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Blood, 1 July 2006, Vol. 108, No. 1, pp. 403-404. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zonder, J. A. Articles by Gertz, M. A. Search for Related Content PubMed PubMed Citation Articles by Zonder, J. A. Articles by Gertz, M. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE To the editor: Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis Lenalidomide (LEN) is an immunomodulatory compound with significant activity versus relapsed/refractory multiple myeloma (RRMM).1 In Blood, Rajkumar et al2 reported striking efficacy of LEN plus dexamethasone (DEX) versus newly diagnosed multiple myeloma (NDMM). While structurally similar to thalidomide (THAL), also used to treat MM,3 LEN has a unique activity profile. Both agents appear to increase the risk of thromboembolic events (TEEs), although the actual baseline incidence is unclear. The TEE incidence in NDMM patients receiving THAL+DEX without thrombosis prophylaxis is approximately 15%.4,5 An 8.5% incidence of TEE in RRMM patients getting DEX+LEN without routine prophylaxis has been reported.1 Rajkumar et al2 described a 3% incidence in NDMM with DEX+LEN and daily aspirin (ASA; 80 mg or 325 mg). The Southwest Oncology Group is conducting a double-blind randomized trial comparing DEX (40 mg/day on days 1-4, 9-11, and 17-20 every 35 days for 3 induction cycles, then 40 mg/day on days 1-4 and 15-18 every 28 days as maintenance thereafter) plus placebo versus DEX (same schedule) plus LEN (25 mg/day on days 1-28 every 35 days during induction, then 25 mg/day on days 1-21 every 28 days during maintenance). Crossover from DEX to DEX+LEN is permitted for progressive MM. Initially, no thrombosis prophylaxis was mandated. After 21 patients were enrolled, an increased incidence of TEEs in 1 arm became apparent: 9 (75%) of 12 patients receiving DEX+LEN developed TEEs (8 lower-extremity deep-vein thromboses with 2 pulmonary embolic events, 1 ischemic stroke) after a median of 50 days, versus 0 (0%) of 9 patients on DEX alone (P < .001). The study was modified to require 325 mg ASA daily, based on the low TEE incidence observed by Rajkumar et al,2 as well as a report showing low-dose ASA reduced TEE risk in MM patients receiving chemotherapythalidomide combinations.6 As of October 31, 2005, 76 patients have been enrolled. Since mandating ASA prophylaxis, 6 TEEs have occurred among 55 additional patients: 4 (15%) of 26 randomized to DEX+LEN (P < .001 for comparison of TEE incidence on DEX+LEN before and after aspirin) and 2 (7%) of 29 on DEX alone (P = .41 for DEX vs DEX+LEN after ASA). Of interest, both of the patients randomized to DEX who developed clots had already crossed over from DEX to DEX+LEN due to progressive disease. One of these patients was noncompliant with ASA prophylaxis. Overall, 6 (19%) of 32 patients receiving DEX+LEN have developed TEEs since modification of the protocol to include ASA prophylaxis (P < .001 before vs after ASA). In summary, although adding ASA markedly reduced the risk of TEEs in NDMM patients receiving DEX+LEN, we observed a much higher incidence of TEE than reported by Rajkumar et al.4 Potential reasons include higher DEX dose, longer LEN exposure during induction in our trial, or other factors such as possible differences in the use of recombinant erythropoietin. The 19% TEE incidence we observed is similar to that reported for NDMM patients treated with anthracycline-THAL combinations plus either 81 mg ASA6 or low-dose enoxaparin.7 At present, using one of these prophylaxis strategies during DEX+LEN treatment for NDMM is highly recommended. Further research is needed to determine the optimal prophylaxis strategy. Jeffrey A. Zonder, Bart Barlogie, Brian G. M. Durie, Jason McCoy, John Crowley, and Mohamad A. Hussein Correspondence: Jeffrey A. Zonder, Karmanos Cancer Institute, 4th Floor Hudson-Webber Cancer Research Center, 4100 John R, Detroit, MI 48201; e-mail: zonderj{at}karmanos.org. Footnotes Supported in part by Celgene Corporation. References 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]. Blood. 