Thalidomide Therapy and Deep Venous Thrombosis in Multiple Myeloma

Abstract

The treatment of multiple myeloma (MM) has undergone radical changes in recent years with the arrival of active agents such as thalidomide and bortezomib.1Kyle RA Rajkumar SV Multiple myeloma [published correction appears in N Engl J Med. 2005;352:1163].N Engl J Med. 2004; 351: 1860-1873Crossref PubMed Scopus (1258) Google Scholar, 2Rajkumar SV Kyle RA Multiple myeloma: diagnosis and treatment.Mayo Clin Proc. 2005; 80: 1371-1382Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 3Kyle RA Gertz MA Witzig TE et al.Review of 1027 patients with newly diagnosed multiple myeloma.Mayo Clin Proc. 2003; 78: 21-33Abstract Full Text Full Text PDF PubMed Scopus (1652) Google Scholar, 4Anderson KC Multiple myeloma: how far have we come? [editorial].Mayo Clin Proc. 2003; 78: 15-17Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Thalidomide, once discarded because of its teratogenicity, is now widely used alone or in combination with other active drugs to treat disease.5Singhal S Mehta J Desikan R et al.Antitumor activity of thalidomide in refractory multiple myeloma [published correction appears in N Engl J Med. 2000;342:364].N Engl J Med. 1999; 341: 1565-1571Crossref PubMed Scopus (2371) Google Scholar, 6Dimopoulos MA Anagnostopoulos A Weber D Treatment of plasma cell dyscrasias with thalidomide and its derivatives.J Clin Oncol. 2003; 21: 4444-4454Crossref PubMed Scopus (112) Google Scholar, 7Kumar S Witzig TE Rajkumar SV Thalidomide: current role in the treatment of non-plasma cell malignancies [published correction appears in J Clin Oncol. 2004;22:2973].J Clin Oncol. 2004; 22: 2477-2488Crossref PubMed Scopus (87) Google Scholar, 8Richardson P Schlossman R Jagannath S et al.Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.Mayo Clin Proc. 2004; 79: 875-882Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar In fact, the combination of thalidomide plus dexamethasone (Thal/Dex) has rapidly become one of the most commonly used regimens in the United States9Rajkumar SV Multiple myeloma: the death of VAD as initial therapy.Blood. 2005; 106: 2-3Crossref Scopus (24) Google Scholar for patients with newly diagnosed MM. Thalidomide has profoundly affected patients with MM. Before thalidomide, no new agent with substantial single-agent activity had been identified in decades for the treatment of MM, and patients with relapsed MM had limited therapeutic options.10Kyle RA Five decades of therapy for multiple myeloma: a paradigm for therapeutic models.Leukemia. 2005; 19: 910-912Crossref PubMed Scopus (23) Google Scholar, 11Kumar SK Therneau TM Gertz MA et al.Clinical course of patients with relapsed multiple myeloma.Mayo Clin Proc. 2004; 79: 867-874Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Thalidomide, which has multiple proposed mechanisms of action, such as anti-angiogenesis, tumor necrosis factor a inhibition, and immune modulation, also causes several unique adverse effects.12Kumar S Witzig TE Dispenzieri A et al.Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma.Leukemia. 2004; 18: 624-627Crossref PubMed Scopus (93) Google Scholar Besides teratogenicity, other important toxicities include peripheral neuropathy, rash (rarely Stevens-Johnson syndrome and toxic epidermal necrolysis), sedation, constipation, and hypothyroidism. With the increasing use of thalidomide as initial therapy for MM, deep venous thrombosis (DVT) and other thrombotic events also have emerged as major adverse events. In fact, thalidomide-associated thrombosis can be considered one of the most interesting problems to have emerged in clinical hematology in recent years for the following reasons: (1) The accused drug, already one of the most notorious agents in the history of medicine, is now implicated as causing yet another serious toxicity.13Rajkumar SV Thalidomide: tragic past and promising future.Mayo Clin Proc. 2004; 79: 899-903Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar (2) The incidence of thrombosis associated with thalidomide-based therapy in certain settings is strikingly high. Specifically, venous thrombosis rates after thalidomide treatment are almost unheard of in any other clinical situation, including most inherited and acquired thrombotic disorders, except for immune-mediated heparin-induced thrombocytopenia.14Warkentin TE Kelton JG A 14-year study of heparin-induced thrombocytopenia.Am J Med. 1996; 101: 502-507Abstract Full Text PDF PubMed Scopus (810) Google Scholar (3) In a peculiar manner, the increased risk of thrombosis in patients with MM is almost nonexistent when thalidomide is used as a single agent, but risk increases substantially when the drug is combined with high-dose corticosteroids or certain chemotherapy drugs.6Dimopoulos MA Anagnostopoulos A Weber D Treatment of plasma cell dyscrasias with thalidomide and its derivatives.J Clin Oncol. 