Prognostic Impact of Measurable Residual Disease Evaluated By Next Generation Flow and PET-CT in Clinical Practice at Fundación Santa Fe De Bogotá Hospital, Colombia

Introduction

Measurable residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM). Current standardized methods for its assessment include next-generation flow (NGF), next-generation sequencing (NGS), and Positron Emission Tomography/CT (PET-CT). However, limited resources and the need for specialized training can hinder the performance of highly sensitive and accurate MRD assessments in resource-limited settings. Our study evaluates the real-life performance of NGF and PET-CT in assessing MRD and its prognostic value in non-clinical trial MM patients at Fundación Santa Fe de Bogotá, Colombia.

Methods

A total of 92 MM patients treated with VRd were enrolled. 11% of them additionally received Daratumumab quadruplet. MRD was evaluated using EuroFlow NGF at the end of induction, at day 100 after HSCT or during maintenance, using FACSCanto II flow cytometer and Infinicyt software. Median limit of detection was 2.8X10^-6. Patients were then classified as having undetectable MRD (uMRD) or persistent MRD (pMRD) (Paiva B, 2020). Considering the limitations of NGF in MM (patchy marrow involvement and extramedullary infiltration), we also evaluated the impact of using FDG PET-CT (n=45) at baseline and before starting maintenance with Discovery MI-digital General-Electric PET-CT. Using the five-point Deauville scale (DS), patients were classified as having Complete Metabolic Response (CMR) or NonCMR (nCMR) when DS score ≥ 4. Statistical analysis was performed using the Kaplan-Meier method and Mantel-Cox for survival evaluation (IBM SPSS software).

Results

43.4% of patients achieved uMRD-NFG <10^-6. There were no differences in clinical characteristics between uMRD and pMRD, but uMRD was associated with longer PFS (not reached vs. 26.4 months, P<0.001) and an 88.18% risk reduction of progression (RR 0.1182; 95% CI: 0.015-0.877). After 65 months of follow up, none of the uMRD patients had relapsed, while 36.53% of pMRD patients did. uMRD was also associated with longer OS (130.38 vs. 90.4 months, P=0.012). Sustained uMRD during the first-year post-treatment significantly improved PFS compared to non-sustained uMRD (P=0.02). Regarding PET-CT, 64.4% of patients achieved CMR, which was associated with longer PFS (26.8 vs. 12.8 months, P<0.001) and OS (131 vs. 40.6 months, P<0.001). 6.9% of CMR patients relapsed vs. 46.7% of nCMR patients within 29 months. PET-CT findings correlated with the last MRD assessment, showing that 28.8% of patients were double negative (uMRD/CMR) and 22% double positive (pMRD/nCMR). 37.8% of pMRD had CMR, and 11% of uMRD were nCMR. The combination of uMRD and CMR showed the longest OS (P=0.001) and PFS (P<0.001). Among patients with Standard Risk (SR) and High Risk (HR) cytogenetics, uMRD/SR had superior PFS (P=0.002) and OS (P=0.001) compared to pMRD/HR. Achieving uMRD, regardless of cytogenetic risk, resulted in superior PFS and OS. None of these patients relapsed or died within a maximum follow-up time of 137 and 12 months for SR and HR, respectively. pMRD/SR had inferior PFS compared to uMRD/SR (P=0,01). pMRD/HR had inferior OS (P=0,016), but no difference in PFS (P=0,056) compared to pMRD/SR. Similar PET-CT results were found for PFS based on cytogenetic risk, and nCMR status in both HR and SR patients was associated with inferior OS.

Conclusions

There is scarce information about MRD evaluation with new generation technologies in Latin American non-clinical trial MM patients. In this study, we showed that 43.4% of patients achieved uMRD-NFG <10-6 with current therapies. MRD evaluation using NGF and PET-CT is a valuable tool that discriminates two subgroups of MM with different outcomes. Achieving uMRD/CMR was associated with significant improvement in PFS and OS, suggesting that these analyses have superior risk stratification performance. MRD status is a dynamic analysis, and its true prognostic value relied on the maintenance of uMRD over time. Finally, we emphasized that this evaluation with high sensitivity can also be performed in countries with resource-limited settings, like ours, and it should be incorporated in routine clinical practice to provide prognostic information, and guidance to therapy.