2005;106: 6a. Abstract 6. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106: 4050-4053.[Abstract/Free Full Text] Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. 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: 431-436.[Abstract/Free Full Text] Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20: 4319-4323.[Abstract/Free Full Text] 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: 16-19.[Abstract/Free Full Text] 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: 1568-1574.[Abstract/Free Full Text] 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: 715-721.[CrossRef][Medline] [Order article via Infotrieve]   Response: Lenalidomide therapy and deep-vein thrombosis in multiple myeloma The importance of thromboprophylaxis with the use of lenalidomide and high-dose dexamethasone is well illustrated in this report by Zonder and colleagues. The incidence of deep-vein thrombosis (DVT) in their study decreased significantly when mandatory prophylaxis with aspirin was instituted but remains higher than the 3% risk of DVT observed with the same regimen in our trial, in which routine aspirin prophylaxis was used from the outset. We believe that there are 2 factors that may affect the incidence of DVT in this setting, namely, the dose of dexamethasone and the use of concomitant erythropoietin. As we noted in our paper, a higher risk of DVT has also been observed in an Eastern Cooperative Oncology Group (ECOG) randomized trial testing lenalidomide plus either high- or low-dose dexamethasone as initial treatment for myeloma.1 In this trial, the increased DVT risk was seen in the high-dose dexamethasone arm, which uses doses of dexamethasone similar to those used in the Southwest Oncology Group and Mayo Clinic trials. In contrast, the risk of DVT did not appear to be much increased in patients treated on the lenalidomide plus low-dose dexamethasone arm. These findings, coupled with earlier observations that show no increased risk of DVT with single-agent lenalidomide,2 suggest that it may be possible to reduce DVT risk by optimizing the dose of dexamethasone that is used in combination with lenalidomide. A higher risk of DVT has been observed with the concurrent use of erythropoietic agents in patients receiving either thalidomide or lenalidomide.3,4 Clinical trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program now recommend routine thromboprophylaxis when lenalidomide and erythropoietin are used concurrently. We recommend that all patients receiving lenalidomide plus dexamethasone receive routine thromboprophylaxis. More data are needed on the best form of DVT prophylaxis. In the ECOG trial, we are requiring aspirin as the minimum mandatory prophylaxis, with a recommendation to consider either low-molecular-weight heparin or warfarin in the high-dose dexamethasone arm. S. Vincent Rajkumar, and Morie A. Gertz Correspondence: S. Vincent Rajkumar, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: rajkumar.vincent{at}mayo.edu. References Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma [letter]. N Engl J Med. 2006;354: 2080. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352: 549-557.[Abstract/Free Full Text] Steurer 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: 101-103.[CrossRef][Medline] [Order article via Infotrieve] Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma [letter]. N Engl J Med. 2006;354: 2079-2080.[Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma S. Vincent Rajkumar, Suzanne R. Hayman, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer, Brian Kabat, Steven R. Zeldenrust, Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust, Stephen J. Russell, Robert A. Kyle, Thomas E. Witzig, and Morie A. Gertz Blood 2005 106: 4050-4053. [Abstract] [Full Text] [PDF] This article has been cited by other articles: M. Zangari, L. M. Fink, F. Elice, F. Zhan, D. M. Adcock, and G. J. Tricot Thrombotic Events in Patients With Cancer Receiving Antiangiogenesis Agents J. Clin. Oncol., October 10, 2009; 27(29): 4865 - 4873. [Abstract] [Full Text] [PDF] A. A. Khorana and G. C. Connolly Assessing Risk of Venous Thromboembolism in the Patient With Cancer J. Clin. Oncol., October 10, 2009; 27(29): 4839 - 4847. [Abstract] [Full Text] [PDF] P. Rana and M. N. Levine Prevention of Thrombosis in Ambulatory Patients With Cancer J. Clin. Oncol., October 10, 2009; 27(29): 4885 - 4888. [Abstract] [Full Text] [PDF] E. T.H. Yeh and C. L. Bickford Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2231 - 2247. [Abstract] [Full Text] [PDF] D. C. Johnson, S. Corthals, C. Ramos, A. Hoering, K. Cocks, N. J. Dickens, J. Haessler, H. Goldschmidt, J. A. Child, S. E. Bell, et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping Blood, December 15, 2008; 112(13): 4924 - 4934. [Abstract] [Full Text] [PDF] E. N. Brown and J. D. Herrington Review of the Relationship Between Venous Thromboembolism, Malignancy and Its Treatment Journal of Pharmacy Practice, April 1, 2008; 21(2): 126 - 137. [Abstract] [PDF] C. W. Francis, A. K. Kakkar, M. N. Levine, and G. H. Lyman Prevention of Venous Thromboembolism in Patients with Cancer ASCO Educational Book, January 1, 2008; 2008(1): 250 - 256. [Abstract] [Full Text] [PDF] G. H. Lyman, A. A. Khorana, A. Falanga, D. Clarke-Pearson, C. Flowers, M. Jahanzeb, A. Kakkar, N. M. Kuderer, M. N. Levine, H. Liebman, et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer J. Clin. Oncol., December 1, 2007; 25(34): 5490 - 5505. [Abstract] [Full Text] [PDF] D. M. Weber, C. Chen, R. Niesvizky, M. Wang, A. Belch, E. A. Stadtmauer, D. Siegel, I. Borrello, S. V. Rajkumar, A. A. Chanan-Khan, et al. Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America N. Engl. J. Med., November 22, 2007; 357(21): 2133 - 2142. [Abstract] [Full Text] [PDF] A. Palumbo, P. Falco, P. Corradini, A. Falcone, F. Di Raimondo, N. Giuliani, C. Crippa, G. Ciccone, P. Omede, M. T. Ambrosini, et al. Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA Italian Multiple Myeloma Network J. Clin. Oncol., October 1, 2007; 25(28): 4459 - 4465. [Abstract] [Full Text] [PDF] K. V. Rao Lenalidomide in the treatment of multiple myeloma Am. J. Health Syst. Pharm., September 1, 2007; 64(17): 1799 - 1807. [Abstract] [Full Text] [PDF] R. Fonseca and A. K. Stewart Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach Mol. Cancer Ther., March 1, 2007; 6(3): 802 - 810. [Abstract] [Full Text] [PDF] V. Sanchorawala, D. G. Wright, M. Rosenzweig, K. T. Finn, S. Fennessey, J. B. Zeldis, M. Skinner, and D. C. Seldin Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial Blood, January 15, 2007; 109(2): 492 - 496. [Abstract] [Full Text] [PDF] J. Hirsh Risk of Thrombosis With Lenalidomide and Its Prevention With Aspirin Chest, January 1, 2007; 131(1): 275 - 277. [Abstract] [Full Text] [PDF] C. L. Bennett, C. Angelotta, P. R. Yarnold, A. M. Evens, J. A. Zonder, D. W. Raisch, and P. Richardson Thalidomide- and Lenalidomide-Associated Thromboembolism Among Patients With Cancer JAMA, December 6, 2006; 296(21): 2558 - 2560. [Full Text] [PDF] R Baz, E Walker, M. Karam, T. Choueiri, R. Jawde, K Bruening, J Reed, B Faiman, Y Ellis, C Brand, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy Ann. Onc., December 1, 2006; 17(12): 1766 - 1771. [Abstract] [Full Text] [PDF] J. A. Zonder Thrombotic Complications of Myeloma Therapy Hematology, January 1, 2006; 2006(1): 348 - 355. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zonder, J. A. Articles by Gertz, M. A. Search for Related Content PubMed PubMed Citation Articles by Zonder, J. A. Articles by Gertz, M. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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