Mass Spectrometry-Based Assessment of M-Protein in Peripheral Blood during Maintenance Therapy in Multiple Myeloma (MM) in the Phase III ATLAS Trial

Introduction Minimal residual disease (MRD) assessment in bone marrow (BM) has emerged as one of the strongest prognostic factors in MM. Mass spectrometry (MS), capable of detecting MM-derived monoclonal proteins in peripheral blood with high sensitivity, has the potential to complement standard methods. While its role in evaluating residual disease and its prognostic performance compared to routine MRD assessments is not yet established, other unanswered questions remain: (1) What is the role of MS in response assessment for patients without a high disease burden baseline sample? (2) What is the optimal timing of MS assessment, considering the long half-life of immunoglobulins? Methods Stored serum samples collected at different timepoints [screening, cycle 6 (C6), C12, C18, C24, C36] from patients treated in the ATLAS trial, were analyzed using the EXENT® Immunoglobulin isotypes (GAM) assay (EXENT® Solution, in development by The Binding Site, part of Thermo Fisher Scientific), which utilizes MALDI-TOF MS. ATLAS is an ongoing phase 3 trial that randomized 180 patients with newly diagnosed MM after autologous stem cell transplantation (ASCT) to maintenance therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide alone (R). In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R, from C9. No baseline diagnostic samples were available, and samples were not available for every patient at every timepoint. A sample was called positive by MS when the EXENT® solution confirmed the presence of an M protein, matching the known (diagnostic) isotype. BM MRD was assessed at the same timepoints using multicolor flow cytometry (MFC) with a limit of detection (LoD) of 10 -5 and next-generation sequencing (NGS, clonoSEQ, Adaptive, LoD 10 -6). Progression-free survival (PFS) was analyzed using the Kaplan-Meier method, with log-rank test for comparisons between groups. The data cutoff (31-Dec-2021) was the same as was used in the ATLAS publication by Dytfeld et al. Lancet Oncology 2023. Results 585 samples from 138 patients were analyzed by MS. There were 349 paired BM MRD results by NGS; patients with MRD 10 -5 were considered MRD(+). The overall agreement between the two methods equaled 70%, with a comparable number of patients being MS+/NGS- (56/349, 16%) and MS-/NGS+ (50/349, 14%). The agreement at screening was 61%, but it improved at further timepoints and reached the