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DOI: 10.1160/TH08-01-0009
Pathophysiological considerations to thrombophilia in the treatment of multiple myeloma with thalidomide and derivates
Financial support: This study was supported by the Deutsche Forschungsgemeinschaft (DFG).Publication History
Received
07 January 2008
Accepted after minor revision
20 April 2008
Publication Date:
27 November 2017 (online)
Summary
Lenalidomide, a derivate of thalidomide, has recently been approved in Europe for the treatment of patients with multiple myeloma. Although the substance has a better effect/side-effect profile, especially with regard to teratogenicity and neurotoxicity, the rate of therapy-induced thrombosis seems comparable to thalidomide. The observed thromboembolic events were accompanied with a high rate of deleterious pulmonary embolism. Interestingly, the substances alone are not thrombogenic but combination with anthracyclines, dexamethasone or erythropesis-stimulating factors increases the risk considerably. As up to one third of patients treated with such combinations are affected, antithrombotic co-medication is highly recommended. This review elucidates the complex interactions between an activated coagulation-system in myeloma patients and the molecular effects of these drugs. This perception is important to choose the proper prophylactic co-medication without increasing the risk of bleeding, especially in first-line treatment, patients with high paraprotein-levels, or thrombopenia, either therapy-induced or due to bone-marrow infiltration.
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References
- 1 D'Amato RJ, Loughnan MS, Flynn E. et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 4082-4085.
- 2 Bellamy WT, Richter L, Frutiger Y. et al. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999; 59: 728-733.
- 3 Singhal S, Mehta J, Desikan R. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565-1571.
- 4 Moehler TM, Neben K, Ho AD. et al. Angiogenesis in hematologic malignancies. Ann Hematol 2001; 80: 695-705.
- 5 Neben K, Moehler T, Kraemer A. et al. Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion. Br J Haematol 2001; 115: 605-608.
- 6 Marriott JB, Clarke IA, Dredge K. et al. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol 2002; 130: 75-84.
- 7 Teo SK. Properties of thalidomide and its analogues: implications for anticancer therapy. Aaps J 2005; 7: E14-19.
- 8 Lentzsch S, Chatterjee M, Gries M. et al. PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia 2004; 18: 1883-1890.
- 9 Verhelle D, Corral LG, Wong K. et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67: 746-755.
- 10 Hideshima T, Chauhan D, Shima Y. et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943-2950.
- 11 Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354: 2079-2080.
- 12 Richardson P. Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. Semin Hematol 2005; 42 (Suppl. 04) S9-15.
- 13 Hussein MA. Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Thromb Haemost 2006; 95: 924-930.
- 14 Hussein MA. Lenalidomide: patient management strategies. Semin Hematol 2005; 42 (Suppl. 04) S22-25.
- 15 Barlogie B, Tricot G, Anaissie E. Thalidomide in the management of multiple myeloma. Semin Oncol 2001; 28: 577-582.
- 16 Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M. et al. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol 2006; 132: 584-593.
- 17 Kumar A, Loughran T, Alsina M. et al. Management of multiple myeloma: a systematic review and critical appraisal of published studies. Lancet Oncol 2003; 4: 293-304.
- 18 Kumar S, Gertz MA, Dispenzieri A. et al. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 2003; 78: 34-39.
- 19 Tosi P, Cavo M. Thalidomide in multiple myeloma: state of art. Haematologica 2002; 87: 233-234.
- 20 Minnema MC, Breitkreutz I, Auwerda JJ. et al. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy. Leukemia 2004; 18: 2044-2046.
- 21 Zangari M, Barlogie B, Anaissie E. et al. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation. Br J Haematol 2004; 126: 715-721.
- 22 Potenza L, Luppi M, Morselli M. et al. Thrombotic complications associated with thalidomide in multiple myeloma: an old problem with new questions and quandaries in decision-making. Thromb Haemost 2004; 91: 834-836.
- 23 El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and thrombosis. A meta-analysis. Thromb Haemost 2007; 97: 1031-1036.
- 24 Cavo M, Zamagni E, Cellini C. et al. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood 2002; 100: 2272-2273.
- 25 Rajkumar SV. Thalidomide in newly diagnosed multiple myeloma and overview of experience in smoldering/ indolent disease. Semin Hematol 2003; 40 (Suppl. 04) 17-22.
