Residual Monoclonal Free Light Chain Positivity By Mass Spectrometry Identifies Patients at Increased Risk of Early Relapse Following First-Line Anti-Myeloma Treatment

Introduction Bone marrow based minimal residual disease (MRD) assessments provide greater sensitivity for residual disease detection compared to the standard serological techniques and MRD negativity is associated with improved progression-free survival (PFS). However, the frequency at which MRD can be assessed is limited by the invasive nature and cost of the current assays. These assays may also give false negative results due to the heterogeneous nature of marrow involvement in multiple myeloma and extramedullary disease. Mass spectrometry (MS) methodologies are emerging as a more sensitive way of monitoring monoclonal proteins in the peripheral blood. In this study we assessed the prognostic impact of detectable residual monoclonal FLC by matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) MS in patients with transplant-eligible newly diagnosed multiple myeloma. Methods Patients treated with carfilzomib, lenalidomide, cyclophosphamide and dexamethasone followed by autologous stem cell transplantation (ASCT) and randomisation between lenalidomide maintenance versus observation in the Myeloma XI trial were included in this study. Patients with no residual serum for MS testing from baseline or post cycle one of induction chemotherapy were excluded as a baseline sample was required to establish the isotype and mass-to-charge ratio of the monoclonal FLC. 293 patients were included in this study: 58.4% (171/293) had an IgG monoclonal protein; 23.9% (70/293) had an IgA monoclonal protein;16.4% (48/293) had a FLC only monoclonal protein; 1.0% (3/293) had an IgD monoclonal protein and 0.3% (1/293) had non-secretory myeloma. MS analysis was performed on all available samples from post-induction (n=219), day+100 post ASCT (n=189) and post maintenance randomisation (n=137). Serum samples underwent immunoprecipitation with antisera specific for kappa and lambda FLC conjugated to magnetic microparticles, FLC were eluted and the spectra were acquired by MALDI-TOF MS. Progression free survival (PFS) analysis was performed with SPSS 27.0.1.0 using the Kaplan-Meier method. The log-rank test was used to assess the statistical significance of differences between survival curves. Median follow-up was calculated using the reverse Kaplan-Meier method. Results At all three time points MS positivity was associated with shorter PFS: 43.9 months v. not reached (NR) p