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Semin Thromb Hemost 2011; 37(3): 209-219
DOI: 10.1055/s-0031-1273085
© Thieme Medical Publishers

Multiple Myeloma, Venous Thromboembolism, and Treatment-Related Risk of Thrombosis

Elena Zamagni1 , Annamaria Brioli1 , Paola Tacchetti1 , Beatrice Zannetti1 , Lucia Pantani1 , Michele Cavo1
  • 1“Istituto di Ematologia “Seràgnoli,” Università degli Studi di Bologna, Bologna, Italy
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Publication History

Publication Date:
31 March 2011 (online)

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ABSTRACT

Venous thromboembolism (VTE) is a disease with a high prevalence in elderly people, affecting > 5% of the population > 65 years of age. Cancer patients have a 4.3-fold higher incidence of thrombotic complications, due to multiple risk factors that are not always related to the disease. Among hematologic malignancies, multiple myeloma (MM) confers a high risk of developing such complications, with a VTE rate of nearly 10%. Multiple factors are involved in MM-related VTE, such as increased blood viscosity, high levels of immunoglobulin, procoagulant activity of monoclonal protein, and inflammatory cytokines. Since the introduction of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide in the therapeutic armamentarium of MM, VTE has emerged as one of the leading complications, in particular in patients with newly diagnosed MM. In this setting, IMiDs-based treatments are associated with rates of VTE reaching values up to 14 to 26%, particularly when dexamethasone or chemotherapy are added. The optimal prophylaxis for patients receiving these antiangiogenetic agents is still a matter of debate. Due to the lack of prospective randomized clinical trials, different studies have used various anticoagulant prophylaxes, including fixed low-dose warfarin (1 mg or 1.25 mg), therapeutic doses of warfarin (international normalized ratio between 2.0 and 3.0), low molecular weight heparin, or low-dose aspirin. As yet, no study has clearly demonstrated a significant superiority of one prophylactic regimen in comparison with the others. Further investigation and more randomized clinical trials are needed to define the best thromboprophylaxis.

KEYWORDS

Multiple myeloma (MM) - deep vein thrombosis (DVT) - thalidomide - lenalidomide - venous thromboembolism (VTE)

