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A global strategy to monitor M-Protein in patients with multiple myeloma using clonotypic peptides by mass spectrometry
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Edité par CCSD -
International audience. Multiple myeloma is a blood cancer characterized by the proliferation of monoclonal plasma cells in the bone marrow. These abnormal cells produce intact monoclonal immunoglobulin (Ig) or free light chains, which serve as biomarkers for disease monitoring. While inexpensive diagnostic tests are currently available, highly effective combination therapies often lead to undetectable biomarkers, resulting in false negative results and minimal residual disease state (MRD).To address this challenge, sensitive and specific approaches are needed to accurately estimate and monitor MRD, as even minimal cell presence poses risks. Two complementary approaches are proposed: accurate intact protein detection and a shotgun clonotypic peptide method. In intact protein detection, immunoglobulin light chains are used as biomarkers, characterized by their molecular mass in diagnostic samples with high concentrations. The specific mass is then monitored in the patient’s serum during treatment and relapse. The clonotypic peptide method utilizes specific peptides.Current MRD tests require painful bone marrow aspirations, hindering frequent sampling. To overcome this limitation, we collaborate with Pitie-Salpetriere Hospital and Saint-Antoine Hospital, receiving serum samples from diverse patients. We enrich the light chains with nanobodies before measuring their mass using middle-down mass spectrometry. Once undetectable in the middle-down, the enriched samples are lysed with trypsin, separated, and analyzed using bottom-up mass spectrometry. Data processing techniques, including library searches, De Novo sequencing, and Blast, are then employed to identify the patient’s clonotypic sequences.Through these innovative approaches, we aim to improve the sensitivity and specificity of MRD detection in multiple myeloma. This will enable better estimation and monitoring of MRD, even at levels below one cell per million, reducing the risks associated with undetected disease persistence. Our collaboration with the two hospitals and utilization of nanobodies in the sample enrichment process allows for more accessible and less invasive monitoring, eliminating the need for frequent bone marrow aspirations.
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