Potential mechanisms of resistance to current anti-thrombotic strategies in Multiple Myeloma

Abstract

Multiple Myeloma (MM) is a common haematological malignancy that is associated with a high rate of venous thromboembolism (VTE) with almost 10% of patients suffering thrombosis during their disease course. Recent studies have shown that, despite current thromboprophylaxis strategies, VTE rates in MM remain disappointingly high. The pathophysiology behind this consistently high rate of VTE is likely multifactorial. A number of factors such as anti-thrombin deficiency or raised coagulation Factor VIII levels may confer resistance to heparin in these patients, however, the optimal method of clinically evaluating this is unclear at present, though some groups have attempted its characterisation with thrombin generation testing (TGT). In addition to testing for heparin resistance, TGT in patients with MM has shown markedly varied abnormalities in both endogenous thrombin potential and serum thrombomodulin levels. Apart from these thrombin-mediated processes, other mechanisms potentially contributing to thromboprophylaxis failure include activated protein C resistance, endothelial toxicity secondary to chemotherapy agents, tissue factor abnormalities and the effect of immunoglobulins/“M-proteins” on both the endothelium and on fibrin fibre polymerisation. It thus appears clear that there are a multitude of factors contributing to the prothrombotic milieu seen in MM and further work is necessitated to elucidate which factors may directly affect and inhibit response to anticoagulation and which factors are contributing in a broader fashion to the hypercoagulability phenotype observed in these patients so that effective thromboprophylaxis strategies can be employed.

Keywords

Multiple myeloma / heparin resistance / thromboprophylaxis / venous thromboembolism / thrombin generation testing / endothelium / immunoglobulin

References

[1] Kristinsson SY,Gridley G.Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.Blood2008;112:3582-6 PMCID:PMC2572787

[2] Barrett A,Lavin M.Validation of risk-adapted venous thromboembolism prediction in multiple myeloma patients.J Clin Med2021;10:3536 PMCID:PMC8396929

[3] Schoen MW,Gage B,Sanfilippo KM.Association of venous thromboembolism with increased mortality in patients with multiple myeloma.J Clin Oncol2018;36:8051

[4] Kristinsson SY,Björkholm M,Landgren O.Thrombosis is associated with inferior survival in multiple myeloma.Haematologica2012;97:1603-7 PMCID:PMC3487563

[5] Moreau P.How I treat myeloma with new agents.Blood2017;130:1507-13

[6] Gandolfi S,Richardson PG.How I treat the young patient with multiple myeloma.Blood2018;132:1114-24

[7] Moreau P,Sonneveld P.ESMO Guidelines CommitteeMultiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol2017;28:iv52-61

[8] Dimopoulos M,Attal M.Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma: a systemic review.N Engl J Med2007;357:2123-32

[9] Zonder JA,Hussein MA.Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232).Blood2010;116:5838-41 PMCID:PMC3031379

[10] Khorana AA,Liebman H,Connors JM.Prediction and prevention of cancer-associated thromboembolism.Oncologist2021;26:e2-7 PMCID:PMC7794203

[11] Snyder PB,Leonard AW,Wilson HR.Development and validation of a predictive model for the pedestal height.Phys Plasmas2009;16:056118

[12] Sanfilippo KM,Wang TF.Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score.Am J Hematol2019;94:1176-84 PMCID:PMC7058359

[13] Palumbo A,Dimopoulos MA.International Myeloma Working GroupPrevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.Leukemia2008;22:414-23

[14] Li A,Luo S.Derivation and validation of a risk assessment model for immunomodulatory drug-associated thrombosis among patients with multiple myeloma.J Natl Compr Canc Netw2019;17:840-7 PMCID:PMC7808759

[15] Santoro M,Mancuso S.Prevention of venous thromboembolic events occurring in myeloma patients treated with second-generation novel agents.Panminerva Med2021;63:1-6

[16] McBane RD 2nd,Le-Rademacher JG.Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial.J Thromb Haemost2020;18:411-21

[17] Moik F,Ay C.How I treat cancer-associated thrombosis.ESMO Open2020;5:e000610 PMCID:PMC7003382

[18] Raskob GE,Verhamme P.Hokusai VTE Cancer InvestigatorsEdoxaban for the treatment of cancer-associated venous thromboembolism.N Engl J Med2018;378:615-24

