Treatment Resistance Risk in Patients with Newly Diagnosed Multiple Myeloma Is Associated with Blood Hypercoagulability: The ROADMAP-MM Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Control Group
3. Results
3.1. Hypercoagulability at Diagnosis of Multiple Myeloma Prior to Treatment Initiation
3.2. Biomarkers of Hypercoagulability and Response to the Antimyeloma Treatment at 3 Months
3.3. Biomarkers of Hypercoagulability and Overall Mortality at 3 Months
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patient Clinical Characteristics | ||
Responders (n = 111) | Non-Responders (n = 33) | |
Age (years) | 66.0 ± 12.0 (37–86) | 65.0 ± 11.0 (36–82) |
Male/female | 59/52 (53%/47%) | 17/16 (51%/49%) |
BSA (m2) | 1.84 ± 0.19 (1.41–2.50) | 1.87 ± 0.20 (1.46–2.30) |
BMI (kg/m2) | 25.9 ± 5.3 (17.2–44.8) | 24.6 ± 4.9 (17.9–43.4) |
ISS stage—n (%) | ||
I | 35 (31%) | 11 (33%) |
II | 26 (24%) | 7 (21%) |
III | 50 (45%) | 15 (46%) |
Anti-myeloma Treatment—n(%) | ||
PI-based | 73 (65%) VCD (65), VMP (7), ICD (1) | 19 (58%) VCD (15), VD (2), VMP (1), ICD (1) |
IMiD-based | 35 (32%) RAD (23), CTD (5), Rd (4), VRD (2), VTD (1) | 11 (33%) RAD (5), CTD (1), Rd (5) |
Other | 3 (3%) MDex (3) | 3 (9%) CD (2), MDex (1) |
ECOG Performance Status—n(%) | ||
0 | 50 (45) | 7 (21) |
1 | 45 (41) | 14 (43) |
2 | 12 (11) | 11 (33) |
3 | 3 (2) | 1 (3) |
4 | 1 (1) | 0 (0) |
Dialysis at diagnosis—n (%) | 12 (11%) | 2 (6%) |
Bone disease present—n (%) | 79 (71%) | 23 (70%) |
High risk cytogenetics—n (%) | 21 (19%) | 6 (18%) |
Thromboprophylaxis after Enrolment in the Study—n (%) | ||
None | 30 (27) | 17 (51) |
Aspirin | 61 (55) | 13 (39) |
LMWH (tinzaparin) | 20 (18) | 3 (10) |
Patients’ Biological Data(mean ± SD; range) | ||
β2-microglobulin (mg/dl) | 7.6 ± 8.0 (0.06–39) | 8.5 ± 8.7 (2.5–48.5) |
M-peak (g/dl) | 2.7 ± 2.6 (0–7.6) | 3.4 ± 2.8 (0–9) |
U-peak (mg/24 h) | 313 ± 880 (0–5987) | 413 ± 980 (0–6667) |
Bone marrow infiltration (%) | 61.0 ± 26.4 (0–100) | 64 ± 23.0 (0–100) |
Total protein (g/dl) | 8.2 ± 2.4 (5.1–12.0) | 8.7 ± 1.9 (5.4–14.3) |
Creatinine (mg/dl) | 1.77 ± 3.2 (0.47–15.0) | 1.98 ± 2.9 (0.9–28.0) |
Urea (mg/dl) | 56.1 ± 40.0 (5–180) | 60.4 ± 43.9 (5–276) |
GFR (mL/min) | 73.0 ± 43.0 (4.2–230.0) | 73.0 ± 43.0 (4.2–230.0) |
LDH (U/L) | 190 ± 96 (70–690) | 211 ± 93 (99–789) |
ALT (U/L) | 24.1 ± 21.2 (7–162) | 24.6 ± 19.9 (6–159) |
