Mass spectrometry assay tracks myeloma M-protein in blood without sequencing

Researchers have developed a blood-based mass spectrometry assay, called MyeloTrak, that can identify patient-specific M-protein peptides in multiple myeloma without requiring bone marrow RNA or full-length antibody sequencing. The work, published in Clinical Proteomics, addresses a growing need in myeloma care: as therapies drive disease burden below the detection limits of conventional assays, clinicians need sensitive ways to monitor residual disease, and the current gold standard, bone marrow-based minimal residual disease assessment, is invasive enough to make frequent longitudinal monitoring difficult.

MyeloTrak is a bottom-up proteomics approach that detects clonotypic peptides, the unique sequences that mark a patient’s malignant antibody, directly in plasma. What distinguishes it from most existing proteomic methods is that its discovery workflow does not depend on prior sequencing. Instead, the assay leverages intrinsic biological signatures of M-proteins to select candidate clonotypic peptides from the enormous polyclonal background of circulating immunoglobulins.

To validate the peptide-selection strategy, the team used monoclonal antibody-spiked samples and a patient cohort, benchmarking the selected peptides against known antibody and bone marrow RNA sequences. In these experiments, clonotypic peptides were enriched approximately 1,000-fold from the polyclonal background, allowing confident identification in 23 patients across diverse M-protein levels and isotypes.

Sensitivity was tested in serial dilution experiments using monoclonal antibody-spiked samples. Selected clonotypic peptides remained detectable, with isotope dot-product values of at least 0.9, at concentrations of 1 to 4 mg/L. The authors note that these dilution findings come from spiked samples, so they represent analytical performance under controlled conditions rather than results from patient plasma alone.

Longitudinal tracking was carried out in 19 patients. Trends in the clonotypic peptide measurements were generally concordant with conventional assays, supporting the feasibility of using plasma-based monitoring to follow residual M-protein over time. However, four patients exhibited discordant trajectories between the new assay and conventional methods, a limitation the authors report explicitly rather than resolve.

The study is an early-stage validation of a discovery workflow rather than a demonstration of clinical utility. The cohort was modest in size, the spiked-sample dilution experiments do not by themselves establish performance in unmodified patient samples, and the discordant trajectories observed in four of the 19 tracked patients indicate that the relationship between clonotypic peptide levels and conventional disease measures requires further investigation. The published version is also an early-release, peer-reviewed accepted manuscript that is subject to further edits before the final version of record.

Nevertheless, the authors argue that the approach significantly reduces the complexity of blood-based residual M-protein monitoring. By removing the need for bone marrow RNA or full-length immunoglobulin sequencing, MyeloTrak could make it more practical to track residual disease repeatedly over time through simple blood draws, complementing rather than replacing existing bone marrow-based assessment.

Subject of Research: A sequencing-independent mass spectrometry assay for blood-based residual M-protein monitoring in multiple myeloma

Article Title: MyeloTrak: a sequencing-independent mass spectrometry assay for blood-based residual M-protein monitoring in multiple myeloma

Article References: Kong, P.-H., Hsu, T.-L., Huang, Y.-C., Tsai, C.-K., Yeh, C.-M., Shiue, Y.-L., Duen-Ya Jea, J., Yen, L., Liao, C.-C., & Liu, C.-J. (2026). MyeloTrak: a sequencing-independent mass spectrometry assay for blood-based residual M-protein monitoring in multiple myeloma. Clinical Proteomics. https://doi.org/10.1186/s12014-026-09646-9

Image Credits: AI Generated

DOI: 10.1186/s12014-026-09646-9

Keywords: multiple myeloma, mass spectrometry, clonotypic peptides, M-protein, minimal residual disease, plasma proteomics, liquid biopsy, disease monitoring, Clinical Proteomics, MyeloTrak, sequencing-independent, mass