2003; 21: 4444-4454Crossref PubMed Scopus (112) Google Scholar The first report of thrombotic complications related to thalidomide therapy was a small case series of 5 patients, 4 with lupus erythematosus and 1 with severe atopic dermatitis.15Flageul B Wallach D Cavelier-Balloy B Bachelez H Carsuzaa F Dubertret L Thalidomide and thrombosis [in French].Ann Dermatol Venereol. 2000; 127: 171-174PubMed Google Scholar Both arterial and venous events were described. Subsequently, in 2 separate clinical trials, investigators at the Memorial Sloan-Kettering Cancer Center and the Mayo Clinic reported a high rate of DVT with thalidomide-based therapy for patients with newly diagnosed MM.16Osman K Comenzo R Rajkumar SV Deep venous thrombosis and thalidomide therapy for multiple myeloma [letter].N Engl J Med. 2001; 344: 1951-1952Crossref PubMed Scopus (207) Google Scholar In the Memorial Sloan-Kettering Cancer Center trial, 4 of 15 patients (27%) who received the combination of thalidomide, dexamethasone, and doxorubicin developed DVT, resulting in suspension of the trial to allow protocol modifications. Similar findings were reported independently by Zangari et al17Zangari M Siegel E Barlogie B et al.Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.Blood. 2002; 100: 1168-1171Crossref PubMed Scopus (218) Google Scholar from a trial at the University of Arkansas Cancer Center. The incidence of DVT with thalidomide-based therapy and the comparative rates associated with other antimyeloma therapies from various studies are summarized in Table 1.16Osman K Comenzo R Rajkumar SV Deep venous thrombosis and thalidomide therapy for multiple myeloma [letter].N Engl J Med. 2001; 344: 1951-1952Crossref PubMed Scopus (207) Google Scholar, 18Barlogie 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: 492-494Crossref PubMed Scopus (522) Google Scholar, 19Kumar 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: 34-39Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 20Rajkumar SV Gertz MA Lacy MQ et al.Thalidomide as initial therapy for early-stage myeloma.Leukemia. 2003; 17: 775-779Crossref PubMed Scopus (204) Google Scholar, 21Rajkumar SV Blood E Vesole DH Shepard R Greipp PR 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].Blood. 2004; 104 (Abstract 205.): 63aGoogle Scholar, 22Barlogie B Jagannath S Desikan KR et al.Total therapy with tandem transplants for newly diagnosed multiple myeloma.Blood. 1999; 93: 55-65PubMed Google Scholar, 23Rajkumar SV Hayman S Gertz MA et al.Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.J Clin Oncol. 2002; 20: 4319-4323Crossref PubMed Scopus (461) Google Scholar, 24Cavo 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: 826-831PubMed Google Scholar, 25Weber D Rankin K Gavino M Delasalle K Alexanian R Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.J Clin Oncol. 2003; 21: 16-19Crossref PubMed Scopus (525) Google Scholar, 26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar, 27Baz R Li L Kottke-Marchant K et al.Aspirin decreases the thrombotic complications induced by thalidomide when combined with anthracycline based chemotherapy regimens for the treatment of multiple myeloma.Mayo Clin Proc. 2005; 80: 1568-1574Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 28Minnema 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 [letter].Leukemia. 2004; 18: 2044-2046Crossref PubMed Scopus (98) Google Scholar As readily apparent from the table, the risk of DVT is minimal with thalidomide alone but increases substantially with the addition of dexamethasone and further still with the addition of doxorubicin-based chemotherapy. This incremental risk suggests that the risk of DVT may be related to the interaction between drugs and their collective effect on malignant cells and the vascular endothelium.TABLE 1DVT in MM*DVT = deep venous thrombosis; INR = international normalized ratio; MM = multiple myeloma; VAD = vincristine, doxorubicin (Adriamycin), and dexamethasone.Treatment regimen†All treatment regimens and corresponding rates listed in the table are from studies in patients with newly diagnosed MM, except single-agent thalidomide, which includes 1 study in newly diagnosed smoldering MM and 2 in relapsed refractory disease. In general, rates of DVT are lower in the setting of relapsed refractory disease compared with newly diagnosed MM.Incidence of DVT within the first 4 months of therapy (%)Thalidomide (single-agent) No prophylaxis18Barlogie 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: 492-494Crossref PubMed Scopus (522) Google Scholar, 19Kumar 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: 34-39Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 20Rajkumar SV Gertz MA Lacy MQ et al.Thalidomide as initial therapy for early-stage myeloma.Leukemia. 