REFERENCES

  • 1 Silverstein M D, Heit J A, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med. 1998;  158 (6) 585-593
    CrossrefPubMedGoogle Scholar
  • 2 Blom J W, Doggen C J, Osanto S, Rosendaal F R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.  JAMA. 2005;  293 (6) 715-722
    CrossrefPubMedGoogle Scholar
  • 3 Caine G J, Stonelake P S, Lip G Y, Kehoe S T. The hypercoagulable state of malignancy: pathogenesis and current debate.  Neoplasia. 2002;  4 (6) 465-473
    CrossrefPubMedGoogle Scholar
  • 4 Heit J A, O'Fallon W M, Petterson T M et al.. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study.  Arch Intern Med. 2002;  162 (11) 1245-1248
    CrossrefPubMedGoogle Scholar
  • 5 Eby C. Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias.  Br J Haematol. 2009;  145 (2) 151-163
    CrossrefPubMedGoogle Scholar
  • 6 Falanga A, Marchetti M. Venous thromboembolism in the hematologic malignancies.  J Clin Oncol. 2009;  27 (29) 4848-4857
    CrossrefPubMedGoogle Scholar
  • 7 Barlogie B, Jagannath S, Desikan K R et al.. Total therapy with tandem transplants for newly diagnosed multiple myeloma.  Blood. 1999;  93 (1) 55-65
    PubMedGoogle Scholar
  • 8 Sallah S, Husain A, Wan J, Vos P, Nguyen N P. The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance.  Ann Oncol. 2004;  15 (10) 1490-1494
    CrossrefPubMedGoogle Scholar
  • 9 Srkalovic G, Cameron M G, Rybicki L, Deitcher S R, Kattke-Marchant K, Hussein M A. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease.  Cancer. 2004;  101 (3) 558-566
    CrossrefPubMedGoogle Scholar
  • 10 Kristinsson S Y, Fears T R, Gridley G et al.. Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.  Blood. 2008;  112 (9) 3582-3586
    CrossrefPubMedGoogle Scholar
  • 11 Kerr R, Stirling D, Ludlam C A. Interleukin 6 and haemostasis.  Br J Haematol. 2001;  115 (1) 3-12
    CrossrefPubMedGoogle Scholar
  • 12 Esmon C T. Does inflammation contribute to thrombotic events?.  Haemostasis. 2000;  30 (Suppl 2) 34-40
    CrossrefPubMedGoogle Scholar
  • 13 Zangari M, Saghafifar F, Mehta P, Barlogie B, Fink L, Tricot G. The blood coagulation mechanism in multiple myeloma.  Semin Thromb Hemost. 2003;  29 (3) 275-282
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Gabriel D A, Smith L A, Folds J D, Davis L, Cancelosi S E. The influence of immunoglobulin (IgG) on the assembly of fibrin gels.  J Lab Clin Med. 1983;  101 (4) 545-552
    PubMedGoogle Scholar
  • 15 Carr Jr M E, Dent R M, Carr S L. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma.  J Lab Clin Med. 1996;  128 (1) 83-88
    CrossrefPubMedGoogle Scholar
  • 16 O'Kane M J, Wisdom G B, Desai Z R, Archbold G P. Inhibition of fibrin monomer polymerisation by myeloma immunoglobulin.  J Clin Pathol. 1994;  47 (3) 266-268
    CrossrefPubMedGoogle Scholar
  • 17 Yasin Z, Quick D, Thiagarajan P, Spoor D, Caraveo J, Palascak J. Light-chain paraproteins with lupus anticoagulant activity.  Am J Hematol. 1999;  62 (2) 99-102
    CrossrefPubMedGoogle Scholar
  • 18 Thiagarajan P, Dannenbring R, Matsuura K, Tramontano A, Gololobov G, Paul S. Monoclonal antibody light chain with prothrombinase activity.  Biochemistry. 2000;  39 (21) 6459-6465
    CrossrefPubMedGoogle Scholar
  • 19 Bokarewa M I, Blombäck M, Egberg N, Rosén S. A new variant of interaction between phospholipid antibodies and the protein C system.  Blood Coagul Fibrinolysis. 1994;  5 (1) 37-41
    CrossrefPubMedGoogle Scholar
  • 20 Zangari M, Elice F, Fink L, Tricot G. Hemostatic dysfunction in paraproteinemias and amyloidosis.  Semin Thromb Hemost. 2007;  33 (4) 339-349
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Minnema M C, Fijnheer R, De Groot P G, Lokhorst H M. 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 (3) 445-449
    CrossrefPubMedGoogle Scholar
  • 22 Auwerda J J, Sonneveld P, de Maat M P, Leebeek F W. Prothrombotic coagulation abnormalities in patients with newly diagnosed multiple myeloma.  Haematologica. 2007;  92 (2) 279-280
    CrossrefPubMedGoogle Scholar
