KEY TAKEAWAYS
- The phase 3 trial aimed to compare IsaRd and Isa-VRd in NDMM TI and evaluate the impact of prolonged bortezomib use on outcomes.
- The primary endpoint was to determine MRD.
- Researchers noticed that Isa-VRd showed superior responses and safety.
CD38 targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in newly diagnosed transplant ineligible multiple myeloma (NDMM TI) and considered the current standard of care (SOC). The best treatment combinations are important in NDMM TI, as outcomes worsen with successive lines of therapy. To enhance the current SOC, they investigated the added value of prolonged bortezomib use for 18 months, using a reduced intensity weekly schedule alongside IsaRd.
Xavier P. Leleu and the team’s aim was to evaluate the impact of a proteasome inhibitor (PI) in a quadruplet regimen to improve depth of response. In the BENEFIT/IFM2020-05 study (NCT04751877), they compared the efficacy and safety of IsaRd versus Isa-VRd in NDMM TI.
They performed an inclusive analysis in the BENEFIT trial, a prospective, multicenter, randomized, parallel study. Patients aged 65-79, non-frail, with NDMM TI were randomized 1:1 and stratified by age, high-risk cytogenetic, and center. The Isa-VRd arm received V (1.3 mg/m2 SC weekly up to c12, bimonthly up to c18); both arms received Isa (10 mg/kg IV weekly and bimonthly up to c12, then monthly), R (25 mg), and d (20 mg up to c12).
The primary endpoint was minimal residual disease (MRD) 10-5 negative rate (NGS) at 18 months from treatment start analyzed in ITT. Key secondary endpoints included survival times (OS, PFS, EFS, TTNT), response rates and durations, MRD endpoints, and safety (using NCI CTCAE v5.0).
About 270 patients (135 per arm) were recruited by the data cutoff date (02 Feb 2024). Patients’ baseline characteristics were well balanced across arms, with a median age of 73.2 years [IQR 71;76], 90 patients (33%) aged >75 years, 23 (9%) with high-risk cytogenetic (IFM score >1), 181 (76%) with R-ISS2+3, and 47 (17%) with impaired renal function (eGFR <60 mL/min). MRD negativity rates at 10-5 at 18 months were significantly higher in the Isa-VRd arm compared to the IsaRd arm (47% vs 24%, OR for negative MRD = 2.96 [95%CI 1.73 – 5.07, P<0.001]).
The MRD benefit was consistent across subgroups. At a median follow-up of 21.2 months, 33 (12%) patients had relapsed, and 20 (7%) had died, with no significant difference observed across arms. The addition of a weekly “light” schedule of bortezomib did not significantly affect the relative dose intensity of IsaRd. Forty-four (33%) patients presented with neurological adverse events grade ≥2 in the Isa-VRd arm versus 27 (20%) in the IsaRd arm.
The study concluded that Isa-VRd significantly enhanced responses, notably increasing the MRD negative rate at 10-5 vs. IsaRd. Its safety profile is consistent with bortezomib addition. These findings support Isa-VRd as a new SOC for NDMM TI non-frail patients.
The trial was sponsored by the Poitiers University Hospital
Source: https://meetings.asco.org/abstracts-presentations/231716
Clinical Trial: https://clinicaltrials.gov/study/NCT04751877
Leleu X.P., Hulin C, Lambert J, et al. (2024). “Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI).” presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 16; abstr 7501), 10.1200/JCO.2024.42.16_suppl.7501
