Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues
- Jeffrey Zonder, MD
Jeffrey Zonder, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
- Charles A Schiffer, MD
Charles A Schiffer, MD
- Professor of Medicine and Oncology
- Barbara Ann Karmanos Cancer Institute
- Wayne State University School of Medicine
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Robert A Kyle, MD
Robert A Kyle, MD
- Section Editor — Plasma Cell Disorders
- Professor of Medicine
- Mayo Medical School
The association between cancer and venous thromboembolic events (VTE) has been well documented. There are several possible mechanisms involved, including acquired abnormalities involving clotting factors and the coagulation cascade, extrinsic vessel compression by tumor masses, immobility, surgery, the presence of indwelling central venous catheters, as well as the simultaneous presence of an inherited hypercoagulable state (eg, factor V Leiden). (See "Risk and prevention of venous thromboembolism in adults with cancer" and "Pathogenesis of the hypercoagulable state associated with malignancy".)
Patients with multiple myeloma (MM) or the precursor lesion monoclonal gammopathy of undetermined significance (MGUS) have an increased incidence of venous thromboembolism (VTE). In addition, a few studies have suggested an increased risk of arterial thromboembolism (ATE) in these populations as manifested by stroke, transient ischemic attack, myocardial infarction, or symptomatic peripheral artery disease. The increased rate of VTE appears to be both a result of the malignancy itself and the therapy given. In particular, the rate of VTE is particularly high for patients with MM treated with combination chemotherapy that contains thalidomide or a thalidomide analog such as lenalidomide.
The thrombotic risk associated with the use of thalidomide and its analogues as treatment for MM will be discussed here. Thrombotic risk following the use of other antineoplastic agents (eg, tamoxifen, L-asparaginase) and issues related to the treatment of VTE are presented separately. (See "Drug-induced thrombosis in patients with malignancy", section on 'L-asparaginase' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Drug-induced thrombosis in patients with malignancy", section on 'Tamoxifen'.)
Patients with multiple myeloma are at increased risk of having comorbidities known to be risk factors for the development of venous thromboembolism (VTE) in the general population. In addition, treatment with thalidomide and its analogs has been associated with high rates of VTE. Thalidomide has a wide spectrum of biological effects, including immune modulation, alteration of adhesion molecule and cytokine expression, and inhibition of angiogenesis . (See 'General risk factors' below and "Overview of angiogenesis inhibitors", section on 'Immunomodulatory drugs (IMiDs)'.)
While the exact mechanism by which thalidomide contributes to thrombosis is not known, the following mechanisms have been postulated:
- Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003; 21:4444.
- 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.
- Kaushal V, Kaushal GP, Melkaveri SN, Mehta P. Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology. J Thromb Haemost 2004; 2:327.
- 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.
- 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.
- Deitcher SR, Choueiri T, Srkalovic G, Hussein MA. Acquired activated protein C resistance in myeloma patients with venous thromboembolic events. Br J Haematol 2003; 123:959.
- Minnema MC, Fijnheer R, De Groot PG, Lokhorst HM. 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.
- Johnson DC, Corthals S, Ramos C, et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping. Blood 2008; 112:4924.
- Tewari P, Kenny E, Staines A, et al. Genetic variants in XRRC5 may predict development of venous thrombotic events in myeloma patients on thalidomide. Blood 2009; 113:5691.
- Cini M, Zamagni E, Valdré L, et al. Thalidomide-dexamethasone as up-front therapy for patients with newly diagnosed multiple myeloma: thrombophilic alterations, thrombotic complications, and thromboprophylaxis with low-dose warfarin. Eur J Haematol 2010; 84:484.
- Pal R, Monaghan SA, Hassett AC, et al. Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood 2010; 115:605.
- Carrier M, Le Gal G, Tay J, et al. Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. J Thromb Haemost 2011; 9:653.
- Scarpace SL, Hahn T, Roy H, et al. Arterial thrombosis in four patients treated with thalidomide. Leuk Lymphoma 2005; 46:239.
- Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22:414.
- Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565.
- Mileshkin L, Biagi JJ, Mitchell P, et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood 2003; 102:69.
- Weber D, Rankin K, Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21:16.
- 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.
- 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.
- Glasmacher A, Hahn C, Hoffmann F, 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.
- Prince HM, Schenkel B, Mileshkin L. An analysis of clinical trials assessing the efficacy and safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma 2007; 48:46.
- Ikhlaque N, Seshadri V, Kathula S, Baumann MA. Efficacy of prophylactic warfarin for prevention of thalidomide-related deep venous thrombosis. Am J Hematol 2006; 81:420.
- Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc 2005; 80:1549.
- Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 2007; 82:323.
- Anagnostopoulos A, Weber D, Rankin K, et al. Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 2003; 121:768.
- Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20:4319.
- 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.
- 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.
- Facon T, Mary JY, Hulin C, et al. Randomized clinical trial comparing melphalan-prednisone (MP), MP-thalidomide (MP-thal), and high-dose therapy using melpalan 100 mg/m(2) (MEL100) for newly-diagnosed myeloma patients aged 65-75 years. Interim analysis of the IFM 99-06 trial (abstract). Blood 2004; 104:63a.
- Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009; 27:3664.
- 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.
- 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). Blood 2004; 104:419a.
- Schütt P, Ebeling P, Buttkereit U, et al. Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. Eur J Haematol 2005; 74:40.
- Zervas K, Dimopoulos MA, Hatzicharissi E, et al. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): a phase II multicenter study. Ann Oncol 2004; 15:134.
- 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.
- Zangari M, Siegel E, Barlogie B, et al. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002; 100:1168.
- 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.
- Hussein MA, Baz R, Srkalovic G, et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc 2006; 81:889.
- Offidani M, Corvatta L, Piersantelli MN, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood 2006; 108:2159.
- Chen C, Reece DE, Siegel D, et al. Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol 2009; 146:164.
- 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.
- Barlogie B. Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience. Semin Hematol 2003; 40:33.
- List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352:549.
- Yang X, Brandenburg NA, Freeman J, et al. Venous thromboembolism in myelodysplastic syndrome patients receiving lenalidomide: results from postmarketing surveillance and data mining techniques. Clin Drug Investig 2009; 29:161.
- Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357:2123.
- Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357:2133.
- Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354:2079.
- Zonder JA, Crowley J, Hussein MA, et al. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood 2010; 116:5838.
- Rajkumar SV, Jacobus S, Callender N, et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group (abstract). J Clin Oncol 2007; 25:968s.
- Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116:679.
- 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.
- Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 2009; 27:5008.
- Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013; 121:1961.
- Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood 2013; 121:1968.
- Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Results and Age Subgroup Analysis (abstract 450). Blood 2012; 120.
- Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31:2189.
- Menon SP, Rajkumar SV, Lacy M, et al. Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 2008; 112:1522.
- Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011; 29:986.
- Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119:933.
- Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354:1021.
- 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.
- Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol 2009; 88:67.
- Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11:29.
- Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106:4050.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S.
- POTENTIAL MECHANISMS
- INCIDENCE AND RISK FACTORS
- General risk factors
- Thalidomide-based therapy
- - Single agent thalidomide
- - Thalidomide plus dexamethasone
- - Thalidomide plus melphalan and prednisone
- - Thalidomide plus anthracycline
- Thalidomide analogues
- - Lenalidomide
- - Pomalidomide
- VENOUS THROMBOEMBOLISM PROPHYLAXIS
- Choice of agent
- - Risk stratification
- - Lower risk setting
- - Standard risk setting
- - High risk setting
- Low molecular weight heparin
- - Patients at high risk of bleeding
- Length of prophylaxis
- DIAGNOSIS AND MANAGEMENT OF VENOUS THROMBOEMBOLISM
- SUMMARY AND RECOMMENDATIONS