  • 23 Amrani D L. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control.  Blood Coagul Fibrinolysis. 1990;  1 (4–5) 443-446
    CrossrefPubMedGoogle Scholar
  • 24 Elice F, Fink L, Tricot G, Barlogie B, 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 Haematol. 2006;  134 (4) 399-405
    CrossrefPubMedGoogle Scholar
  • 25 van Marion A M, Auwerda J J, Lisman T et al.. Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens.  Leuk Res. 2008;  32 (7) 1078-1084
    CrossrefPubMedGoogle Scholar
  • 26 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 (3) 187-192
    CrossrefPubMedGoogle Scholar
  • 27 Sarig G, Michaeli Y, Lanir N, Brenner B, Haim N. Mechanism for acquired activated protein C resistance in cancer patients.  J Thromb Haemost. 2005;  3 (3) 589-590
    CrossrefPubMedGoogle Scholar
  • 28 Deitcher S R, Choueiri T, Srkalovic G, Hussein M A. Acquired activated protein C resistance in myeloma patients with venous thromboembolic events.  Br J Haematol. 2003;  123 (5) 959
    CrossrefPubMedGoogle Scholar
  • 29 Cavo M, Di Raimondo F, Zamagni E et al.. Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.  J Clin Oncol. 2009;  27 (30) 5001-5007
    CrossrefPubMedGoogle Scholar
  • 30 Cini M, Zamagni E, Valdré L et al.. Thalidomide-dexamethasone as up-front therapy for patients with newly diagnosed multiple myeloma patients: thrombophilic alterations, thrombotic complications, and thromboprophylaxis with low-dose warfarin.  Eur J Haematol. 2010;  84 (6) 484-492
    CrossrefPubMedGoogle Scholar
  • 31 Rajkumar S V, Gertz M A, Lacy M Q et al.. Thalidomide as initial therapy for early-stage myeloma.  Leukemia. 2003;  17 (4) 775-779
    CrossrefPubMedGoogle Scholar
  • 32 Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.  J Clin Oncol. 2003;  21 (1) 16-19
    CrossrefPubMedGoogle Scholar
  • 33 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 (2) 492-494
    CrossrefPubMedGoogle Scholar
  • 34 Neben K, Moehler T, Benner A et al.. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma.  Clin Cancer Res. 2002;  8 (11) 3377-3382
    PubMedGoogle Scholar
  • 35 Schey S A, Cavenagh J, Johnson R, Child J A, Oakervee H, Jones R W. An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment.  Leuk Res. 2003;  27 (10) 909-914
    CrossrefPubMedGoogle Scholar
  • 36 Tosi P, Zamagni E, Cellini C et al.. Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.  Haematologica. 2002;  87 (4) 408-414
    PubMedGoogle Scholar
  • 37 Bennett C L, Schumock G T, Desai A A et al.. Thalidomide-associated deep vein thrombosis and pulmonary embolism.  Am J Med. 2002;  113 (7) 603-606
    CrossrefPubMedGoogle Scholar
  • 38 Attal M, Harousseau J L, Leyvraz S Inter-Groupe Francophone du Myélome (IFM) et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.  Blood. 2006;  108 (10) 3289-3294
    CrossrefPubMedGoogle Scholar
  • 39 Alexanian R, Weber D, Giralt S, Delasalle K. Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.  Ann Oncol. 2002;  13 (7) 1116-1119
    CrossrefPubMedGoogle Scholar
  • 40 Sidra G, Williams C D, Russell N H, Zaman S, Myers B, Byrne J L. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma.  Haematologica. 2006;  91 (6) 862-863
    PubMedGoogle Scholar
  • 41 Dimopoulos M A, Hamilos G, Zomas A et al.. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma.  Hematol J. 2004;  5 (2) 112-117
    CrossrefPubMedGoogle Scholar
  • 42 Rajkumar S V, Hayman S, Gertz M A et al.. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.  J Clin Oncol. 2002;  20 (21) 4319-4323
    CrossrefPubMedGoogle Scholar
  • 43 Rajkumar S V, Blood E, Vesole D, Fonseca R, Greipp P R. Eastern Cooperative Oncology Group . 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 (3) 431-436
    CrossrefPubMedGoogle Scholar
  • 44 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 (6) 2272-2273
    CrossrefPubMedGoogle Scholar
  • 45 Cavo M, Zamagni E, Tosi P Bologna 2002 study et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma.  Blood. 2005;  106 (1) 35-39
    CrossrefPubMedGoogle Scholar
  • 46 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 (5) 1614-1615