2003; 17: 775-779Crossref PubMed Scopus (204) Google Scholar<2–3Dexamethasone (single-agent) No prophylaxis21Rajkumar SV Blood E Vesole DH Shepard R Greipp PR 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].Blood. 2004; 104 (Abstract 205.): 63aGoogle Scholar3VAD regimen No prophylaxis22Barlogie B Jagannath S Desikan KR et al.Total therapy with tandem transplants for newly diagnosed multiple myeloma.Blood. 1999; 93: 55-65PubMed Google Scholar5–10Thalidomide plus dexamethasone No prophylaxis21Rajkumar SV Blood E Vesole DH Shepard R Greipp PR 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].Blood. 2004; 104 (Abstract 205.): 63aGoogle Scholar, 23Rajkumar SV Hayman S Gertz MA et al.Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.J Clin Oncol. 2002; 20: 4319-4323Crossref PubMed Scopus (461) Google Scholar, 24Cavo 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: 826-831PubMed Google Scholar12–26 Low fixed-dose warfarin (1 mg/d)25Weber D Rankin K Gavino M Delasalle K Alexanian R Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.J Clin Oncol. 2003; 21: 16-19Crossref PubMed Scopus (525) Google Scholar24 Low fixed-dose warfarin (1.25 mg/d)24Cavo 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: 826-831PubMed Google Scholar13 Full-dose warfarin (INR, 2–3)25Weber D Rankin K Gavino M Delasalle K Alexanian R Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.J Clin Oncol. 2003; 21: 16-19Crossref PubMed Scopus (525) Google ScholarRareThalidomide plus doxorubicin No prophylaxis16Osman K Comenzo R Rajkumar SV Deep venous thrombosis and thalidomide therapy for multiple myeloma [letter].N Engl J Med. 2001; 344: 1951-1952Crossref PubMed Scopus (207) Google Scholar, 26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar27–30 Low fixed-dose warfarin (1 mg/d)26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar30 Aspirin27Baz R Li L Kottke-Marchant K et al.Aspirin decreases the thrombotic complications induced by thalidomide when combined with anthracycline based chemotherapy regimens for the treatment of multiple myeloma.Mayo Clin Proc. 2005; 80: 1568-1574Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar19 Prophylactic-dose low-molecular-weight heparin (equivalent of enoxaparin at 40 mg/d)26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar, 28Minnema 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 [letter].Leukemia. 2004; 18: 2044-2046Crossref PubMed Scopus (98) Google Scholar8–15* DVT = deep venous thrombosis; INR = international normalized ratio; MM = multiple myeloma; VAD = vincristine, doxorubicin (Adriamycin), and dexamethasone.† All treatment regimens and corresponding rates listed in the table are from studies in patients with newly diagnosed MM, except single-agent thalidomide, which includes 1 study in newly diagnosed smoldering MM and 2 in relapsed refractory disease. In general, rates of DVT are lower in the setting of relapsed refractory disease compared with newly diagnosed MM. Open table in a new tab The pathogenesis of thalidomide-induced DVT is poorly understood. It has been suggested that the effect may involve a direct action of thalidomide on endothelial cells previously damaged by chemotherapy agents such as doxorubicin.29Kaushal V Kaushal GP Melkaveri SN Mehta P Thalidomide protects endothelial cells from doxorubicin-induced apoptosis but alters cell morphology.J Thromb Haemost. 