AST (U/L) | 23.8 ± 24.0 (7–169) | 24.3 ± 23.0 (6–178) |
Albumin (g/dl) | 3.9 ± 0.84 (2.4–6.7) | 3.6 ± 0.9 (2.1–6.8) |
Calcium (mg/dl) | 9.5 ± 1.3 (6.7–13.0) | 9.8 ± 1.7 (6.9–13.4) |
Hb (g/dl) | 10.4 ± 2.1 (7.0–16.0) | 10.6 ± 2.0 (7.3–17.5) |
White blood cell count (×106/μL) | 7.1 ± 4.0 (0.58–18.0) | 6.0 ± 2.9 (0.48–18.8) |
Neutrophils (×106/μL) | 4.4 ± 2.4 (0.2–10.0) | 4.0 ± 2.3 (0.3–12.6) |
Platelets (×103/μL) | 260 ± 120 (34–879) | 250 ± 119 (26–760) |
Normal Reference Range | Healthy Subjects (n = 30) | MM (n = 144) | p | Non-Responders (n = 33) | Responders (n = 111) | |
---|---|---|---|---|---|---|
Cellular-derived Hypercoagulability | ||||||
Procoag-PPL® (s) | 42–85 | 62.8 ± 8.6 | 45.6 ± 0.22.6 | <0.0001 | 51.9 ± 24.1 | 43.8 ± 21.9 |
TFa (ng/mL) | 0.02–0.45 | 0.26 ± 0.13 | 3.9 ± 13.1 | <0.0001 | 2.4 ± 3.8 | 4.4 ± 14.8 |
Heparanase (ng/mL) | 0.08–0.16 | 0.13 ± 0.03 | 0.3 ± 0.5 | 0.476 | 0.4 ± 0.8 | 0.4 ± 0.5 |
TM (ng/mL) | 70–120 | 90.1 ± 18.1 | 73.2 ± 68.1 | <0.05 | 68.2 ± 88.1 | 74.7 ± 77.0 |
P-selectin (μg/mL) | 82–42 | 62.6 ± 103.9 | 38.1 ± 31.8 | <0.0001 | 31.6 ± 32.7 | 40.1 ± 31.5 |
TFPI (ng/mL) | 15–26 | 18.2 ± 4.0 | 31 ± 18.5 | 0.02 | 37.1 ± 18.6 | 34.4 ± 16.3 |
Blood Coagulation Factors and Natural Inhibitors | ||||||
FVIIa (U/mL) | 73–29 | 50.9 ± 10.6 | 74.1 ± 147.6 | 0.022 | 51.6 ± 47.7 | 75.1 ± 161.3 |
FV (%) | 70–120 | 90.0 ± 12.0 | 78.0 ± 11.0 | 0.23 | 80.5 ± 35.4 | 91.7 ± 34.6 |
AT (%) | 70–120 | 92.0 ± 12.0 | 95.4 ± 17.7 | <0.005 | 95.3 ± 15.3 | 95.4 ± 18.4 |
In vivo Fibrin Formation/lysis | ||||||
D-Dimer (μg/mL) | <0.50 | 0.31 ± 0.08 | 1.80 ± 3.41 | <0.0001 | 2.5 ± 3.8 | 1.6 ± 3.3 |
FM (μg/mL) | 0.5–5.50 | 2.5 ± 0.5 | 14.29 ± 31.8 | <0.0001 | 20.4 ± 40.7 | 19.6 ± 34.8 |
Thrombogram Parameters | ||||||
Lag-time (min) | 2.1–3.8 | 2.5 ± 0.4 | 4.2 ± 2.2 | <0.0001 | 3.9 ± 1.2 | 4.3 ± 2.4 |
ttPeak (min) | 4.0–6.6 | 5.3 ± 0.7 | 7.3 ± 2.8 | <0.0001 | 6.9 ± 1.7 | 7.5 ± 3.1 |
Peak (nM) | 222–330 | 287.8 ± 35.7 | 214.4 ± 80.1 | <0.0001 | 218.1 ± 58.2 | 213.4 ± 85.9 |
MRI (nM/min) | 60–120 | 109.9 ± 24.5 | 80.2 ± 45.7 | <0.0001 | 80.8 ± 34.6 | 80.1 ± 48.7 |
ETP (nMxmin) | 1600–1178 | 1496.8 ± 191.4 | 1181.8 ± 398 | <0.0001 | 1150.6 ± 247.1 | 1191.4 ± 434.7 |
Compared Categories | OR (95% CI) | |
---|---|---|
Cellular-derived Hypercoagulability | ||
