MINIMAL RESIDUAL DISEASE IN PERIPHERAL BLOOD ASSESSED BY MASS SPECTROMETRY
Authors: Noemi Puig
Journal: HemaSphere (2022)

Despite the high rates of complete response (CR) achieved with the current treatments, patients with multiple myeloma (MM) continue to relapse due to the presence of undetected disease. Disease identification in patients in standard CR using more sensitive techniques (flow cytometry and sequencing) has been named “minimal” or “measurable” residual disease (MRD) and numerous studies have demonstrated its capacity to identify patients at a higher risk of progression and/or death. However, the evaluation of MRD in BM might ignore distant foci or extramedullary disease and hemodiluted BM samples could produce false negative results. Further, the procedure to obtain a BM sample is painful, which prevents to perform it frequently. Therefore, there alternative methods for MRD assessment in more accessible and representative samples, such as peripheral blood (PB) need to be tested. Mass spectrometry (MS) is an analytic method based on the measurement of mass-to-charge ratio of ionic species. Each monoclonal protein (MP) is characterized by a unique sequence of amino acids that is specific to each plasma cell clone (and MM patient), thus permitting single-clone tracking overtime with high sensitivity and specificity. The Spanish Myeloma Group GEM/PETHEMA has investigated the use of QIP-MS to assess treatment response vs standard and BM-based MRD analysis by next generation flow (NGF). In the GEM-CESAR trial for patients with high-risk smoldering MM, the presence of an MP was evaluated by QIP-MS for intact immunoglobulins (QIP-Ig-MS) or in combination with free light chains (FLC; QIP-FLC-MS) vs conventional serum protein electrophoresis (SPEP) and immunofixation (sIFE) in 77 patients. When the analysis of FLCs was added to QIP-Ig-MS, the percentages of positive cases increased from 80% to 85% post-induction, from 60% to 68% post-ASCT and from 56% to 63% post-consolidation. Importantly, among patients achieving at least CR, the percentage of positive cases by QIP-Ig-MS + QIP-FLC-MS was 60%, 38% and 43% post-induction, post-ASCT and post-consolidation, respectively. More recently, results from 186 newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial have been presented. As compared to SPEP/IFE, QIP-MS detected the paraprotein in a higher proportion of cases at each time point: 63% vs 52% post-induction, 46% vs 36% post-ASCT and 35% vs 27% post-consolidation. Importantly, QIP-MS identified the MP in a cohort of patients in standard CR and this was associated with a significantly shorter progression free survival (PFS) (p=0.0008). As compared to NGF, the percentage of concordant results was around 80% at all time points analyzed and both techniques exhibited a similar prognostic value in terms of PFS throughout the treatment: post-induction (NGF: p=0.012; QIP-MS: p=0.015), post-ASCT (NGF: p=0.015; QIP-MS: p=0.057) and post-consolidation (NGF: p=0.001; QIP-MS: p=0.005). In conclusion, from our results, MS-based methods can detect the MP in serum with a higher sensitivity as compared to conventional SPEP/IFE. As compared to NGF in BM, MS in PB displays a fair degree of concordance and is associated with a comparable prognostic value. However, more data are needed to define the final role of MS in the follow-up of patients with MM.