Isatuximab, bortezomib, lenalidomide, dexamethasone for multiple myeloma: dynamics of MRD-negativity in the IMROZ study

Quadruplet therapy with isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) followed by Isa-Rd in the randomized Phase 3 IMROZ study provided significant PFS benefit to transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. In the primary analysis, more Isa-VRd/Isa-Rd-treated patients achieved MRD-negativity and MRD-negative complete response (CR) at any timepoint compared with VRd triplet therapy followed by Rd. Here, we report results from landmark analyses of MRD-negativity over time and its impact on clinical outcomes in IMROZ. Treatment with Isa-VRd/Isa-Rd led to deeper responses, with higher rates of MRD-negativity and MRD-negative CR at both the end of the initiation phase and during maintenance vs. VRd/Rd, up to 60 months of follow-up. Benefit with Isa-VRd/Rd was observed across key patient subgroups, including older (>70 years) and frail patients. The deeper responses achieved throughout treatment were associated with improved outcomes, with a significant prolongation in time-to-progression (TTP) in favor of Isa-VRd/Rd vs. VRd/Rd in patients who converted from MRD-positive to MRD-negative. TTP in patients who converted from MRD-negative at the end of initiation to MRD-positive also favored Isa-VRd. Evaluation of MRD status for individual patients at more than one timepoint may thus be useful to support decisions on treatment selection and treatment continuation/discontinuation. Our findings on the extent of MRD-negativity and MRD-negative CR benefit achieved in the initiation and maintenance phases by patients receiving Isa-VRd/Isa-Rd vs. VRd/Rd extend the IMROZ primary analyses and further support the Isa-VRd quadruplet regimen as a standard-of-care for front-line treatment of transplant-ineligible NDMM patients. Clinical Trial Information: ClinicalTrials.gov, NCT03319667.