Characterization of a population with newly diagnosed standard risk multiple myeloma by the 2025 ims/IMWG definition with exceptional long-term outcomes after fixed duration therapy

Abstract

Abstract Introduction: Multiple myeloma has been regarded as incurable, with steady and sizeable risk of progression even for patients without high-risk features. The development of better upfront therapies, namely anti-CD38 monoclonal antibody-containing quadruplet combination therapy (QUAD) with autologous stem cell transplant (ASCT) and better disease classification, outlined in the 2025 International Myeloma Society/International Myeloma Working Group (IMS/IMWG) consensus of high-risk disease, creates the opportunity to refine disease and treatment-response features that may identify a population with very low risk of progression, and for whom initial therapy may have been definitive. Methods We studied a cohort of patients (pts) with newly diagnosed MM (NDMM) who received QUAD induction followed by ASCT, was monitored with serial measurable residual disease (MRD) by next generation sequencing and often had treatment cessation upon confirmation of MRD negativity (MRDneg) at 10-5threshold. MRD assessments were performed post induction, post ASCT and at least yearly thereafter regardless of conventional IMWG response. We retrospectively reclassified pts in standard risk (SR) or high risk using the 2025 IMS/IMWG consensus. We described the outcomes of patients with SR NDMM who also achieved sustained MRDneg (S-MRDneg, two consecutive MRD negative tests ≥ 12 months apart, not interrupted by a positive test) at 10-5 threshold. We utilized Cox regression to estimate the protective effect of S-MRDneg on progression-free (PFS) and overall survival (OS) by inputting MRD as time-varying covariate. Results We identified 213 patients who started therapy >3 years prior to data cut, 128 (60%) were classified as SR. Median age was 61 years (IQR 56-68), 58% were male, 30% of racial-ethnic minority, 20% harbored t(11;14), 28% gain/amp(1q), and 6% t(4;14) or t(14;16). After median follow up of 45.4 mo, 72 patients reached S-MRDneg for a cumulative incidence of S-MRDneg of 56%. Among these SR patients with S-MRDneg, 63 (88%) discontinued therapy upon confirmation of MRDneg and were monitored with sequential MRD assessment. Among S-MRDneg SR patients there has only been one death (due to COVID infection, in absence of disease progression) and 2 disease progressions. The 5-year PFS for patients who reached S-MRDneg was 97% vs. 62% for those who did not, and 5-year OS rates were 99% and 88% respectively. S- MRDneg had a strong protective effect in PFS (HR=0.17, 95% C.I. 0.04-0.62, P=0.007) and OS (HR=0.10, 95% C.I. 0.01-0.94, P=0.04). Overall, there were 200.8 patient-year of observation beyond S-MRDneg with only 2 progressions, resulting in an event rate of 1.0%/year. Conclusions Patients with 2025 IMS/IMWG consensus-defined SR NDMM who received QUAD + ASCT and achieve S-MRDneg have exceptional outcomes in absence of any subsequent therapy with 5-year PFS of 97% and OS of 99%. Given the very low rate of progression events, 1.0%/year, many may not require myeloma therapy for the remaining of their lifetime. Future efforts should validate these findings and develop strategies to increase the proportion of SR patients fitting this definitive therapy frame.