- 26 Rajkumar SV, Gertz MA, Lacy MQ. et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia 2003; 17: 775-779.
- 27 Steurer M, Sudmeier I, Stauder R. et al. Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. Br J Haematol 2003; 121: 101-103.
- 28 Rus C, Bazzan M, Palumbo A. et al. Thalidomide in front line treatment in multiple myeloma: serious risk of venous thromboembolism and evidence for thromboprophylaxis. J Thromb Haemost 2004; 2: 2063-2065.
- 29 Jimenez-Zepeda VH, Dominguez-Martinez VJ. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thromb J 2006; 4: 11.
- 30 Elice F, Fink L, Tricot G. et al. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Br J Haematol 2006; 134: 399-405.
- 31 Bataille R, Boccadoro M, Klein B. et al. C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system. Blood 1992; 80: 733-737.
- 32 Kyriakou D, Papadaki H, Eliopoulos AG. et al. Serum soluble IL-6 receptor concentrations correlate with stages of multiple myeloma defined by serum beta 2-microglobulin and C-reactive protein. Int J Hematol 1997; 66: 367-371.
- 33 Solary E, Guiguet M, Zeller V. et al. Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma. Am J Hematol 1992; 39: 163-171.
- 34 Hugo JZ, Jeanet DM. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thromb J 2006; 4: 11.
- 35 Mitchell CA, Rowell JA, Hau L. et al. A fatal thrombotic disorder associated with an acquired inhibitor of protein C. N Engl J Med 1987; 317: 1638-1642.
- 36 Zivelin A, Gitel S, Griffin JH. et al. Extensive venous and arterial thrombosis associated with an inhibitor to activated protein C. Blood 1999; 94: 895-901.
- 37 Arnout J, Hoylaerts MF, Lijnen HR. Haemostasis. Handb Exp Pharmacol 2006; 1-41.
- 38 Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev 1994; 8: 37-55.
- 39 Corso A, Lorenzi A, Terulla V. et al. Modification of thrombomodulin plasma levels in refractory myeloma patients during treatment with thalidomide and dexamethasone. Ann Hematol 2004; 83: 588-591.
- 40 Xie WZ, Leibl M, Clark MR. et al. Activation of the coagulation system in cancerogenesis and metastasation. Biomed Pharmacother 2005; 59: 70-75.
- 41 Wienhard J, Bielska B, Munstedt K. et al. Increased endothelial thrombomodulin (TM) expression in pregnancies complicated by IUGR. J Perinat Med 2002; 30: 322-328.
- 42 Esmon CT. The protein C pathway. Chest 2003; 124 (Suppl. 03) 26S-32S.
- 43 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746.
- 44 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost 1991; 65: 618-623.
- 45 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3: 1800-1814.
- 46 Hirano K, Kanaide H. Role of protease-activated receptors in the vascular system. J Atheroscler Thromb 2003; 10: 211-225.
- 47 Mackman N. The role of the tissue factor-thrombin pathway in cardiac ischemia-reperfusion injury. Semin Vasc Med 2003; 3: 193-198.
- 48 Ramachandran R, Klufas AS, Molino M. et al. Release of the thrombin receptor (PAR-1) N-terminus from the surface of human platelets activated by thrombin. Thromb Haemost 1997; 78: 1119-1124.
- 49 Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA 1999; 96: 11023-11027.
- 50 Nguyen QD, De Wever O, Bruyneel E. et al. Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. Oncogene 2005; 24: 8240-8251.
- 51 Schiller H, Bartscht T, Arlt A. et al. Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin- induced cell death in vitro. Int J Clin Pharmacol Ther 2002; 40: 329-335.
- 52 Gieseler F, Luhr I, Kunze T. et al. Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy. Thromb Haemost 2007; 97: 1023-1030.
- 53 Coughlin SR. Protease-activated receptors in vascular biology. Thromb Haemost 2001; 86: 298-307.
- 54 Kaushal V, Kaushal GP, Melkaveri SN. et al. Thalidomide protects endothelial cells from doxorubicininduced apoptosis but alters cell morphology. J Thromb Haemost 2004; 2: 327-334.
- 55 Minnema MC, Fijnheer R, De Groot PG. et al. 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 Haemost 2003; 1: 445-449.
