Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations

Summary

Deep vein thrombosis and its lethal complication pulmonary embolism are manifestations of venous thromboembolism (VTE), which is typically associated with cancer and recent major surgery. Certain solid tumors and hematologic malignancies impose an inherently elevated risk of VTE that is compounded by chemotherapy and other risk factors. Multiple myeloma (MM) and other plasma cell dyscrasias are thrombogenic as a consequence of their multiple hemostatic effects, including elevated interleukin-6 levels, pro-coagulant antibody formation, paraprotein interference with fibrin structure, activated protein C re sistance, and endothelial damage. The oral immunomodulatory drugs thalidomide and lenalidomide have produced major therapeutic responses in patients with MM when used in combination with oral steroids and chemotherapy, but a high incidence of VTE has been reported. Various VTE prophylaxis strategies with thalidomide- and lenalidomide-containing combinations have been investigated in clinical studies. This review discusses emerging results on the use of VTE prophylaxis to minimize VTE risks associated with MM treatment regimens containing thalidomide and lenalidomide.

Key words

Multiple myeloma - thrombosis - anticoagulants - thalidomide - lenalidomide

• References

• 1 Khorana AA. Malignancy, thrombosis and Trousseau: the case for an eponym. J Thromb Haemost 2003; 01: 2463-5.
• 2 Browse NL, Thomas ML. Source of non-lethal pulmonary emboli. Lancet 1974; 01: 258-9.
• 3 Heit JA, Silverstein MD, Mohr DN. et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999; 159: 445-53.
• 4 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-93.
• 5 Heit JA, Silverstein MD, Mohr DN. et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-15.
• 6 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 7 Koster T, Rosendaal FR, de Ronde H. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
• 8 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.
• 9 Blom JW, Doggen CJ, Osanto S. et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715-22.
• 10 Haim N, Lanir N, Hoffman R. et al. Acquired activated proteinC resistance is common in cancer patients and is associated with venous thromboembolism. Am J Med 2001; 110: 91-6.
• 11 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 12 Baron JA, Gridley G, Weiderpass E. et al. Venous thromboembolism and cancer. Lancet 1998; 351: 1077-80.
• 13 Sørensen HT, Mellemkjaer L, Steffensen FH. et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 338: 1169-73.
• 14 Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in different cancers. Thromb Haemost 2002; 87: 1076-7.
• 15 Levitan N, Dowlati A, Remick SC. et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy; risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78: 285-91.
• 16 Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107 Suppl: (Suppl. 01) I17-I21.
• 17 Linenberger ML, Wittkowsky AK. Thromboembolic complications of malignancy. Part 1: Risks. Oncology 2005; 19: 853-61.
• 18 Weitz IC, Israel VK, Waisman JR. et al. Chemotherapy-induced activation of hemostasis: effect of a low molecular weight heparin (dalteparin sodium) on plasma markers of hemostatic activation. Thromb Haemost 2002; 88: 213-20.
• 19 Behrendt CE, Ruiz RB. Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy. Thromb Haemost 2003; 90: 734-7.
• 20 Otten HMMB, Mathijssen J, ten Cate H. et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Intern Med 2004; 164: 190-4.
• 21 Caine GJ, Lip GY. Thromboembolism associated with new anti-cancer treatment strategies in combination with conventional chemotherapy: new drugs, old risks?. Thromb Haemost 2003; 90: 567-9.
• 22 International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders:a report of the International Myeloma Working Group. Br J Haematol 2003; 121: 749-57.
• 23 Sallah S, Husain A, Wan J. et al. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance. Ann Oncol 2004; 15: 1490-4.
• 24 Srkalovic G, Cameron MG, Rybicki L. et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer 2004; 101: 558-66.
• 25 Zangari M, Saghafifar F, Mehta P. et al. The blood coagulation mechanism in multiple myeloma. Semin Thromb Hemost 2003; 29: 275-82.
• 26 Gabriel DA, Smith LA, Folds JD. et al. The influence of immunoglobulin (IgG) on the assembly of fibrin gels. J Lab Clin Med 1983; 101: 545-52.
• 27 Lackner H, Hunt V, Zucker MB. et al. Abnormal fibrin ultrastructure, polymerization, and clot retraction in multiple myeloma. Br J Haematol 1970; 18: 625-36.
• 28 Coleman M, Vigliano EM, Weksler ME. et al. Inhibition of fibrin monomer polymerization by lambda myeloma globulins. Blood 1972; 39: 210-23.
• 29 Carr Jr. ME, Dent RM, Carr SL. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma. J Lab Clin Med 1996; 128: 83-8.
• 30 Kyle RA, Therneau TM, Rajkumar SV. et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564-9.
• 31 Zangari M, Saghafifar F, Anaissie E. et al. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications. Blood Coagul Fibrinolysis 2002; 13: 187-92.
• 32 Deitcher SR, Choueiri T, Srkalovic G. et al. Acquired activated protein C resistance in myeloma patients with venous thromboembolic events. Br J Haematol 2003; 123: 959.
• 33 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94: 362-5.
• 34 Camba L, Peccatori J, Pescarollo A. et al. Thalidomide and thrombosis in patients with multiple myeloma. Haematologica 2001; 86: 1108-9.
• 35 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; 01: 445-9.
• 36 Urbauer E, Kaufmann H, Nösslinger T. et al. Thromboembolic events during treatment with thalidomide. Blood 2002; 99: 4247-8.
• 37 Cavo M, Zamagni E, Cellini C. et al. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy [letter]. Blood 2002; 100: 2272-3.
