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* From Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
Correspondence to: Jack Hirsh, CM, MD, DSc, FCCP, Henderson Research Centre, 711 Concession St, Hamilton, L8V 1C3, ON, Canada; e-mail: jhirsh{at}thrombosis.hhscr.org
Abstract
Lenalidomide, an analog of thalidomide, is an effective new treatment for multiple myeloma. Both compounds are associated with an increased risk of venous thromboembolism, particularly when used in combination with high-dose dexamethasone. As new trials with lenalidomide are being planned and performed, investigators are placing high importance on reducing the risk of thrombosis by incorporating an antithrombotic agent into the therapeutic regimen. Low-molecular-weight heparin, warfarin, and aspirin have all been suggested as candidate drugs for thromboprophylaxis, but none of these agents have been evaluated in randomized clinical trials. A body of opinion has evolved that aspirin is very effective in preventing venous thrombosis in myeloma patients treated with lenalidomide. If correct, this view has important implications, because aspirin is inexpensive and is safer and more convenient than anticoagulants. On the other hand, aspirin is less effective than anticoagulants for preventing venous thrombosis in other high-risk groups, and therefore might not be the most appropriate choice for preventing of venous thrombosis in myeloma patients. This commentary examines the strength of the evidence supporting the effectiveness of aspirin in preventing venous thrombosis in multiple myeloma patients treated with lenalidomide. It is concluded that the evidence that aspirin is efficacious in preventing venous thrombosis in myeloma patients is based on "before/after" and retrospective studies, with potential for bias and confounders. There is, therefore, a critical need to incorporate a randomized comparison of aspirin with an anticoagulant in future trials evaluating lenalidomide in multiple myeloma.
Key Words: aspirin • lenalidomide • multiple myeloma • thrombosis
Thalidomide is an effective agent for the treatment of multiple myeloma.1 When used in combination with dexamethasone, response rates of 50% are seen in relapsed refractory disease and of 65 to 70% in newly diagnosed myeloma.1 The advantages of oral administration plus less serious toxicity, compared to other effective chemotherapeutic agents, make the combination of thalidomide and dexamethasone attractive for multiple myeloma. Soon after its "reintroduction" into clinical use (previously withdrawn from the market because of teratogenicity), reports that thalidomide increases the risk of venous thrombosis began to accumulate. Rajkumar and colleagues1 performed a randomized trial in which 204 patients with multiple myeloma were assigned to either the combination of thalidomide and dexamethasone or dexamethasone alone. The incidence of deep venous thrombosis was 17% in the combination arm compared to 3% in the dexamethasone arm (p < 0.001). The risk of thrombosis is increased when thalidomide is used in combination with high-dose dexamethasone2 and with other antimyeloma drugs.2 The risk of thrombosis also appears to be higher when thalidomide is used for initial treatment than for relapse.3 In most reports, the venous thromboembolic events have been symptomatic. Based on this high incidence of venous thrombosis, the authors recommended routine prophylaxis with either low-molecular-weight heparin or warfarin in myeloma patients treated with thalidomide and dexamethasone, whereas in patients with a high risk of bleeding, they recommended aspirin.1 While, the effectiveness of low-molecular-weight heparin and adjusted-dose warfarin is well established, the effectiveness of aspirin for venous thrombosis prophylaxis is less certain.4
Lenalidomide, an analog of thalidomide, has also been shown to be effective in relapsed and refractory myeloma and to have fewer side effects than thalidomide; but like thalidomide, lenalidomide is associated with an increased risk of venous thrombosis.567 Based on data from nonrandomized studies and several between-study comparisons,789 a body of opinion has evolved that aspirin is effective in preventing venous thrombosis in patients treated with lenalidomide. Accordingly, in the ongoing Eastern Cooperative Oncology Group trial evaluating lenalidomide, Rajkumar and Gertz9 mandate that all study subjects receive prophylaxis with, as a minimum, aspirin with consideration for either low-molecular-weight heparin or warfarin in the high-dose dexamethasone arm. Aspirin is relatively safe, inexpensive, and convenient, and has modest efficacy in reducing the risk of venous thrombosis in hip facture patients, but is much less effective than low-molecular-weight heparin or warfarin when compared in randomized trials.4 If indeed, as suggested by a number of investigators, aspirin is effective in preventing venous thrombosis in myeloma patients treated with lenalidomide (or thalidomide), the observation would be important, not only for them, but also for a broader population of patients at risk for venous thrombosis. The purpose of this brief review is to critically examine the evidence that aspirin reduces the risk of venous thrombosis in lenalidomide-treated multiple myeloma patients and, on the basis of current evidence, to comment on the appropriateness of recommending aspirin for prophylaxis in such patients.
Risk of Thrombosis With Lenalidomide
The reported incidence of thrombosis with lenalidomide treatment in multiple myeloma varies widely among reports. Dimopoulos et al5 and Weber et al6 reported DVT rates of 9% and 17.5%, respectively, in studies in patients with relapsed refractory multiple myeloma who were treated with the combination of lenalidomide and dexamethasone. Zonder and colleagues10 reported that thrombosis developed in 9 of 12 patients (75%) assigned to a combination of dexamethasone and lenalidomide, compared to 0 of 9 patients in the dexamethasone (plus placebo) group. In contrast to these high rates, Richardson et al11 reported that thrombosis developed in only 3 of 68 myeloma patients (4.4%) treated with lenalidomide and dexamethasone.
