Retrospective Longitudinal Monitoring of Multiple Myeloma Patients by Mass Spectrometry Using Archived Serum Protein Electrophoresis Gels and De Novo Sequence Analysis

Noori, Somayya; Zajec, Marina; Russcher, Henk; Tintu, Andrei; Broijl, Annemiek; Jacobs, Joannes F.M.; Luider, Theo M.; Rijke, Yolanda B. de; VanDuijn, Martijn M.

doi:10.1097/hs9.0000000000000758

Cited by 5 publications

(5 citation statements)

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“…(2) Peptide selection: clonotypic peptides can be determined from M-protein mRNA obtained from bone marrow as implemented in this research. Alternatively, de novo sequencing can be used to determine the M-protein peptide sequence [ 9 , 19 , 22 ]. (3) Sample preparation: SILuMAB is spiked in the serum and the sample is digested.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we showed adequate linearity, sensitivity and accuracy of SIL peptide based MS-MRD using SIL peptides for M-protein quantification [ 11 ]. Furthermore, MS-MRD allowed for longitudinal monitoring of MM patients [ 16 , 22 , 26 ]. To assess the concordance between MS-MRD data quantified by SIL peptides and SILuMAB, all available longitudinal samples from three patients were digested with both SILuMAB and SIL peptides (data for patient 1 is shown in Figure 4B and other data is available in Supplementary Table S4C ).…”

Section: Resultsmentioning

confidence: 99%

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M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator

Wijnands,

Langerhorst,

Noori

et al. 2023

Clinical Chemistry and Laboratory Medicine (CCLM)

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Objectives Minimal residual disease status in multiple myeloma is an important prognostic biomarker. Recently, personalized blood-based targeted mass spectrometry (MS-MRD) was shown to provide a sensitive and minimally invasive alternative to measure minimal residual disease. However, quantification of MS-MRD requires a unique calibrator for each patient. The use of patient-specific stable isotope labelled (SIL) peptides is relatively costly and time-consuming, thus hindering clinical implementation. Here, we introduce a simplification of MS-MRD by using an off-the-shelf calibrator. Methods SILuMAB-based MS-MRD was performed by spiking a monoclonal stable isotope labeled IgG, SILuMAB-K1, in the patient serum. The abundance of both M-protein-specific peptides and SILuMAB-specific peptides were monitored by mass spectrometry. The relative ratio between M-protein peptides and SILuMAB peptides allowed for M-protein quantification. We assessed linearity, sensitivity and reproducibility of SILuMAB-based MS-MRD in longitudinally collected sera from the IFM-2009 clinical trial. Results A linear dynamic range was achieved of over 5 log scales, allowing for M-protein quantification down to 0.001 g/L. The inter-assay CV of SILuMAB-based MS-MRD was on average 11 %. Excellent concordance between SIL- and SILuMAB-based MS-MRD was shown (R2>0.985). Additionally, signal intensity of spiked SILuMAB can be used for quality control purpose to assess system performance and incomplete SILuMAB digestion can be used as quality control for sample preparation. Conclusions Compared to SIL peptides, SILuMAB-based MS-MRD improves the reproducibility, turn-around-times and cost-efficacy of MS-MRD without diminishing its sensitivity and specificity. Furthermore, SILuMAB can be used as a MS-MRD quality control tool to monitor sample preparation efficacy and assay performance.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator

Wijnands,

Langerhorst,

Noori

et al. 2023

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…While the Fab-profiling workflow presented here is limited to the IgG1 subclass, and the de novo sequencing and glycan profiling methods are best suited for research applications, we believe that a robust implementation of Fab profiling across all IgG subclasses by LC-MS holds promise for the clinical detection of M-proteins and diagnostics of monoclonal gammopathies. The outlined approach in this case study adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and MM with fine molecular detail. − The ability to detect monoclonal gammopathies and determine M-protein sequences straight from peripheral blood samples by mass spectrometry provides opportunities to understand the molecular mechanisms of these diseases.…”

Section: Discussionmentioning

confidence: 99%

Direct Mass Spectrometry-Based Detection and Antibody Sequencing of Monoclonal Gammopathy of Undetermined Significance from Patient Serum: A Case Study

et al. 2023

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Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.

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“…The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and MM with fine molecular detail. [15][16][17][18][19][20] The ability to detect monoclonal gammopathies and determine Mprotein sequences straight from peripheral blood samples by mass spectrometry provides opportunities to understand the molecular mechanisms of these diseases.…”

Section: Discussionmentioning

confidence: 99%

Direct mass spectrometry-based detection and antibody sequencing of Monoclonal Gammopathy of Undetermined Significance from patient serum – a case study

Peng

Boer

Tamara

et al. 2023

Preprint

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Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder, characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.

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Retrospective Longitudinal Monitoring of Multiple Myeloma Patients by Mass Spectrometry Using Archived Serum Protein Electrophoresis Gels and De Novo Sequence Analysis

Cited by 5 publications

References 15 publications

M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator

M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator

Direct Mass Spectrometry-Based Detection and Antibody Sequencing of Monoclonal Gammopathy of Undetermined Significance from Patient Serum: A Case Study

Direct mass spectrometry-based detection and antibody sequencing of Monoclonal Gammopathy of Undetermined Significance from patient serum – a case study

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