Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma

Measurable residual disease (MRD) is a major prognostic factor in newly diagnosed multiple myeloma. An assessment of an MRD-guided consolidation strategy in patients who are eligible for autologous stem-cell transplantation (ASCT) may be useful. In this phase 3 trial, we randomly assigned transplantation-eligible patients with newly diagnosed myeloma who had completed induction therapy with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) to receive consolidation therapy according to their MRD status. Patients who were MRD-negative at 10-5 sensitivity (i.e., <1 cancer cell per 100,000 normal cells, as assessed by next-generation sequencing were assigned to undergo ASCT and receive Isa-KRd for two cycles (ASCT group) or to receive Isa-KRd for six cycles (Isa-KRd group). Patients who were MRD-positive at 10-5 sensitivity were assigned to undergo tandem ASCT (two ASCTs within a short period; tandem ASCT group) or to undergo ASCT and receive Isa-KRd for two cycles (single ASCT group). The primary end point was an MRD-negative status at 10-6 sensitivity before maintenance therapy. Among 485 patients who were MRD-negative at 10-5 sensitivity after induction, a premaintenance MRD-negative status at 10-6 sensitivity occurred in 86% in the ASCT group and in 84% in the Isa-KRd group (adjusted relative risk, 1.02; 95% confidence interval [CI], 0.95 to 1.10; P = 0.64). Among 233 patients who were MRD-positive at 10-5 sensitivity after induction, a premaintenance MRD-negative status at 10-6 sensitivity occurred in 32% in the tandem ASCT group and in 40% in the single ASCT group (adjusted relative risk, 0.82; 95% CI, 0.58 to 1.15; P = 0.31); 15% of the patients in the tandem ASCT group did not undergo a second ASCT. During consolidation, disease progression occurred in 5 patients and death unrelated to disease progression occurred in 2 patients - all were in the Isa-KRd or tandem ASCT groups. No new safety signals were observed. The median follow-up was 16.8 months in the ASCT and Isa-KRd groups and 16.3 months in the tandem ASCT and single ASCT groups. Among patients who were MRD-negative at 10-5 sensitivity after induction, the percentage with a premaintenance MRD-negative status at 10-6 sensitivity was not significantly higher with ASCT than with Isa-KRd. Among patients who were MRD-positive status at 10-5 sensitivity after induction, the percentage with a premaintenance MRD-negative status at 10-6 sensitivity was not significantly higher with tandem ASCT than with single ASCT. (Funded by Intergroupe Francophone du Myélome and others; MIDAS ClinicalTrials.gov number, NCT04934475.).