• 38 Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma [letter]. N Engl J Med 2001; 344: 1951-2.
• 39 Zangari M, Anaissie E, Barlogie B. et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98: 1614-5.
• 40 Barlogie B, Desikan R, Eddlemon P. et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98: 492-4.
• 41 Lee C-K, Barlogie B, Munshi N. et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol 2003; 21: 2732-9.
• 42 Weber D, Rankin K, Gavino M. et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21: 16-9.
• 43 Anagnostopoulos A, Weber D, Rankin K. et al. Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 2003; 121: 768-71.
• 44 Rajkumar SV, Hayman S, Gertz MA. et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 4319-23.
• 45 Rajkumar SV, Gertz MA, Lacy MQ. et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia 2003; 17: 775-9.
• 46 Facon T, Mary JY, Hulin C. et al. Major superiority of melphalan - prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma [abstract 780]. Blood 2005; 106: 230a.
• 47 Rajkumar SV, Blood E, Vesole D. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431-6.
• 48 Zangari M, Siegel E, Barlogie B. et al. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002; 100: 1168-71.
• 49 Rajkumar SV, Blood E, Vesole DH. et al. Thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma (E1A00): results of a phase III trial coordinated by the Eastern Cooperative Oncology Group [abstract 205]. Blood 2004; 104: 63a.
• 50 Zangari M, Barlogie B, Thertulien R. et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 2003; 04: 32-5.
• 51 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: 1568-74.
• 52 Dimopoulos MA, Hamilos G, Zomas A. et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J 2004; 05: 112-7.
• 53 Dimopoulos MA, Repoussis P, Terpos E. et al. Primary treatment with pulsed melphalan, dexamethasone, thalidomide (MDT) for symptomatic patients with multiple myeloma ≥75 years of age [abstract 1482]. Blood 2004; 104: 414a.
• 54 Williams CD, Byrne JL, Sidra G. et al. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone achieves a high response rate in patients with newly diagnosed, VAD-refractory and relapsed myeloma [abstract 1499]. Blood 2004; 104: 419a.
• 55 Richardson PG, Schlossman RL, Weller E. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100: 3063-7.
• 56 Zangari M, Tricot G, Zeldis J. et al. Results of phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT) [abstract 3226]. Blood 2001; 98: 775a.
• 57 Rajkumar SV, Hayman SR, Lacy MQ. et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood 2005; 106: 4050-3.
• 58 Dimopoulos MA, Spencer A, Attal M. et al. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010) [abstract 6]. Blood 2005; 106: 6a-7a.
• 59 Schey SA, Fields P, Bartlett JB. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 22: 3269-76.
• 60 Streetly M, Hunt BJ, Parmar K. et al. Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid™ (CC-4047) and their relationship with venous thrombosis. Eur J Haematol 2005; 74: 293-6.
• 61 Zangari M, Barlogie B, Lee CK. et al. Protective effect of VELCADE(R) on thalidomide-associated deep vein thrombosis (DVT) [abstract 4914]. Blood 2004; 104: 4914.
• 62 Baz R, Marchant K, Yiannaki EO. et al. Aspirin decreases the thrombotic complications (DVT) of liposomal doxorubicin, vincristine, decreased frequency dexamethasone and thalidomide (DVd-T) treatment of multiple myeloma (MM) [abstract 2397]. Blood 2004; 104.
• 63 Chanan-Khan AA, Miller KC, McCarthy P. et al. VAD-t (vincristine, adriamycin, dexamethasone and low-dose thalidomide) is an effective initial therapy with high response rates for patients with treatment naive multiple myeloma (MM) [abstract 3463]. Blood 2004; 104: 3463.
• 64 Hassoun H, Reich L, Klimek VM. et al. Doxorubicin and dexamathasone followed by thalidomide and dexamethasone (AD-TD) as initial therapy for symptomatic patients with multiple myeloma [abstract 2409]. Blood 2004; 104: 662a.
• 65 Hussein MA, Karam MA, Brand C. et al. Doxil (D), vincristine (V), reduced frequency dexamethasone (d) and Revlimid (R) (DVd-R) a phase I/II trial in advanced relapsed/refractory multiple myeloma (Rmm) patients [abstract 208]. Blood 2004; 104: 208.
• 66 Minnema MC, Breitkreutz I, Auwerda JJA. et al. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy [letter]. Leukemia 2004; 18: 2044-6.
• 67 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: 715-21.
• 68 Palumbo A, Bringhen S, Caravita T. et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 825-31.
• 69 Baz R, Choueiri TK, Jawde RA. et al. Reduced frequency dexamethasone (d) and Revlimid(R) (DVd-R) results in a high response rate in patients with refractory multiple myeloma (RMM) [abstract 2559]. Blood 2005; 106: 719a.
• 70 Palumbo A, Falco P, Musto P. et al. Oral Revlimid® plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma [abstract 785]. Blood 2005; 106: 231a-2a.
• 71 Zonder JA, Durie BGM, McCoy J. et al. High incidence of thrombotic events observed in patients receiving lenalidomide (L) + dexamethasone (D) (LD) as first-line therapy for multiple myeloma (MM) without aspirin (ASA) prophylaxis [abstract 3455]. Blood 2005; 106: 954a.
• 72 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: 826-31.
• 73 Geerts WH, Pineo GF, Heit JA. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl): 38S-400S.
• 74 Patrono C, Garcia LARodriguez, Landolfi R. et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-83.
• 75 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000 355. 1295-302.
• 76 Barlogie B, Jagannath S, Desikan KR. et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93: 55-65.
• 77 Niesvizky R, Martinez-Banos DM, Gelbshtein U. et al. Prophylactic low-dose aspirin is effective as antithrombotic therapy in patients receiving combination thalidomide or lenalidomide. [abstract 3454]. Blood 2005; 106: 964a.