Real-world study on discontinuation strategies after MRD negativity in multiple myeloma patients

Abstract Background Multiple myeloma (MM) is a malignant clonal plasma cell disorder characterized by uncontrolled proliferation of abnormal plasma cells and monoclonal protein production, leading to bone destruction, anemia, hypercalcemia, and renal impairment. Over the past decade, the introduction of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, autologous stem cell transplantation (ASCT), and maintenance therapy has significantly improved patient outcomes, extending both progression-free survival (PFS) and overall survival (OS). Maintenance therapy, particularly with lenalidomide, is now a standard component of MM treatment and has been shown to deepen responses and prolong remission. However, long-term maintenance is associated with cumulative toxicities, diminished quality of life, financial burden, and an increased risk of secondary primary malignancies, prompting debate over optimal duration. Minimal (measurable) residual disease (MRD) has emerged as a powerful prognostic marker for MM, offering superior predictive value for PFS and OS compared to conventional response criteria. Achieving and sustaining MRD negativity—especially at high-sensitivity thresholds (10^-5 to 10^-6)—has been shown in multiple prospective studies to correlate with excellent long-term outcomes. This has led to increasing interest in exploring MRD-guided treatment de-escalation or discontinuation strategies, although robust real-world evidence on when and in whom maintenance can be safely stopped remains limited.Methods We conducted a single-center, retrospective, observational study of 357 newly diagnosed multiple myeloma (NDMM) patients treated between January 2010 and January 2024. All patients received induction therapy with novel agents, followed by ASCT and maintenance treatment. MRD assessment was performed regularly using multi-parameter flow cytometry (sensitivity 10^-4 to 10^-5). We identified 25 patients who discontinued maintenance therapy after achieving MRD negativity, defined as two consecutive negative MRD assessments without clinical or radiographic evidence of disease. We analyzed patient characteristics, timing and reasons for discontinuation, MRD dynamics post-discontinuation, and factors associated with MRD resurgence.Results Among the 25 patients who discontinued therapy, the median time from achieving MRD negativity to treatment cessation was 44.8 months (range, 0.26–143.21), and the median duration off therapy was 19.9 months (range, 2.4–66.1). Median follow-up post-discontinuation was 15.5 months. Twelve patients (48%) experienced MRD conversion to positivity, with a median time to MRD resurgence of 24.7 months. Baseline characteristics: 72% were male, median age 50 years (38–66), and 32% had high-risk cytogenetic abnormalities (e.g., t(4;14), t(14;16), del17p). Most patients (92%) received triplet induction, and maintenance regimens included thalidomide or lenalidomide. Notably, only 12% discontinued within 2 years of MRD negativity. Univariate analysis revealed that patients achieving MRD negativity during induction (n=13) had significantly lower MRD resurgence rates compared to those converting during maintenance (31.4% vs 74%, P=0.028). MRD negativity sustained for ≥24 months prior to discontinuation was associated with reduced recurrence risk (P=0.040). High-risk cytogenetics trended toward higher recurrence risk (HR=1.96, P=0.18). Multivariate analysis identified duration of sustained MRD negativity as an independent predictor of post-discontinuation MRD resurgence.Conclusion Duration of sustained MRD negativity is a critical determinant of safe maintenance discontinuation in MM. Patients achieving deep remission early and maintaining MRD negativity for at least 2 years appear to have a lower risk of MRD resurgence. Our real-world findings support the feasibility of MRD-guided discontinuation in selected low-risk patients, aligning with emerging data from prospective studies. These results contribute valuable evidence toward personalized, time-limited MM treatment approaches. Future prospective trials are warranted to validate optimal MRD thresholds and refine patient selection for treatment cessation.