    CrossrefPubMedGoogle Scholar
  • 47 Osman K, Comenzo R, Rajkumar S V. Deep venous thrombosis and thalidomide therapy for multiple myeloma.  N Engl J Med. 2001;  344 (25) 1951-1952
    CrossrefPubMedGoogle Scholar
  • 48 Facon T, Mary J Y, Hulin C Intergroupe Francophone du Myélome et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial.  Lancet. 2007;  370 (9594) 1209-1218
    CrossrefPubMedGoogle Scholar
  • 49 Oakevree H, Baugh H, Boots M et al.. A study of the safety and the efficacy of oral melphalan, prednisolone and thalidomide (MPT) in the treatment of multiple myeloma: a UK Myeloma Forum Pilot Study.  Br J Haematol. 2002;  117 (Suppl 1) 66 (Abst)
    PubMedGoogle Scholar
  • 50 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 (12) 1568-1574
    CrossrefPubMedGoogle Scholar
  • 51 Dimopoulos M A, Anagnostopoulos A, Terpos E Greek Myeloma Study Group et al. Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.  Haematologica. 2006;  91 (2) 252-254
    PubMedGoogle Scholar
  • 52 Zangari M, Siegel E, Barlogie B et al.. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.  Blood. 2002;  100 (4) 1168-1171
    CrossrefPubMedGoogle Scholar
  • 53 Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. Thalidomide and dexamethasone for resistant multiple myeloma.  Br J Haematol. 2003;  121 (5) 768-771
    CrossrefPubMedGoogle Scholar
  • 54 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 (14) 2732-2739
    CrossrefPubMedGoogle Scholar
  • 55 Johnson D C, Corthals S, Ramos C et al.. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping.  Blood. 2008;  112 (13) 4924-4934
    CrossrefPubMedGoogle Scholar
  • 56 Pal R, Kennedy R, Mansour L R et al.. Cathepsin G, a potent platelets aggregation activator, is upregulated in multiple myeloma patients during treatment with lenalidomide (Revlimid).  Blood. 2007;  110 738 (Abst)
    PubMedGoogle Scholar
  • 57 Richardson P G, Blood E, Mitsiades C S et al.. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.  Blood. 2006;  108 (10) 3458-3464
    CrossrefPubMedGoogle Scholar
  • 58 Zonder J A, Barlogie B, Durie B G, McCoy J, Crowley J, Hussein M A. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis.  Blood. 2006;  108 (1) 403-404 author reply 404
    CrossrefPubMedGoogle Scholar
  • 59 Dimopoulos M, Spencer A, Attal M Multiple Myeloma (010) Study Investigators et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma.  N Engl J Med. 2007;  357 (21) 2123-2132
    CrossrefPubMedGoogle Scholar
  • 60 Weber D M, Chen C, Niesvizky R Multiple Myeloma (009) Study Investigators et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.  N Engl J Med. 2007;  357 (21) 2133-2142
    CrossrefPubMedGoogle Scholar
  • 61 Zangari M, Tricot G, Polavaram L et al.. Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone.  J Clin Oncol. 2010;  28 (1) 132-135
    CrossrefPubMedGoogle Scholar
  • 62 Rajkumar S V, Jacobus S, Callander N S 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 (1) 29-37
    CrossrefPubMedGoogle Scholar
  • 63 Rajkumar S V, Blood E. Lenalidomide and venous thromboembolism in multiple myeloma.  N Engl J Med. 2006;  354 (19) 2079-2080
    CrossrefPubMedGoogle Scholar
  • 64 Menon S P, Rajkumar S V, Lacy M, Falco P, Palumbo A. Thromboembolic events with lenalidomide-based therapy for multiple myeloma.  Cancer. 2008;  112 (7) 1522-1528
    CrossrefPubMedGoogle Scholar
  • 65 Morgan G J, Schey S A, Wu P et al.. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients.  Br J Haematol. 2007;  137 (3) 268-269
    CrossrefPubMedGoogle Scholar
  • 66 Baz R, Walker E, Karam M A et al.. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy.  Ann Oncol. 2006;  17 (12) 1766-1771
    CrossrefPubMedGoogle Scholar
  • 67 Knop S, Gerecke C, Topp M S et al.. Lenalidomide (RevlimidTM), adriamycin and dexamethasone chemotherapy (RAD) is safe and effective in treatment of relapsed multiple myeloma: first results of a German multicenter phase I/II trial.  Blood. 2006;  108 408 (Abst)
    PubMedGoogle Scholar
