Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept
Abstract
:1. Introduction
2. Results and Discussion
2.1. EVs Were Isolated from the PB and BM of MM Patients
2.2. EVs Were Isolated from Diagnosis and Remission PB and BM Samples of MM Patients
2.2.1. EVs Isolated from Diagnostic PB and BM Samples Present MM Markers in Their Cargo
2.2.2. MM Markers Can Be Found in EVs from Both BM and PB Samples
2.2.3. EVs from Diagnosis and Remission PB and BM Patient Samples Present Different Levels of MM Markers
2.3. EVs from Healthy Controls Do Not Present Most of the MM Markers
3. Material and Methods
3.1. Patients and Samples
3.2. Minimal Residual Disease (MRD) Determination by Flow Cytometry
3.3. Platelet-Poor Plasma (PPP) Isolation
3.4. Extracellular Vesicles (EVs) Isolation from Platelet-Poor Plasma (PPP)
3.4.1. Size Exclusion Chromatography (SEC)
3.4.2. Ultrafiltration (UF)
3.5. Protein Quantification
3.6. EVs Characterization
3.6.1. Nanoparticle Tracking Analysis (NTA)
3.6.2. Transmission Electron Microscopy (TEM)
3.6.3. Western Blot (WB)
3.7. Multiple Myeloma (MM) Marker Analysis by Western Blot (WB)
3.8. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AS-PCR | allele-specific oligonucleotide polymerase chain reaction |
ASCT | autologous stem cell transplant |
BM | bone marrow |
CAR-T cells | chimeric antigen receptor-T cells |
CHUSJ | Centro Hospitalar Universitário São João |
cfDNA | cell-free DNA |
CTCs | circulating tumor cells |
ctDNA | circulating tumor DNA |
CR | complete response |
D100 | day 100 after ASCT |
ECL | enhanced chemiluminescence |
EMD | extramedullary disease |
EVs | Extracellular Vesicles |
FDG-PET/CT | 18-fluoro-2-deoxyglucos positron emission tomography/computed tomography |
FISH | Fluorescence in situ hybridization |
FPM | Fuji Medical Film Processor |
Ig | immunoglobulin |
IMWG | International Myeloma Working Group |
ISS | International Staging System |
K | immunoglobulin kappa (κ) chain |
L | immunoglobulin lambda (λ) chain |
LOD | limit of detection |
MFC | multiparameter flow cytometry |
MM | Multiple Myeloma |
MRD | measurable residual disease |
MSCs | BM mesenchymal stem cells |
MW | molecular weight |
NGF | next-generation flow |
NGS | next-generation sequencing |
NTA | Nanoparticle Tracking Analysis |
OS | overall survival |
PB | peripheral blood |
PBS | phosphate-buffered saline |
PC | plasma cells |
PFS | progression free-survival |
PPP | Platelet-Poor Plasma |
PRP | Platelet-Rich Plasma |
R-ISS | revised-ISS |
RT | room temperature |
sCR | stringent complete response |
SEC | Size Exclusion Chromatography |
TBS-T | Tris-buffered saline solution with 0.1% Tween-20 |
TEM | Transmission Electron Microscopy |
UF | ultrafiltration |
UF | ultrafiltrated pool from SEC fractions 3 to 6 |
VEGF | vascular endothelial growth factor |
VGPR | very good partial response |
WB | Western Blot |
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Patient | MM Isotype | ISS | FISH | EMD | % of PCs at Diagnosis | MM Markers by WB at EVs PB/BM at Diagnosis | IMWG Response Criteria at D100 | MRD at D100 by Flow Cytometry | % of PCs at D100 | MM Markers by WB at EVs PB/BM at D100 | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PB | BM | CD38 | CD138 | K | L | BM | BM | PB | BM | CD38 | CD138 | K | L | |||||
01 | IgG/K | 2 | no abnormality | Yes | ≤0.05 | ≤10 | wd/wd | nd | ++/++ | +/++ | sCR | negative | 0 | ≤0.05 | wd/− | nd | +/+ | ++/+ |
02 | IgG/K | 3 | amp1q21 | No | 0 | ≥40 and ≤50 | ++/++ | nd | ++/++ | ++/++ | sCR | negative | 0 | ≥0.05 and ≤0.1 | +/+ | nd | +/+ | +/+ |
03 | IgG/K | 3 | t(4;14) | Yes | ≤0.05 | ≤10 | −/− | nd | ++/++ | +/++ | sCR | positive | ≤0.01 | ≥0.1 and ≤0.5 | wd/wd | nd | +/+ | +/wd |
04 | IgA/L | 3 | t(4;14), del17p | No | ≤0.05 | ≥10 and ≤20 | ++/++ | +/++ | ++/++ | ++/++ | VGPR | positive | ≤0.01 | ≥0.1 and ≤0.5 | ++/++ | ++/++ | +/+ | +/+ |
05 | IgG/L | 2 | no abnormality | No | ≤0.002 | ≥10 and ≤20 | ++/++ | nd | +/wd | ++/++ | sCR | positive | 0 | ≤0.05 | ++/+ | nd | ++/++ | ++/++ |
06 | L | 3 | no abnormality | No | ≤0.002 | ≥20 and ≤30 | +/+ | nd | ++/++ | +/+ | sCR | negative | 0 | ≤0.05 | ++/++ | nd | ++/++ | +/+ |
07 | K | 3 | del17p | Yes | 0 | ≤10 | nd | ++/+ | +/++ | +/++ | CR | negative | 0 | ≤0.05 | nd | ++/+ | +/+ | ++/++ |
08 | IgG/L | 3 | amp1q21 | No | ≤0.05 | ≥40 and ≤50 | +/++ | +/++ | wd/+ | +/+ | sCR | negative | ≤0.01 | ≤0.05 | wd/wd | −/− | wd/wd | ++/++ |
09 | IgG/K | 2 | no abnormality | No | 0 | ≥30 and ≤40 | +/wd | nd | ++/++ | +/+ | sCR | negative | 0 | ≤0.05 | +/wd | nd | ++/++ | +/+ |
10 | K | 3 | t(4;14) | Yes | 0 | ≥10 and ≤20 | wd/− | nd | ++/++ | wd/+ | CR | positive | 0 | ≤0.05 | wd/wd | nd | +/+ | ++/++ |
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Bergantim, R.; Peixoto da Silva, S.; Polónia, B.; Barbosa, M.A.G.; Albergaria, A.; Lima, J.; Caires, H.R.; Guimarães, J.E.; Vasconcelos, M.H. Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept. Int. J. Mol. Sci. 2022, 23, 13686. https://doi.org/10.3390/ijms232213686
Bergantim R, Peixoto da Silva S, Polónia B, Barbosa MAG, Albergaria A, Lima J, Caires HR, Guimarães JE, Vasconcelos MH. Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept. International Journal of Molecular Sciences. 2022; 23(22):13686. https://doi.org/10.3390/ijms232213686
Chicago/Turabian StyleBergantim, Rui, Sara Peixoto da Silva, Bárbara Polónia, Mélanie A. G. Barbosa, André Albergaria, Jorge Lima, Hugo R. Caires, José E. Guimarães, and M. Helena Vasconcelos. 2022. "Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept" International Journal of Molecular Sciences 23, no. 22: 13686. https://doi.org/10.3390/ijms232213686