[19] Storrar NPF,Johnson PRE.Safety and efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomide- and lenalidomide-containing regimens.Br J Haematol2019;185:142-4

[20] Cornell RF,Engelhardt BG.Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents.Br J Haematol2020;190:555-61

[21] Swan D,Bradbury C.Venous thromboembolism in multiple myeloma - choice of prophylaxis, role of direct oral anticoagulants and special considerations.Br J Haematol2018;183:538-56

[22] Leclerc V,Herledan C.Thromboembolic events and thromboprophylaxis associated with immunomodulators in multiple myeloma patients: a real-life study.J Cancer Res Clin Oncol2021;

[23] Lapietra G,Fazio F,Chistolini A.Venous thromboembolism prophylaxis in patients with multiple myeloma: where are we and where are we going?.J Thromb Thrombolysis2021;52:584-9

[24] Leleu X,Hulin C.MELISSE, a large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs.Thromb Haemost2013;110:844-51

[25] Bradbury CA,Cook G.Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials.Blood2020;136:1091-104 PMCID:PMC7453153

[26] Patel VG.Cardiovascular complications associated with multiple myeloma therapies: incidence, pathophysiology, and management.Curr Oncol Rep2019;21:29

[27] Atrash S,Panozzo S.Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib.Blood Cancer J2015;5:e272 PMCID:PMC4314456

[28] Landgren O,Jakubowiak A.Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma.Leukemia2019;33:2127-43 PMCID:PMC6756042

[29] Piedra K,Tan C.Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis.Br J Haematol2022;196:105-9

[30] Parks AL,Fakhri B.Incidence, management and outcomes of arterial and venous thromboembolism after chimeric antigen receptor modified T cells for B-cell lymphoma and multiple myeloma.Blood2020;136:7-7

[31] Levy JH.Heparin resistance - clinical perspectives and management strategies.N Engl J Med2021;385:826-32

[32] Wang TF,Antic D.Management of hemostatic complications in acute leukemia: guidance from the SSC of the ISTH.J Thromb Haemost2020;18:3174-83 PMCID:PMC7909744

[33] Kumar S,Nitsch D.Proteinuria and hypoalbuminemia are risk factors for thromboembolic events in patients with idiopathic membranous nephropathy: an observational study.BMC Nephrol2012;13:107 PMCID:PMC3480900

[34] Auwerda JJA,De Maat MPM.Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma.Haematologica2007;92:279-80

[35] van Marion AM,Lisman T.Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens.Leuk Res2008;32:1078-84

[36] Minnema MC,De Groot PG.Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment.J Thromb Haemost2003;1:445-9

[37] Ay C,Simanek R.Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study.J Clin Oncol2011;29:2099-103

[38] Chalayer E,Montmartin A,Genthon A.Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients.Br J Haematol2019;186:337-9

[39] Gracheva MA,Sinauridze EI.Thromboelastography, thrombin generation test and thrombodynamics reveal hypercoagulability in patients with multiple myeloma.Leuk Lymphoma2015;56:3418-25

[40] Leiba M,Budnik I.Thrombin generation as a predictor of thromboembolic events in multiple myeloma patients.Blood Cells Mol Dis2017;65:1-7

[41] Fotiou D,Papageorgiou L.Longer procoagulant phospholipid-dependent clotting time, lower endogenous thrombin potential and higher tissue factor pathway inhibitor concentrations are associated with increased VTE occurrence in patients with newly diagnosed multiple myeloma: results of the prospective ROADMAP-MM-CAT study.Blood Cancer J2018;8:102 PMCID:PMC6221885

[42] Legendre P,Martin M.Hypocoagulability as assessed by thrombin generation test in newly-diagnosed patients with multiple myeloma.Blood Cells Mol Dis2017;66:47-9

[43] Corso A,Terulla V.Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone.Ann Hematol2004;83:588-91

[44] Zappasodi P,Terulla V.Thrombomodulin levels are not modified during thalidomide treatment.Eur J Haematol2006;77:453-4

[45] Robak M,Chojnowski K.Hemostatic changes after 1 month of thalidomide and dexamethasone therapy in patients with multiple myeloma.Med Oncol2012;29:3574-80 PMCID:PMC3505549