2004; 2: 327-334Crossref PubMed Scopus (55) Google Scholar Zangari et al26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar have identified concomitant doxorubicin therapy, newly diagnosed disease, and activated protein C resistance as major risk factors for the development of thrombosis in MM. Although the risk of thrombosis does not appear to increase with single-agent therapy in MM (which is similar to observations of thalidomide treatment of myelofibrosis with myeloid metaplasia30Mesa RA Elliott MA Schroeder G Tefferi A Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia.Mayo Clin Proc. 2004; 79: 883-889Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 31Silver RT Myelofibrosis: thalidomide finds a new disease [editorial].Mayo Clin Proc. 2004; 79: 857-858Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar), an increased risk has been reported in renal cell cancer,32Escudier B Lassau N Couanet D et al.Phase II trial of thalidomide in renal-cell carcinoma.Ann Oncol. 2002; 13: 1029-1035Crossref PubMed Scopus (106) Google Scholar suggesting that the tumor type also may play a role in the pathogenesis. Lower extremity DVT is the most frequent type of thrombotic event seen with thalidomide therapy, and pulmonary embolism occurs in approximately half of these patients.33Dimopoulos MA Eleutherakis-Papaiakovou V Adverse effects of thalidomide administration in patients with neoplastic diseases.Am J Med. 2004; 117: 508-515Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Cerebral venous sinus thrombosis also has been reported. Arterial events including unstable angina, myocardial infarction, and stroke have occurred with thalidomide therapy for MM, but the precise excess risk that can be attributed to the drug has not been quantified. Once DVT has occurred, patients are treated with standard anticoagulation with heparin or with low-molecular-weight heparin followed by warfarin. Thalidomide can be resumed safely after adequate anticoagulation, and anticoagulant therapy is administered until at least as long as therapy with thalidomide is continued.26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar Given the high risk of thrombotic events, several preventive strategies have been tried (Table 1). Although there have been no randomized trials to investigate the efficacy of anticoagulation, because of the magnitude of the risk, all patients receiving combination therapy with thalidomide for MM, either with high-dose dexamethasone or other chemotherapy, usually need some form of thromboprophylaxis. The 2 most commonly accepted and effective prophylactic strategies are therapeutic doses of warfarin, targeting an international normalized ratio of 2.0 to 3.0, and low-molecular-weight heparin (equivalent of 40 mg once daily of subcutaneous enoxaparin).6Dimopoulos MA Anagnostopoulos A Weber D Treatment of plasma cell dyscrasias with thalidomide and its derivatives.J Clin Oncol. 2003; 21: 4444-4454Crossref PubMed Scopus (112) Google Scholar However, both approaches are cumbersome and, at least in the case of low-molecular-weight heparin, add substantial cost. In the current issue of the Mayo Clinic Proceedings, Baz et al27Baz R Li L Kottke-Marchant K et al.Aspirin decreases the thrombotic complications induced by thalidomide when combined with anthracycline based chemotherapy regimens for the treatment of multiple myeloma.Mayo Clin Proc. 2005; 80: 1568-1574Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar report that aspirin alone may offer significant protection against thrombosis associated with thalidomide therapy. In their study, the risk of a venous thromboembolic event with thalidomide-liposomal doxorubicin-based therapy was significantly lower in patients receiving aspirin (81 mg/d) from the outset of therapy compared with patients who did not receive aspirin, 19% vs 58%, respectively. There was no significant increase in the risk of bleeding with aspirin use in this population, although Zangari et al26Zangari 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: 715-721Crossref PubMed Scopus (210) Google Scholar have shown that the same is true of low-molecular-weight heparin, even in the presence of thrombocytopenia. How does one explain the efficacy of aspirin in preventing venous thrombosis when conventional wisdom says the drug primarily prevents arterial events? Although typically used to prevent arterial thromboembolism, aspirin was shown to be effective in preventing venous thrombosis in patients who underwent surgery for hip fracture in a large randomized trial involving more than 17,000 patients,34Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.Lancet. 2000; 355: 1295-1302Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar as well as in patients with conditions such as antiphospholipid antibody syndrome.35Hansen KE Kramm HL Boh D et al.Risk factors for thrombosis and the beneficial effect of aspirin in patients with antiphospholipid antibodies (aPL) [abstract].Blood. 