Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Collection of MM Cells
2.3. Determination of Human Protein Level in Plasma Cells
2.4. Statistical Analysis
3. Results
3.1. Characteristics of the Patients Included in the Analysis
3.2. Protein Levels According to Clinical and Laboratory Characteristics
3.3. Influence of ASCT and ISS Protein Levels on Overall Survival and Progression-Free Survival
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ASCT | autologous stem cell transplantation |
ACTB | Beta–actin protein |
BM | bone marrow |
ELISA | enzyme-linked immunosorbent assay |
LCD | light chain disease |
IMWG | International Myeloma Working Group |
MAF | musculoaponeurotic fibrosarcoma |
MM | Multiple myeloma |
NRF2 | Nuclear factor erythroid 2-related factor 2 |
NF-κB | nuclear factor kappa B |
OS | overall survival |
PC | plasma cells |
PFS | progression-free survival |
POMP | proteasome maturation protein |
PI | Proteasome inhibitors |
PSMB5 | proteasome subunit β5 |
UPR | unfolded protein response |
VCD | bortezomib, cyclophosphamide and dexamethasone; |
VD | bortezomib and dexamethasone; |
VMP | bortezomib, melphalan and prednisone; |
VTD | bortezomib, thalidomide and dexamethasone |
XBP1 | X–box binding protein 1 |
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Protein | Characteristics | Significance in MM | Reference |
---|---|---|---|
POMP | A short-lived maturation factor essential for 20S proteasome subunit biogenesis. | POMP over-expression contributes to proteasome inhibitor resistance, while suppression enhances bortezomib and carfilzomib activity. | [12,17] |
PSMB5 | A component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. | Overexpression observed in bortezomib-resistant cell lines, PSMB5 contributes to bortezomib resistance in MM patients. | [18,19,20,21] |
NRF2 | A transcription activator that binds to antioxidant response elements in the promoter regions of target genes. | A key regulator of MM survival in treatment naive and PI-treated cells, PI increases expression of NRF2 in MM cells. | [22,23] |
XBP1 | A transcription factor found during endoplasmic reticulum stress; a regulator of the UPR; needed for differentiation of B cells into PCs. | XBP1 levels correlate with bortezomib resistance in MM; XBP1 levels are low in bortezomib-refractory MM patients | [24,25] |
cMAF | A bZIP zipper transcription factors, belonging to the AP-1 family. | Overexpressed in MM, enhancing tumor-stroma interactions. | [26,27,28,29] |
MAFB | bZIP transcription factor that plays an important role in the regulation of lineage-specific hematopoiesis. | High expression is associated with resistance to proteasome inhibitors, frequent event in the progression of MM. | [26,27,28,30,31] |
Characteristics | Overall (N = 39) |
---|---|
Sex | M: 23 (59.0) |
F: 16 (41.0) | |
Age mean ± SD | 66.8 ± 8.9 |
(range) | (39–81) |
ISS at diagnosis | I: 12 (30.8) |
II: 7 (17.9) | |
III: 17 (43.6) | |
Data missing: 3 (7.7) | |
Paraprotein | |
IgG | 23 (59.0) |
LCD | 8 (20.5) |
IgA | 8 (20.5) |
HB < 10 g/dL at diagnosis | 14 (35.9) |
Creatinine > 2 mg/dL at diagnosis | 4 (10.3) |
Calcium > 2.5 mmol/L at diagnosis | 11 (28.2) |
Bone disease | 20 (51.3) |
CRP > 5 mg/L | 16 (41) |
LDH > 240 U/L | 10 (25.6) |
Cytogenetics * | |
amp(1q) | 11 (28.2) |