Several unique factors influence the risk of venous thrombosis in patients treated with lenalidomide or thalidomide: the concomitant use of erythropoietin12; concomitant use of high-dose, rather than low-dose dexamethasone212; treatment of new rather than relapsed cases of myeloma13; and concomitant use of other chemotherapeutic agents.2 Therefore, reliable estimates of the efficacy of aspirin in myeloma require the drug to be evaluated in properly designed randomized trials. Whereas there are solid grounds to generalize from the large body of evidence that anticoagulants are likely to be effective in preventing venous thrombosis in high-risk myeloma, such an extrapolation is not appropriate for aspirin.
Aspirin for Prevention of Venous Thrombosis
What evidence, then, forms the basis of the recommendation that aspirin should be used to prevent venous thrombosis in lenalidomide-treated patients with multiple myeloma? The first indication that aspirin might be effective in reducing venous thrombosis in the setting of treated multiple myeloma came from a report by Baz and associates.14 In a phase 2 clinical trial, 105 patients were treated with doxorubicin, vincristine, dexamethasone, and thalidomide. A high rate of venous thrombosis was noted after 35 patients were enrolled. Therefore, it was decided to use aspirin in selected patients for the duration of the study. Aspirin (81 mg) was administered to 26 of the original 35 patients enrolled, 19 patients did not receive aspirin, and 58 of the new cohort received aspirin. Venous thrombosis developed in 26 patients of the 58 patients (19%) who received aspirin from the start of enrollment, 15% of those who received aspirin after the study started, and 58% of those who never received aspirin. It was not clear how patients were selected for aspirin treatment, so it is difficult to draw conclusions about the efficacy of aspirin from this study.
In a preliminary report of two placebo-controlled trials, Knight and associates12 reported a high incidence of venous thrombosis in patients treated with the combination of lenalidomide, dexamethasone, and erythropoietin. The authors also noted that thrombosis did not develop in any of 23 patients who received aspirin or salicylates during the first month of treatment, and that thrombosis occurred in 52 of 668 patients (8.1%) who did not receive aspirin or salicylates. As in the other report, it is unclear how patients were selected for treatment with aspirin.
In a phase 2 trial in which all 34 patients with myeloma received lenalidomide, dexamethasone, and aspirin, Rajkumar et al7 reported that the incidence of venous thrombosis was only 3% in lenalidomide-treated patients, an incidence that they noted was much lower than that reported by Dimopoulos et al.5 In a retrospective analysis of different trials, Palumbo and associates8 noted that thromboembolism developed in only 1 in 50 patients treated with lenalidomide, melphalan, prednisone, and aspirin, and concluded that aspirin seems appropriate for prophylaxis of lenalidomide-associated thrombosis.
In a preliminary communication of a randomized trial in multiple myeloma, Zonder et al10 reported that thrombosis developed in 9 of 12 patients (75%) assigned to a combination of dexamethasone and lenalidomide. The protocol was then modified by adding aspirin, 325 mg/d, to all patients; after 76 patients were enrolled, the incidence of thrombosis in the combination of lenalidomide/dexamethasone arm who received aspirin was 6/32 (19%).10
Summary of the Evidence of the Efficacy of Aspirin
Recommendations on the use of antithrombotic drugs to prevent venous thrombosis in lenalidomide-treated myeloma patients should be based on their relative benefits and risks as determined in appropriately designed randomized trials. To date, the evidence that aspirin is efficacious is based on flawed evidence, "before/after" and retrospective studies, with potential for bias and confounders. There is a critical need to perform a randomized control study.
Conclusions
In summary, a number of investigators have noted that the incidence of venous thromboembolism in thalidomide- and lenalidomide-treated myeloma patients is high and the risk is reduced substantially with aspirin. Unfortunately, all of the studies reporting on the efficacy of aspirin have serious limitations in their design. Therefore, we consider these results to be hypothesis generating rather than definitive evidence that aspirin is effective. The evidence that both thalidomide and its analog, lenalidomide (when used in combination with high-dose dexamethasone) are associated with a clinically important risk of venous thromboembolism is strong, and corroborated by the results of a randomized control trial.1 Based on studies of venous thrombosis prophylaxis, there is overwhelming evidence that anticoagulants such as low molecular weight heparin and warfarin are effective in the prevention of venous thrombosis in several high-risk groups, whereas aspirin is either less effective or ineffective. Therefore, rather than mandating aspirin as minimum prophylaxis, it would seem more appropriate to incorporate a randomized comparison of aspirin with an anticoagulant in future trials evaluating lenalidomide in multiple myeloma.
Acknowledgements
I am grateful to Drs. Jeffery Ginsberg and Mark Levine for reviewing the manuscript and providing helpful comments.
Footnotes
The author has no conflicts of interest to disclose.
Received for publication September 25, 2006. Accepted for publication September 29, 2006.
References
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