Role of Composite Measurable Residual Disease Assessment with PET-CT and flow cytometry in Multiple Myeloma patients undergoing Autologous Transplant

Abstract

Background: Bone marrow (BM) Measurable Residual Disease (MRD) assessments underestimate disease burden in multiple myeloma, as focal lesions can exist outside the marrow. Functional imaging, like positron emission tomography-computed tomography (PET-CT), offers valuable insights into residual disease beyond the marrow. Combining marrow flow cytometry (FCM) with PET-CT for a composite MRD (cMRD) assessment before and after autologous stem cell transplant (ASCT) is expected to provide prognostic information, particularly in settings where patients receive extended duration of anti-myeloma therapy prior to ASCT.

Methods: In this retrospective cohort study, we evaluated the prognostic impact of cMRD in newly diagnosed multiple myeloma (NDMM) patients who underwent triplet/quadruplet-based induction followed by ASCT from January 2017 to June 2023. cMRD was assessed before ASCT and again around day 100 post-transplant. cMRD negativity was defined as undetectable residual clonal plasma cells (sensitivity 1×10^-5) on multi coloured FCM and PET-CT negativity per The International Myeloma Working Group criteria.

Results: Among 106 patients undergoing ASCT, 82 had cMRD assessments before and on day 100 post-ASCT. Median pre-ASCT treatment duration was 11 months (interquartile range [IQR]: 4-18). At the pre-ASCT time point, sixty seven percent patients were bone marrow MRD negative (BM-MRD^PRE-), while 38% were PET-CT negative (PET^PRE-). Post-ASCT, these rates were 74% (BM-MRD^POST-) and 49% (PET-CT^POST-) respectively. At a median follow-up of 35 months (IQR: 23.5-58), median time to next treatment (TTNT) and overall survival (OS) were not reached. At three years, TTNT was significantly higher in patients who were cMRD-negative before ASCT compared to those who were cMRD-positive [91% (confidence interval (CI): 77-100) versus 67% (CI: 52-80); p=0.027]. BM-MRD^PRE- and PET^PRE- were both independently associated with improved TTNT on univariate analysis [Hazard Ratio: 0.32 (0.14-0.74) and 0.45 (0.23-0.94) respectively]. Post-ASCT cMRD status did not significantly impact TTNT [82% (CI: 68-96) versus 65% (CI: 51-69); p=0.116]. Three-year TTNT rates were similar among patients with and without baseline high-risk cytogenetic abnormalities (HRCA) if they maintained sequential cMRD negativity. In multivariate analysis, the absence of HRCA, complete response before ASCT, cMRD^PRE-, and sustained cMRD negativity at both time points were independent predictors of longer TTNT.

Conclusions: Pre-ASCT cMRD assessment using both PET-CT and bone marrow FCM provides prognostic value in NDMM. This approach is particularly relevant in real-world settings where patients often receive prolonged induction therapy before ASCT.

Keywords: PET-CT; autologous transplant; measurable residual disease; multiple myeloma.

Figure 1.

MRD Conversion Pre and Post-Autologous Stem Cell Transplant using both modalities (BM-MRD and PET-CT) Numbers in solid black indicate the response status before and after ASCT. Numbers in solid white indicate proportion of patients transitioning from one MRD category to another after ASCT. Pos, positive; Neg, negative; BM-MRD, bone marrow measurable residual disease; cMRD, composite measurable residual disease using BM-MRD and PET-CT)

Figure 2.

Kaplan Meier survival analysis showing TTNT plots between (A) cMRD^pre Positive vs Negative, (B) cMRD^post Positive vs Negative, (C) cMRD^pre stratified by status of Both modalities (BM MRD and PET CT), and (D) cMRD^post stratified by status of both modalities (BM MRD and PET CT)

Figure 3.

Kaplan Meier survival analysis showing TTNT plots stratified by groups based on Pre-ASCT and Post-ASCT cMRD status

Figure 4.

Multivariate analysis for (A) TTNT among patients who had sequential cMRD assessment at two time points and (B) multivariate analysis for overall survival among patients who had sequential cMRD assessment at two time points