[46] Gomperts ED,Lynch SR.Factor VIII and factor-VIII-related antigen in multiple myelomatosis and related conditions.Br J Haematol1976;32:249-55

[47] Crowley MP,O’Shea SI.Plasma thrombin generation and sensitivity to activated protein C among patients with myeloma and monoclonal gammopathy of undetermined significance.Clin Appl Thromb Hemost2016;22:554-62

[48] Auwerda JJ,de Maat MP.Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma.Haematologica2007;92:279-80

[49] Patmore S,O'Sullivan JM.Von Willebrand factor and cancer; metastasis and coagulopathies.J Thromb Haemost2020;18:2444-56

[50] Dahlbäck B.The discovery of activated protein C resistance.J Thromb Haemost2003;1:3-9

[51] Jiménez-Zepeda VH.Acquired activated protein C resistance and thrombosis in multiple myeloma patients.Thromb J2006;4:11 PMCID:PMC1564129

[52] De Lucia D,Orditura M.Hypercoagulable state in patients with advanced gastrointestinal cancer: evidence for an acquired resistance to activated protein C.Tumori1997;83:948-52

[53] Elice F,Tricot G,Zangari M.Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.Br J Haematol2006;134:399-405

[54] Dri AP,Gialeraki A,Kanellias N.Decreased incidence of EPCR 4678G/C SNP in multiple myeloma patients with thrombosis.Thromb Res2013;132:400-1

[55] Kistler KD,Sahni G.Incidence and risk of cardiac events in patients with previously treated multiple myeloma versus matched patients without multiple myeloma: an observational, retrospective, cohort study.Clin Lymphoma Myeloma Leuk2017;17:89-96.e3

[56] Kerachian MA,Harvey EJ.Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion.J Steroid Biochem Mol Biol2009;116:127-33

[57] Bird JM,D’Sa S.Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma ForumGuidelines for the diagnosis and management of multiple myeloma 2011.Br J Haematol2011;154:32-75

[58] Li W,Cornell RF.Cardiovascular and thrombotic complications of novel multiple myeloma therapies: a review.JAMA Oncol2017;3:980-8

[59] Kaushal V,Melkaveri SN.Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology.J Thromb Haemost2004;2:327-34

[60] Martinez-Sanchez J,Torramade-Moix S.The induction strategies administered in the treatment of multiple myeloma exhibit a deleterious effect on the endothelium.Bone Marrow Transplant2020;55:2270-8

[61] Eby C.Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias.Br J Haematol2009;145:151-63

[62] Chapin JC.Fibrinolysis and the control of blood coagulation NIH Public Access.Blood Rev2015;29:17-24

[63] Wolberg AS.Thrombin generation and fibrin clot structure.Blood Rev2007;21:131-42

[64] Carr ME Jr.Abnormal clot retraction, altered fibrin structure, and normal platelet function in multiple myeloma.Am J Physiol1994;266:H1195-201

[65] Carr ME,Carr SL.Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma.J Lab Clin Med1996;128:83-8

[66] Undas A,Helbig G.Altered plasma fibrin clot properties and fibrinolysis in patients with multiple myeloma.Eur J Clin Invest2014;44:557-66

[67] Wolberg AS,Roberts HR.Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk.Blood2003;101:3008-13

[68] Undas A.Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases.Arterioscler Thromb Vasc Biol2011;31:e88-99

[69] López-Pedrera C,Dorado G,Velasco F.Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies.Leukemia2006;20:1331-40

[70] Hanna DL,Wun T.Biomolecular markers of cancer-associated thromboembolism.Crit Rev Oncol Hematol2013;88:19-29 PMCID:PMC3742654

[71] Papageorgiou L,Thouroude S.Modelization of blood-borne hypercoagulability in myeloma: a tissue-factor-bearing microparticle-driven process.TH Open2019;3:e340-7 PMCID:PMC6828570

[72] Auwerda JJ,Osanto S.Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma.Thromb Haemost2011;105:14-20

[73] Nielsen T,Gregersen H,Christiansen G.Extracellular vesicle-associated procoagulant phospholipid and tissue factor activity in multiple myeloma.PLoS One2019;14:e0210835 PMCID:PMC6331130