Efficacy and safety of the Isa-VRd quadruplet regimen for patients with transplant-ineligible newly-diagnosed multiple myeloma

The BENEFIT study is the first academic phase III study of an anti-CD38 monoclonal antibody in combination with bortezomib, lenalidomide and dexamethasone (VRd) in patients with transplant-ineligible newly-diagnosed multiple myeloma (TI NDMM). Isatuximab plus VRd (Isa-VRd) resulted in deep response rates with a statistically significant improvement in minimal residual disease negativity rate as compared to Isa-Rd.

At present, CD38 targeting immunotherapy in combination with lenalidomide and dexamethasone is approved for use in patients with transplant-ineligible newly-diagnosed multiple myeloma (NDMM) and is considered to be the standard of care. It is well known that each successive line of therapy is lower in efficacy for these patients, and there is thus a call for improvements to the standard of care. To investigate potential improvements, the BENEFIT (IFM 2020-05) phase III trial compared the triplet regimen of isatuximab plus lenalidomide and dexamethasone (Isa-Rd) against a quadruplet of isatuximab plus lenalidomide, dexamethasone and bortezomib (Isa-VRd).

Study design

In total, 270 patients were stratified by age, high-risk cytogenetics, and centre and randomised (1:1) into arm A (induction with Isa-VRd for cycles 1-12, Isa-VR for cycles 13-18, followed by Isa-R from cycle 19 until progressive disease (PD)) or arm B (induction with Isa-Rd for cycles 1-12, Isa-R for cycles 13-18, followed by Isa-R from cycle 19 until PD). The primary endpoint was minimal residual disease (MRD) 10^-5 negative rate (NGS) at 18 months from treatment start, analysed in the intention-to-treat (ITT) population, with complete response (CR) rate as a key secondary endpoint.

Results

At 18 months, the MRD negativity rate at 10^-5 and 10^-6 was significantly higher in the Isa-VRd arm vs. Isa-Rd in the ITT population (10^-5: 53% vs. 26%, OR[95%CI]: 3.16[1.89-5.28], p< 0.0001; 10^-6: 36% vs. 17%, OR[95%CI]: 2.74[1.54-4.87], p= 0.0006). The MRD negativity rate in the CR population also supported the benefit of Isa-VRd vs. Isa-Rd (10^-5: 37% vs. 17%, OR[95%CI]: 2.9[1.64-5.16], p= 0.0003; 10^-6: 27% vs. 12%, OR[95%CI]: 2.85[1.49-5.45], p= 0.002). This benefit was also seen across most patient subgroups, including difficult-to-treat populations and those with negative prognostic factors. Patients who received Isa-VRd also displayed a deeper response rate (overall response rate: 85% vs. 78%; CR 58% vs. 31%, OR[95%CI]: 2.97[2-5], p< 0.0001). The time to very good partial response (VGPR) was also shorter in the Isa-VRd arm (2.1 months [1.9-2.9] vs.3.7 months [3-4.9]; HR[95%CI]: 1.65[1.27-2.14]). At this point, the survival analysis is immature. Similar relative dose intensity of isatuximab, lenalidomide and dexamethasone were reported in both arms. In terms of safety, 91.6% of patients in the Isa-VRd arm were able to receive the bortezomib dose as expected in the protocol. In the Isa-VRd arm, 69% of patients experienced a grade ≥3 treatment-related adverse event vs. 67% in the Isa-Rd arm. 10% of patients in the Isa-VRd arm discontinued due to bortezomib.

Conclusion

Overall, the quadruplet therapy with bortezomib was well tolerated and the safety profile remains consistent with previous reports. The improved efficacy seen with Isa-VRd vs. Isa-Rd, combined with a consistent safety profile, highlights Isa-VRd as a potential new standard of care for transplant-ineligible patients with NDMM.

Reference

Leleu X, et al. Isatuximab plus lenalidomide and dexamethasone with weekly bortezomib versus isatuximab plus lenalidomide and dexamethasone in newly diagnosed transplant ineligible multiple myeloma. The BENEFIT (IFM 2020-05) study. Presented at EHA 2024; Abstract S203.