MM). However, quadruplet regimens consisting of an anti-CD38 antibody in combination with a proteasome inhibitor and an immunomodulatory agent resulted in improved outcomes for transplant-eligible patients with newly-diagnosed MM (NDMM). The phase III IMROZ study investigated the safety and efficacy of isatuximab combined with VRd (Isa-VRd) versus VRd in transplant-ineligible NDMM patients.
Study design
IMROZ is a global, prospective, randomised, open-label study that is conducted at 102 study sites across 21 countries. The trial enrolled patients with active, measurable NDMM who were not considered for transplantation due to elderly age or comorbidities. Patients of age 80 years and older were excluded from enrolment. Patients were randomised in a 3:2 ratio to Isa (10 mg/kg on Days 1, 8, 15, 22, 29 in Cycle 1; every 2 weeks [Q2W] thereafter), plus V (1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32), R (25 mg on Days 1–14, Days 22–35), and d (20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33), or VRd alone for 4 6-week cycles (induction phase). After Cycle 4, patients will receive Rd with or without Isa in 4-week cycles (R on Days 1–21; d weekly; Isa Q2W) until disease progression, unacceptable adverse events, or patient decision to discontinue (continuous phase). Isa will be reduced to monthly dosing from Cycle 18. Patients who progress on Rd can cross-over to Isa plus Rd. Primary endpoint of the study was progression-free survival (PFS), with secondary endpoints being complete response (CR), minimal residual disease (MRD) in patients with CR, very good partial response or better, and overall survival (OS).
Results
In total, 265 patients were randomised to the Isa-VRd regimen and 181 patients received the standard VRd treatment. Patient characteristics were well-balanced in both treatment arms. At a median follow-up of 59.7 months, Isa-VRd followed by Isa-Rd led to a statistically significant reduction in the risk of progression or death by 40.4% (median PFS not reached vs. 54.34 months, HR[98.5%CI]: 0.596[0.406-0.876], p= 0.0005). The five-year PFS rates were 63.2% and 45.2% in the Isa-VRd and VRd arms, respectively. A PFS benefit was observed with Isa-VRd vs. VRd across most subgroups, including some difficult-to-treat populations with negative prognostic factors. Furthermore, Isa-VRd followed by Isa-Rd resulted in deep response rates, with a significant improvement in the MRD-negativity CR rate (55.5% vs. 40.9%), as well as higher rates of MRD-negativity and sustained MRD-negativity for at least twelve months (46.8% vs. 24.3%). At a median follow-up of five years, OS is still immature. However, a favourable trend was observed for the Isa-VRd arm, with a 22.4% risk reduction compared to the VRd arm (HR[99.7%CI]: 0.776[0.407-1.48]). Isa-VRd was well tolerated and the safety profile remains consistent with the known safety profiles of each agent. Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 91.6% of patients in the Isa-VRd arm and in 84.0% of patients in the VRd arm. Grade 5 TEAEs occurred in respectively 11.0% vs. 5.5% of patients. However, these numerical differences in TEAEs can largely be explained by longer exposure in the Isa-VRd arm (53.2 months) as compared to the VRd arm (31.3 months).
Conclusion
IMROZ is the first global, phase III study of an anti-CD38 mAb in combination with VRd in patients with transplant-ineligible NDMM. Isa-VRd followed by Isa-Rd led to a statistically significant reduction in the risk of progression or death. In addition, Isa-VRd resulted in deep responses, with a statistically significant improvement in MRD negativity rates in patients with CR. Isa-VRd was well tolerated and the safety profile remains consistent with that of each agent.
Reference
Facon T, 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). Presented at EHA 2024; Abstract S100.