  • 68 Knight R, DeLap R J, Zeldis J B. Lenalidomide and venous thrombosis in multiple myeloma.  N Engl J Med. 2006;  354 (19) 2079-2080
    CrossrefPubMedGoogle Scholar
  • 69 Galli M, Elice F, Crippa C, Comotti B, Rodeghiero F, Barbui T. Recombinant human erythropoietin and the risk of thrombosis in patients receiving thalidomide for multiple myeloma.  Haematologica. 2004;  89 (9) 1141-1142
    PubMedGoogle Scholar
  • 70 Schey S A, Fields P, Bartlett J B et al.. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma.  J Clin Oncol. 2004;  22 (16) 3269-3276
    CrossrefPubMedGoogle Scholar
  • 71 Lonial S, Waller E K, Richardson P G SUMMIT/CREST Investigators et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma.  Blood. 2005;  106 (12) 3777-3784
    CrossrefPubMedGoogle Scholar
  • 72 Zangari M, Guerreri J, Cavallo F et al.. Coagulation related effect of bortezomib treatment in patients with relapsed or refractory multiple myeloma.  Blood. 2007;  110 2733 (Abst)
    PubMedGoogle Scholar
  • 73 Avcu F, Ural A U, Cetin T, Nevruz O. Effects of bortezomib on platelet aggregation and ATP release in human platelets, in vitro.  Thromb Res. 2008;  121 (4) 567-571
    CrossrefPubMedGoogle Scholar
  • 74 Parry G C, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells.  Arterioscler Thromb Vasc Biol. 1995;  15 (5) 612-621
    CrossrefPubMedGoogle Scholar
  • 75 Hamaguchi E, Takamura T, Shimizu A, Nagai Y. Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells.  J Pharmacol Exp Ther. 2003;  307 (3) 987-994
    CrossrefPubMedGoogle Scholar
  • 76 Sohn R H, Deming C B, Johns D C et al.. Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B.  Blood. 2005;  105 (10) 3910-3917
    CrossrefPubMedGoogle Scholar
  • 77 Lonial S, Richardson P G, San Miguel J et al.. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma.  Br J Haematol. 2008;  143 (2) 222-229
    CrossrefPubMedGoogle Scholar
  • 78 Jagannath S, Durie B GM, Wolf J L et al.. Long term follow up of patients treated with bortezomib alone and in combination with dexamethasone as frontline therapy for multiple myeloma.  Blood. 2006;  108 238 (Abst)
    PubMedGoogle Scholar
  • 79 Harousseau J L, Avet-Loiseau H, Attal M et al.. High complete and very good partial response rates with bortezomib-dexamethasone as induction prior to ASCT in newly diagnosed patients with high-risk myeloma: results of the IFM2005–01 phase 3 trial.  Blood. 2009;  114 353 (Abst)
    PubMedGoogle Scholar
  • 80 Cavo M, Tacchetti P, Patriarca F et al.. A phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: superior clinical outcomes with VTD compared to TD.  Blood. 2009;  114 351 (Abst)
    PubMedGoogle Scholar
  • 81 Zangari M, Barlogie B, Burns M J et al.. Velcade (V)-thalidome (T)-dexamethasone(D) for advanced and refractory multiple myeloma (MM): long term follow up of phase I–II trial UARK 2001–37: superior outcome in patients with normal cytogenetics and no prior T.  Blood. 2005;  106 2552 (Abst)
    PubMedGoogle Scholar
  • 82 Chanan-Khan A A, Padmanabhan S, Miller K C et al.. Final results of a phase II study of bortezomib (Velcade) in combination with liposomal doxorubicin (Doxil) and thalidomide (VDT) demonstrate a sustained high response in patients (pts) with relapsed (rel) or refractory (ref) multiple myeloma.  Blood. 2006;  108 3539 (Abst)
    PubMedGoogle Scholar
  • 83 Richardson P G, Jagannath S, Avigan D E et al.. Lenalidomide plus bortezomib (Rev-Vel) in relapsed and/or refractory multiple myeloma (MM): final results of a multicenter phase I trial.  Blood. 2006;  108 405 (Abst)
    PubMedGoogle Scholar
  • 84 Richardson P, Jagannath S, Raje N et al.. Lenalidomide, bortezomib and dexamethasone (Rev/Vel/Dex) as front line therapy for patients with multiple myeloma (MM): preliminary results of a phase I/II study.  Blood. 2007;  110 187 (Abst)
    PubMedGoogle Scholar
  • 85 Richardson P, Jagannath S, Raje N et al.. Lenalidomide, bortezomib and dexamethasone (Rev/Vel/Dex) in patients with relapsed or relapsed/refractory multiple myeloma (MM): preliminary results of a phase II study.  Blood. 2007;  110 2714 (Abst)