- 56 Parker RI, Gralnick HR. Effect of aspirin on platelet-von Willebrand factor surface expression on thrombin and ADP-stimulated platelets. Blood 1989; 74: 2016-2021.
- 57 Cleator JH, Zhu WQ, Vaughan DE. et al. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood 2006; 107: 2736-2744.
- 58 Klarenbach SW, Chipiuk A, Nelson RC. et al. Differential actions of PAR2 and PAR1 in stimulating human endothelial cell exocytosis and permeability: the role of Rho-GTPases. Circ Res 2003; 92: 272-278.
- 59 Schmugge M, Rand ML, Freedman J. Platelets and von Willebrand factor. Transfus Apher Sci 2003; 28: 269-277.
- 60 Mendolicchio GL, Ruggeri ZM. New perspectives on von Willebrand factor functions in hemostasis and thrombosis. Semin Hematol 2005; 42: 5-14.
- 61 Montalescot G, Collet JP, Lison L. et al. Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina. J Am Coll Cardiol 2000; 36: 110-114.
- 62 Kes P, Pecanic Z, Getaldic B. et al. Treatment of hyperviscosity syndrome in the patients with plasma cell dyscrasias. Acta Med Croatica 1996; 50: 173-177.
- 63 Frank RD, Kunz D, Wirtz DC. Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion. Am J Hematol 2002; 70: 64-71.
- 64 Jakway JL. Acquired von Willebrand's disease. Hematol Oncol Clin North Am 1992; 6: 1409-1419.
- 65 Mohri H, Noguchi T, Kodama F. et al. Acquired von Willebrand disease due to inhibitor of human myeloma protein specific for von Willebrand factor. Am J Clin Pathol 1987; 87: 663-668.
- 66 Bovill EG, Ershler WB, Golden EA. et al. A human myeloma-produced monoclonal protein directed against the active subpopulation of von Willebrand factor. Am J Clin Pathol 1986; 85: 115-123.
- 67 Coleman M, Vigliano EM, Weksler ME. et al. Inhibition of fibrin monomer polymerization by lambda myeloma globulins. Blood 1972; 39: 210-223.
- 68 Kasturi J, Saraya AK. Platelet functions in dysproteinaemia. Acta Haematol 1978; 59: 104-113.
- 69 Shinagawa A, Kojima H, Berndt MC. et al. Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor. Thromb Haemost 2005; 93: 889-896.
- 70 Hassan AA, Kroll MH. Acquired disorders of platelet function. Hematology Am Soc Hematol Educ Program 2005; 403-408.
- 71 DiMinno G, Coraggio F, Cerbone AM. et al. A myeloma paraprotein with specificity for platelet glycoprotein IIIa in a patient with a fatal bleeding disorder. J Clin Invest 1986; 77: 157-164.
- 72 Kast RE. Aspirin use in myeloma: a note of caution regarding potential tumour necrosis factor-alpha elevation. Br J Haematol 2006; 133: 216.
- 73 Palumbo A, Rus C, Zeldis JB. et al. Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide. J Thromb Haemost 2006; 4: 1842-1845.
- 74 Zonder JA, Barlogie B, Durie BG. et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood 2006; 108: 403 author reply 404.
- 75 Hassoun H, Reich L, Klimek VM. et al. Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma. Br J Haematol 2006; 132: 155-161.
- 76 Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc 2005; 80: 1549-1551.
- 77 Baz R, Li L, Kottke-Marchant K. et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80: 1568-1574.
- 78 Cavo M, Zamagni E, Tosi P. et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89: 826-831.
- 79 Baz R, Hussein MA. Does low-dose aspirin have antineoplastic effects in multiple myeloma?. Br J Haematol 2006; 134: 349-350.
- 80 Zonder JA. Thrombotic complications of myeloma therapy. Hematology Am Soc Hematol Educ Program 2006; 348-355.
- 81 Zangari M. Anticoagulation regimens for thalidomide and lenalidomide. Clin Adv Hematol Oncol 2006; 4: 658-659.
- 82 Zangari M, Elice F, Fink L. et al. Thrombosis in multiple myeloma. Expert Rev Anticancer Ther 2007; 7: 307-315.
- 83 Lyman GH, Khorana AA, Falanga A. et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5505.
- 84 Kakkar AK. Low-molecular-weight heparin and survival in patients with malignant disease. Cancer Control 2005; 12 (Suppl. 01) 22-30.