Sensitive peripheral residual disease (PRD) detection using clonotypic mass spectrometry (EasyM) in patients with newly diagnosed multiple myeloma (NDMM)

Abstract Background: Achieving minimal residual disease (MRD) negative status has been associated with favourable outcomes confirming its utility as a reliable surrogate marker for progression free survival (PFS) and overall survival (OS). The current methods include next generation sequencing (NGS) or next generation flow cytometry (NGF) but these rely on serial, invasive bone marrow (BM) assessments, which is often limited by heterogeneously patchy disease and suboptimal sampling. EasyM (Rapid Novor) is a peripheral blood based clonotypic mass spectrometry assay that employs de novo sequencing of the serum M-protein to identify a 'patient-specific peptide fingerprint’ allowing for the quantitative tracking of peripheral residual disease (PRD) (Liyasova 2021). In this study, we prospectively aimed to evaluate the clinical applicability of PRD assessments by EasyM. Methods: This is a prospective, multi-center, investigator-initiated study in newly diagnosed multiple myeloma (NDMM). The study enrols both transplant eligible (TE) and transplant ineligible (TI) NDMM patients within 4 months of treatment initiation; with screening M protein of 2g/L and/or involved free light chains (iFLC) of 200mg/L. Conventional myeloma tests are done monthly. EasyM is performed at screening (visit (v)1), and q3 months (v2+) for TI patients; and post-induction (v2), at day100 post-autologous stem cell transplant (ASCT; v3) and q3 monthly (v4+) thereafter for TE patients. BM MRD assessment by NGF (sensitivity 10-5) was performed once patients had negative PRD assessment by EasyM. The primary objective is to prospectively compare conventional myeloma assessments, PRD by EasyM and BM MRD by NGF to establish the role of EasyM in clinical practice. Results: As of July 25, 2025, 55 patients have been pre-screened with successful identification of unique clonotypic peptide in 54 patients- one patient was a screen failure due to iFLC levels below the detection threshold. The median age was 61 (range 33-77) years and 53% (n=29) were males. Among 48 patients with measurable intact paraprotein, the median M concentration at screening was 15.35 (range 1.1-68.1) g/L; isotypes included IgG in 74% (n=41) and IgA in 13% (n=7). In 7 patients with light chain (LC) myeloma (13%; kappa=3; lambda=4), median iFLC was 2616 (range 22.9-9381) mg/L; one LCMM was had iFLC below thresshold so excuded from the study. All 54 patients meeting eligibility criteria had successful baseline identification of clonotypic peptide, including 2 patients with M-protein 2g/L and 6 evaluable patients with LC MM. Thirty-seven (68%) patients were TE. At the time of analysis, 23 (43%) had completed ASCT (19 single, 4 tandem) and 14 (26%) patients had started induction with the intent to proceed to ASCT. Four patients had received induction therapy followed by T cell redirecting therapy. Eight patients (9%) were TI, and 5 patients were yet to start myeloma treatment. At a median follow up of 5.6 (range 1-14) months, 30, 21 and 8 patients had completed the 2nd, 3rd and 4th visit assessments, respectively. At v2, 83% (25/30) had achieved ≥VGPR, with 11 SPEP (-), 2 SIFE (-) and no PRD (-) by EasyM. At v3, 90% (19/21) were in ≥VGPR with 9 SPEP (-), 7 SIFE (-) and 3 PRD (-) by EasyM highlighting that PRD could still detect M protein in 4 SIFE (-)patients. Amongst the patients with matched BM MRD assessments (n=9) performed within 30 days of PRD testing, six revealed concordances between BM MRD by NGF and PRD by EasyM: 4 were negative and 2 were positive by both methods. All but one of the patients demonstrating MRD (-) and PRD (-) remained SIFE (+), demonstrating an IgG kappa likely due to prior daratumumab exposure. Notably, 3 patients showed discordance between MRD and PRD assessments, with negativity by BM MRD post 4 cycles of induction yet remained SIFE (+) and PRD (+), likely reflecting delayed clearance of M-protein due to its longer half-life. All three patients had an IgG paraprotein and follow up PRD assessments are pending. To date, one TI patient has shown biochemical progression evidenced rising EasyM and iFLC levels. Conclusion: This ongoing study explores the utility of longitudinal PRD monitoring using clonotypic mass spectrometry (EasyM) which is a sensitive, non-invasive serum-based method for reliably detecting PRD and predicting BM MRD status. Updated results with longer follow up data will be presented.