    PubMedGoogle Scholar
  • 86 Terpos E, Anagnostopoulos A, Heath D et al.. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) is an effective regimen for relapsed/refractory myeloma and reduces serum levels of Dickkopf-1, RANKL, MIP-1-alpha and angiogenic cytokines.  Blood. 2006;  108 3541 (Abst)
    PubMedGoogle Scholar
  • 87 Ciolli S, Leoni F, Casini C, Breschi C, Bosi A. Liposomal doxorubicin increases antitumor efficacy of low dose bortezomib, thalidomide and dexamethasone therapy in advanced multiple myeloma.  Haematologica. 2007;  92 94-95 (Abst)
    CrossrefPubMedGoogle Scholar
  • 88 Jagannath S, Bensinger B, Vescio R et al.. A phase II study of bortezomib (Velcade), cyclophosphamide (Cytoxan), thalidomide (Thalomid) and dexamethasone as first line therapy for multiple myeloma.  Blood. 2007;  110 188 (Abst)
    PubMedGoogle Scholar
  • 89 Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma.  Hematology. 2007;  12 (3) 235-239
    CrossrefPubMedGoogle Scholar
  • 90 Zamagni E, Valdrè L, Cini M et al.. Thrombophilic alterations and risk of venous thromboembolism in newly diagnosed multiple myeloma patients treated with thalidomide and high dose dexamethasone.  Haematologica. 2008;  93 (s1) 363
    CrossrefPubMedGoogle Scholar
  • 91 Zamagni E, Valdrè L, Palareti G, Cavo M. Prevention of VTE in multiple myeloma patients.  Thromb Res. 2007;  120 (Suppl 2) S133-S136
    CrossrefPubMedGoogle Scholar
  • 92 Wang M, Weber D M, Delasalle K, Alexanian R. Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma.  Am J Hematol. 2005;  79 (3) 194-197
    CrossrefPubMedGoogle Scholar
  • 93 Palumbo A, Bringhen S, Caravita T Italian Multiple Myeloma Network, GIMEMA 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 (9513) 825-831
    CrossrefPubMedGoogle Scholar
  • 94 Minnema M C, Breitkreutz I, Auwerda J J et al.. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy.  Leukemia. 2004;  18 (12) 2044-2046
    CrossrefPubMedGoogle Scholar
  • 95 Offidani M, Corvatta L, Piersantelli M N et al.. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma.  Blood. 2006;  108 (7) 2159-2164
    CrossrefPubMedGoogle Scholar
  • 96 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 (5) 715-721
    CrossrefPubMedGoogle Scholar
  • 97 Barlogie B, Tricot G, Anaissie E et al.. Thalidomide and hematopoietic-cell transplantation for multiple myeloma.  N Engl J Med. 2006;  354 (10) 1021-1030
    CrossrefPubMedGoogle Scholar
  • 98 Cavo M, Palumbo A, Bringhen S et al.. A phase III study of enoxaparin versus low-dose of warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens.  Blood. 2008;  112 3017 (Abst)
    PubMedGoogle Scholar
  • 99 Palumbo A, Dimopoulos M A, Delforge M et al.. Phase III study to determine the efficacy and safety of Lenalidomide in combination with Melphalan and Prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma.  Blood. 2009;  114 613 (Abst)
    PubMedGoogle Scholar
  • 100 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 (1) 67-71
    CrossrefPubMedGoogle Scholar
  • 101 Palumbo A, Rajkumar S V, Dimopoulos M A International Myeloma Working Group et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.  Leukemia. 2008;  22 (2) 414-423
    CrossrefPubMedGoogle Scholar
  • 102 Lyman G H, Khorana A A, Falanga A American Society of Clinical Oncology et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer.  J Clin Oncol. 2007;  25 (34) 5490-5505
    CrossrefPubMedGoogle Scholar
  • 103 Rajkumar S V, Hayman S R, Lacy M Q et al.. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.  Blood. 2005;  106 (13) 4050-4053
    CrossrefPubMedGoogle Scholar
  • 104 Zangari M, Fink L M, Elice F, Zhan F, Adcock D M, Tricot G J. Thrombotic events in patients with cancer receiving antiangiogenesis agents.  J Clin Oncol. 2009;  27 (29) 4865-4873
    CrossrefPubMedGoogle Scholar

Elena Zamagni

Istituto di Ematologia “Seràgnoli,” Università degli Studi di Bologna - Policlinico S. Orsola-Malpighi, Via Massarenti

9 – 40138 Bologna, Italy

Email: e.zamagni@unibo.it

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