t(4;14) | 4 (10.3) |
del(13q) | 2 (5.1) |
del(17p) | 2 (5.1) |
t(11;14) | 1 (2.6) |
del(1p) | 1 (2.6) |
t(14;16) | 0 (0) |
t(14;20) | 0 (0) |
IGH rearrangements | 7 (17.9) |
Prior treatment | 10 (25.6) |
Bortezomib regimen: | |
VCD | 30 (76.9) |
VMP | 4 (10.3) |
VD | 4 (10.3) |
VTD | 1 (2.6) |
ASCT | 18 (46.2) |
RTx | 10 (25.6) |
Response to treatment | |
CR | 10 (25.6) |
VGPR | 10 (25.6) |
PR | 8 (20.5) |
SD | 5 (12.8) |
PD | 6 (15.4) |
Refractoriness to bortezomib | 12 (30.8) |
Variables | PFS | OS | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Coefficient | p-Value | HR | 95% CI | Coefficient | p-Value | HR | 95% CI | |||
Lower | Higher | Lower | Higher | |||||||
ISS III | 0.38 | 0.0308 | 2.12 | 1.07 | 4.19 | 0.34 | 0.1284 | 1.95 | 0.82 | 4.64 |
Previous treatment | 0.49 | 0.0178 | 2.65 | 1.18 | 5.91 | 0.16 | 0.5265 | 1.36 | 0.52 | 3.56 |
≥VGPR | −0.38 | 0.0292 | 0.47 | 0.24 | 0.93 | −0.18 | 0.4102 | 0.69 | 0.29 | 1.66 |
ASCT | −0.53 | 0.0035 | 0.35 | 0.17 | 0.71 | −0.65 | 0.0074 | 0.27 | 0.10 | 0.70 |
Sex (M) | 0.12 | 0.4781 | 1.28 | 0.65 | 2.53 | 0.05 | 0.8298 | 1.10 | 0.45 | 2.69 |
HB < 10 g/dL | 0.12 | 0.4967 | 1.27 | 0.64 | 2.54 | 0.07 | 0.7431 | 1.16 | 0.48 | 2.81 |
Calcium > 2.5 mmol/L | −0.13 | 0.4838 | 0.77 | 0.38 | 1.59 | 0.01 | 0.9747 | 1.02 | 0.40 | 2.55 |
Creatinine > 2 mg/dL | −0.14 | 0.6125 | 0.76 | 0.27 | 2.17 | 0.22 | 0.482 | 1.57 | 0.45 | 5.46 |
Bone disease | 0.03 | 0.8753 | 1.06 | 0.54 | 2.06 | −0.06 | 0.7691 | 0.88 | 0.37 | 2.08 |
High POMP | −0.064 | 0.7434 | 0.880 | 0.410 | 1.889 | 0.515 | 0.0277 | 2.802 | 1.120 | 7.010 |
High PSMB5 | 0.059 | 0.7343 | 1.125 | 0.570 | 2.219 | 0.271 | 0.2319 | 1.720 | 0.707 | 4.188 |
High NRF2 | −0.205 | 0.2784 | 0.663 | 0.315 | 1.394 | −0.264 | 0.3104 | 0.590 | 0.213 | 1.635 |
High XBP1 | −0.047 | 0.7954 | 0.911 | 0.450 | 1.845 | −0.301 | 0.2419 | 0.548 | 0.200 | 1.501 |
High cMAF | 0.237 | 0.1972 | 1.608 | 0.781 | 3.310 | 0.280 | 0.0988 | 2.522 | 0.841 | 7.565 |
High MAFB | −0.270 | 0.1582 | 0.583 | 0.276 | 1.233 | −0.572 | 0.0147 | 0.319 | 0.127 | 0.798 |
Variables | PFS | ||||
---|---|---|---|---|---|
Coefficient | p-Value | HR | 95% CI | ||
Lower | Higher | ||||
≥VGPR | −0.43 | 0.0170 | 0.43 | 0.21 | 0.86 |
ASCT | −0.56 | 0.0021 | 0.32 | 0.16 | 0.66 |
OS | |||||
ASCT | −0.79 | 0.0025 | 0.20 | 0.07 | 0.57 |
High MAFB | −0.92 | 0.0005 | 0.16 | 0.06 | 0.45 |
High POMP | 0.60 | 0.0189 | 3.30 | 1.22 | 8.94 |
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Robak, P.; Szemraj, J.; Mikulski, D.; Drozdz, I.; Juszczak, K.; Jarych, D.; Misiewicz, M.; Kościelny, K.; Fendler, W.; Robak, T. Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens. J. Clin. Med. 2021, 10, 5028. https://doi.org/10.3390/jcm10215028
Robak P, Szemraj J, Mikulski D, Drozdz I, Juszczak K, Jarych D, Misiewicz M, Kościelny K, Fendler W, Robak T. Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens. Journal of Clinical Medicine. 2021; 10(21):5028. https://doi.org/10.3390/jcm10215028
Chicago/Turabian StyleRobak, Paweł, Janusz Szemraj, Damian Mikulski, Izabela Drozdz, Karolina Juszczak, Dariusz Jarych, Małgorzata Misiewicz, Kacper Kościelny, Wojciech Fendler, and Tadeusz Robak. 2021. "Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens" Journal of Clinical Medicine 10, no. 21: 5028. https://doi.org/10.3390/jcm10215028