Procoag-PPL® (s) | ≥41.7 vs. <41.7 | 3.41 (1.45–8.03) |
TFa (ng/mL) | ≥0.6 vs. <0.6 | 0.63 (0.28–1.41) |
Heparanase (ng/mL) | ≥0.373 vs. <0.373 | 0.41 (0.13–1.27) |
TMa (%) | ≥43 vs. <43 | 0.36 (0.10–1.28) |
P-selectin (pg/mL) | ≥23477 vs. <23477 | 0.23 (0.08–0.65) |
TFPI (ng/mL) | ≥35.71 vs. <35.71 | 1.57 (0.61–4.03) |
Blood Coagulation Factors and Natural Inhibitors | ||
FVIIa (ng/mL) | ≥23.31 vs. <23.31 | 1.95 (0.69–5.54) |
FV (%) | ≥92 vs. <92 | 0.50 (0.18–1.36) |
ATIII (%) | ≥94 vs. <94 | 0.62 (0.28–1.37) |
In vivo Thrombin Generation | ||
D-Dimer (μg/mL) | ≥1.44 vs. <1.44 | 3.21 (1.43–7.22) |
FM (μg/mL) | ≥5.46 vs. <5.46 | 1.52 (0.59–3.90) |
Thrombogram Parameters | ||
Lag-time (min) | ≥2.75 vs. <2.75 | 0.59 (0.23–1.52) |
ETP (Mxmin) | ≥1188.03 vs. <1188.03 | 0.51 (0.22–1.22) |
Peak (nM) | ≥181.66 vs. <181.66 | 2.73 (1.03–7.23) |
ttPeak (min) | ≥7.74 vs. <7.74 | 0.49 (0.18–1.30) |
MRI (nM/min) | ≥50.46 vs. <50.46 | 2.14 (0.81–5.70) |
Compared Categories | Adjusted OR (95% CI) | |
---|---|---|
Procoag-PPL® (s) | ≥41.7 vs. <41.7 | 4.06 (1.59–10.38) |
D-Dimer (μg/mL) | ≥1.44 vs. <1.44 | 2.52 (1.06–6.01) |
Peak (nM) | ≥181.66 vs. <181.66 | 3.29 (1.17–9.26) |
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Gerotziafas, G.T.; Fotiou, D.; Sergentanis, T.N.; Papageorgiou, L.; Fareed, J.; Falanga, A.; Sabbah, M.; Garderet, L.; Terpos, E.; Elalamy, I.; et al. Treatment Resistance Risk in Patients with Newly Diagnosed Multiple Myeloma Is Associated with Blood Hypercoagulability: The ROADMAP-MM Study. Hemato 2022, 3, 188-203. https://doi.org/10.3390/hemato3010016
Gerotziafas GT, Fotiou D, Sergentanis TN, Papageorgiou L, Fareed J, Falanga A, Sabbah M, Garderet L, Terpos E, Elalamy I, et al. Treatment Resistance Risk in Patients with Newly Diagnosed Multiple Myeloma Is Associated with Blood Hypercoagulability: The ROADMAP-MM Study. Hemato. 2022; 3(1):188-203. https://doi.org/10.3390/hemato3010016
Chicago/Turabian StyleGerotziafas, Grigorios T., Despina Fotiou, Theodoros N. Sergentanis, Loula Papageorgiou, Jawed Fareed, Anna Falanga, Michèle Sabbah, Laurent Garderet, Evangelos Terpos, Ismail Elalamy, and et al. 2022. "Treatment Resistance Risk in Patients with Newly Diagnosed Multiple Myeloma Is Associated with Blood Hypercoagulability: The ROADMAP-MM Study" Hemato 3, no. 1: 188-203. https://doi.org/10.3390/hemato3010016