Predictors and MRD-Driven Treatment Strategies of Unsustained Measurable Residual Disease Negativity in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Objective: Most transplant eligible NDMM patients can achieve bone marrow MRD negativity after standardized treatment, but how to maintain long-term MRD-negative status after achieving MRD negativity is a current challenge. The aim of this study was to identify predictive factors for the reappearance of minimal residual disease (MRD) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) who had achieved bone marrow MRD negativity and provided some clinical recommendations for MRD-driven treatment strategies.

Methods: We retrospectively analyzed data from transplant-eligible NDMM patients who had been detected as MRD-negative by two-time multiparametric flow cytometry tests. Regular and dynamic bone marrow MRD monitoring was performed at our center, and patients were monitored at the end of induction and every 3 to 12 months after transplantation.

Results: Out of 390 enrolled patients, 261 (66.9%) achieved MRD negativity with follow-up data. The median age was 55 years, with 70.1% of patients being R-ISS stage II-III. The median time to MRD-negative was 10.3 months. After a median follow-up of 27 months, 37.2% of patients lost MRD-negative status. Among these patients, 28.9% had maintained 3 years of persistent MRD negativity. Additionally, 47.4% (46) of patients had a positive MRD test result before biochemical or clinical progression. The median time from MRD positivity to a progression survival event (progressive disease or death) was 11.4 months.HRCA ≥1, PLT <100*10^9/L, and reaching first MRD negativity after maintenance therapy were significant predictors of failure to maintain MRD negativity. Maintenance therapy, such as lenalidomide, bortezomib + dexamethasone, and daratumumab, reduced the risk of MRD reappearance compared with thalidomide/interferon administration. Among the 46 patients who showed MRD positivity before clinical/biochemical relapse, 8 patients immediately changed their treatment regimen upon MRD positivity, while 26 patients waited until clinical or biochemical relapse to change their treatment. Data indicated that immediate modification of the treatment regimen upon MRD positivity was significantly more effective in achieving MRD negativity again (75.0% vs 24.0%, P=0.009). Among the patients who achieved MRD negativity, 25 patients discontinued maintenance therapy due to drug intolerance, financial reasons, or other personal reasons, but continued to be monitored for bone marrow MRD. The median time from MRD negativity to treatment discontinuation was 44.8 months (range 0.26-143.21 months), and the median follow-up after discontinuation was 15.5 months. Among these 25 patients, 12 experienced MRD positivity again (48%), with a median time of 24.7 months from treatment discontinuation to MRD positivity. Subgroup analysis of these patients revealed that achieving MRD negativity after maintenance therapy, having high-risk cytogenetic abnormalities, and discontinuing therapy within two years of achieving MRD negativity were significant adverse factors for subsequent MRD positivity.

Conclusions: This study highlights the factors that contribute to the reappearance of MRD in transplant-eligible NDMM patients and emphasizes the importance of early attainment of MRD-negative status and maintenance therapy options to maintain long-term MRD negativity. This study also provides some clinical recommendations for MRD-driven treatment strategies.