2004; 104 (Abstract 279.): 83aGoogle Scholar Although aspirin may not be as effective as full-dose anticoagulation with warfarin or low-molecular-weight heparin, there is no question that it can reduce the risk of venous thrombosis. Furthermore, there is clear evidence that the use of aspirin as thromboprophylaxis is better than no prophylaxis, at least in certain circum-stances.36Antiplatelet Trialists' CollaborationCollaborative overview of randomised trials of antiplatelet therapy, III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.BMJ. 1994; 308: 235-246Crossref PubMed Scopus (32) Google Scholar Indirect confirmation of the efficacy of aspirin, specifically in preventing thalidomide-associated DVT, comes from recent studies with lenalidomide, a closely related investigational drug that appears to be safer and more effective (in vitro and in vivo) than thalidomide for treatment of MM.37Lentzsch S LeBlanc R Podar K et al.Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo.Leukemia. 2003; 17: 41-44Crossref PubMed Scopus (162) Google Scholar, 38Richardson 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: 3063-3067Crossref PubMed Scopus (765) Google Scholar Although, as with thalidomide, the DVT risk in MM is not increased with single-agent lenalidomide, 2 phase III trials on relapsed refractory MM that used lenalidomide (Revlimid) plus dexamethasone (Rev/Dex), conducted without routine thromboprophylaxis, reported an increased incidence of DVT (9%-15%).39Dimopoulos M Weber D Chen C et al.Evaluating oral lenalidomide (Revlimid) and dexamethasone versus placebo and dexamethasone in patients with relapsed or refractory multiple myeloma [abstract].Haematologica. 2005; 90 (Abstract 0402.): 160Google Scholar In contrast, the risk of DVT with Rev/Dex was substantially lower (3%) in a recent Mayo Clinic study that was conducted with routine aspirin prophy-laxis,40Rajkumar SV Hayman SR Lacy MQ et al.Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma.Blood. 2005; ([Epub ahead of print])Google Scholar supporting the findings of Baz et al that aspirin may have unique antithrombotic effects in this setting. Given this information, what should be the standard DVT prophylaxis when initiating thalidomide (or lenalidomide) therapy in patients with MM? If thalidomide is used as a single agent for MM, no routine prophylaxis is probably necessary beyond that indicated on the basis of patients' performance status and other related clinical factors. In the setting of newly diagnosed MM, when thalidomide is used in combination with other agents (including the Thal/Dex regimen), I prefer warfarin use to a target international normalized ratio of 2.0 to 3.0, with low-molecular-weight heparin as second choice. Results with fixed low-dose warfarin are contradictory, and more data are needed to assess this approach. The study by Baz et al suggests that aspirin is a reasonable third alternative. However, the rate of thrombosis with aspirin is relatively high in this study, and it would be preferable, until there is further confirmation, to reserve aspirin prophylaxis to patients unable or unwilling to take warfarin or low-molecular-weight heparin. In addition to the use of thromboprophylaxis, erythropoietin, a drug known to increase the risk of thrombosis (including DVT associated with thalidomide therapy),41Steurer M Sudmeier I Stauder R Gastl G Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha.Br J Haematol. 2003; 121: 101-103Crossref PubMed Scopus (69) Google Scholar should be avoided as much as possible during induction therapy for MM. In the absence of chronic renal failure, anemia related to newly diagnosed MM resolves typically as patients respond to induction therapy, and the need for erythropoietin is not pressing in most patients. Clearly, the pathogenesis of thalidomide-induced (and lenalidomide-induced) thrombosis and the mechanism of action of aspirin in preventing thrombotic events need more detailed study. Such investigation may even provide insight into the mechanism of action of these drugs in MM, which is still poorly understood. In an indirect manner, the results of 2 large ongoing cooperative group randomized trials with Rev/Dex also may shed light on the efficacy of aspirin prophylaxis for therapy-related thrombosis in MM. The Role of Aspirin in the Prevention of Thrombotic Complications of Thalidomide and Anthracycline-Based Chemotherapy for Multiple MyelomaMayo Clinic ProceedingsVol. 80Issue 12PreviewTo study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T). Full-Text PDF