Clonotypic Features of Rearranged Immunoglobulin Genes Yield Personalized Biomarkers for Minimal Residual Disease Monitoring in Multiple Myeloma

Abstract Background Due to improved treatment, more patients with multiple myeloma (MM) reach a state of minimal residual disease (MRD). Different strategies for MM MRD monitoring include flow cytometry, allele-specific oligonucleotide–quantitative PCR, next-generation sequencing, and mass spectrome...

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Published in:Clinical chemistry (Baltimore, Md.) Md.), 2021-06, Vol.67 (6), p.867-875
Main Authors: Langerhorst, Pieter, Brinkman, Arie B, VanDuijn, Martijn M, Wessels, Hans J C T, Groenen, Patricia J T A, Joosten, Irma, van Gool, Alain J, Gloerich, Jolein, Scheijen, Blanca, Jacobs, Joannes F M
Format: Article
Language:English
Subjects:
Analysis
Biological markers
Biomarkers
Care and treatment
Chemical fingerprinting
Disease Progression
Flow cytometry
Genes, Immunoglobulin - physiology
Genetic aspects
Humans
Identification and classification
Immunoglobulins
Mass spectrometry
Mass spectroscopy
Minimal residual disease
Monitoring
Multiple myeloma
Multiple Myeloma - diagnosis
Multiple Myeloma - genetics
Neoplasm, Residual - genetics
Next-generation sequencing
Oligonucleotides
Patients
Peptides
Peptides - chemistry
Peptides - genetics
Physiological aspects
Stability analysis
Telemedicine
Uniqueness
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Summary:Abstract Background Due to improved treatment, more patients with multiple myeloma (MM) reach a state of minimal residual disease (MRD). Different strategies for MM MRD monitoring include flow cytometry, allele-specific oligonucleotide–quantitative PCR, next-generation sequencing, and mass spectrometry (MS). The last 3 methods rely on the presence and the stability of a unique immunoglobulin fingerprint derived from the clonal plasma cell population. For MS-MRD monitoring it is imperative that MS-compatible clonotypic M-protein peptides are identified. To support implementation of molecular MRD techniques, we studied the presence and stability of these clonotypic features in the CoMMpass database. Methods An analysis pipeline based on MiXCR and HIGH-VQUEST was constructed to identify clonal molecular fingerprints and their clonotypic peptides based on transcriptomic datasets. To determine the stability of the clonal fingerprints, we compared the clonal fingerprints during disease progression for each patient. Results The analysis pipeline to establish the clonal fingerprint and MS-suitable clonotypic peptides was successfully validated in MM cell lines. In a cohort of 609 patients with MM, we demonstrated that the most abundant clone harbored a unique clonal molecular fingerprint and that multiple unique clonotypic peptides compatible with MS measurements could be identified for all patients. Furthermore, the clonal immunoglobulin gene fingerprints of both the light and heavy chain remained stable during MM disease progression. Conclusions Our data support the use of the clonal immunoglobulin gene fingerprints in patients with MM as a suitable MRD target for MS-MRD analyses.
ISSN:0009-9147
1530-8561
DOI:10.1093/clinchem/hvab017