Patterns of minimal residual disease trajectories in 323 newly diagnosed patients with multiple myeloma and correlation with progression-free survival

Abstract Introduction Minimal residual disease (MRD) is a sensitive tool for evaluating treatment response in multiple myeloma (MM) and is a surrogate marker of progression-free survival (PFS) and overall survival (OS). Sequential MRD testing offers important insights into the depth and sustainability of response to treatment and may inform treatment decisions. Methods This single center, retrospective study included consecutive patients with newly diagnosed MM (NDMM) who underwent MRD evaluation using the Euroflow technique as per clinical practice, until May 1st, 2025. All were evaluated with at least 3 consecutive MRD tests. The first MRD evaluation was performed at the time of complete response and consecutive MRD measurements were done every 6-12 months. Four subgroups of patients were identified: sustained MRD positive (sMRDpos), sustained MRD negative (sMRDneg), converted to MRD negative (conMRDneg) and converted to MRD positive (conMRDpos). The aim of the study was to compare PFS between groups. Results Overall, 323 NDMM patients were included. The median age at diagnosis was 59 years (range 35-87) and 55.1% were males. Overall, 55 patients (17.0%) were labeled as high-risk per the new IMS/IMWG HRMM criteria. The median number of MRD evaluations in each patient was 5 (range 3-13). Eighty-one (25.1%) patients received first line treatment with a quadruplet; an anti-CD38 antibody was included in 104 (32.2%). The median PFS for the whole cohort was 22.6 months while the median OS was not reached. Patient distribution according to MRD status was as follows: 165 (51.1%) sustained negativity, 41 (12.7%) sustained positivity, 52 (16.1%) converted to negative, whereas 65 (20.1%) converted to positive. The median follow-up was 3.9 years (95% CI: 3.6-4.2 years). Sustained MRD negativity was associated with superior PFS compared to all the other subgroups (HR=0.26, 95% CI: 0.11 – 0.60, p=0.002). Sustained MRD positivity was associated with significantly inferior PFS compared to the sustained negativity subgroup (HR=5.92; 95% CI: 1.53-22.94; p=0.01). Those who converted from MRD negative to MRD positive had also inferior PFS compared to the sustained negativity subgroup (HR=5.19; 95% CI: 1.58-17.05, p=0.007). Furthermore, patients who converted from MRD positive to MRD negative had a worse prognosis compared to those with sustained MRD negativity, although this was not statistically significant (HR=2.85; 95% CI: 0.58-14.0; p=0.196). Interestingly, the presence of at least one MRD positive result, at any time-point, was associated with inferior PFS compared to the sustained negativity subgroup (HR=5.93; 95% CI: 1.73-20.30; p=0.005). A total of 227 (70.3%) patients underwent HDM with ASCT. Among them, 118 (52.0%) sustained MRD negativity, 38 (16.7%) converted to MRD negative, 49 (21.6%) converted to MRD positive and 22 (9.7%) sustained MRD positivity, after a median of 5 (range 3-13) consecutive assessments. The allocation of the MRD subgroups did not differ between patients who underwent HDM-ASCT and those who did not (p=0.102). Sustained MRD negativity was associated with significantly superior PFS in this subpopulation (HR=0.18, 95% CI: 0.06-0.55, p=0.002) and seemed to have a beneficial trend for OS (HR=0.16, 95% CI: 0.01-2.09, p=0.163), compared to all other MRD subgroups. On the other hand, at least one positive MRD result was associated with particularly dismal PFS outcomes between these patients (HR = 7.07, 95% CI: 2.06-24.22, p=0.002). Out of the 55 high-risk patients per the novel HRMM criteria, the 28 (50.9%) sustained MRD negativity; these patients had significantly superior PFS compared to others (HR=0.14, 95% CI: 0.03 – 0.67, p=0.015). On the other hand, at least one MRD positive result seemed to confer particularly dismal PFS outcomes in this subgroup (HR=16.1, 95% CI: 1.94 – 134.50, p=0.010), while a similar trend was observed for those who converted to MRD positive (HR=3.41, 95% CI: 0.90 – 12.80, p=0.070). Therefore, MRD seems to be a tool able to identify patient with particularly adverse prognosis in high-risk patient subgroups. Conclusion In patients with NDMM who achieve CR during their first line treatment in the real-world setting, sustained MRD negativity is associated with prolonged PFS, whereas the presence of even one MRD positive result impacted PFS. These findings further support the integration of sequential MRD assessment in NDMM in the clinical practice.