Usual risk factors do not predict venous thromboembolism in newly diagnosed myeloma treated with immunomodulatory drugs
Authors: Emilie Chalayer, Céline Chapelle, Xavier Leleu, Ismail Elalamy, Silvy Laporte, Bernard Tardy
Journal: American Journal of Hematology (2016)

Immunomodulatory drugs (IMIDs) brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and refractory multiple myeloma (MM). However, IMIDs are associated with an increased thromboembolic (TE) risk 1, 2 and we read with great interest the article by Rajkumar reporting the treatment for patients with MM and specifically on the prevention of TE complications 3. We strongly agree with the author's perspective that IMiDs require specific management. Indeed, current guidelines have proposed aspirin or low-molecular-weight heparin (LMWH) for thromboprophylaxis in MM patients, treated with IMIDS, based on TE risk stratification. The International Myeloma Working Group recommended aspirin for patients with no more than one TE risk factor and prophylactic LMWH or full-dose warfarin for patients with two or more TE risk factors 4. The American Society of Clinical Oncology recommended aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone 5. In fact, the major problem with these strategies is that no one knows precisely which factors are TE risk factors in MM patients treated with IMIDs. Indeed, in a large French prospective multicenter observational study in 524 MM patients receiving IMIDs in either first, second or third line of chemotherapy (MELISSE) 6, designed to evaluate the venous TE (VTE) incidence and the associated risk factors in a real-life practice, only a shorter time duration from diagnosis to IMIDs initiation and a recombinant erythropoietin (rEPO) treatment were found to have a significant impact on VTE risk. In the MELISSE study, most patients (86%) received thromboprophylaxis with either aspirin (59%), LMWH (17%) or VKA (9%). VTE reported at 4 and 12 months occurred in 7% on aspirin, 3% on LMWH, none on VKA and 9% in the absence of thromboprophylaxis. In another American large retrospective study including 604 consecutive patients with newly diagnosed MM, the authors concluded that thalidomide and prophylactic rEPO were the only two factors identified as predictors of VTE 2. In this study, in which 25% of patients (152/604) received prophylactic dose of LMWH, an incidence of VTE of 11.3% was reported after completion of three induction cycles with multiagent chemotherapy. As patients with newly diagnosed MM treated with thalidomide seem to display a particularly high risk of VTE, we decided to carry on a new analysis of MELISSE database focused on newly diagnosed MM, to identify in real-life practice the VTE risk factors in such patients. A total of 190 IMiDs-treated MM patients were considered for this analysis; among them 189 patients were evaluable regarding VTE events at 4 months and 178 patients at 12 months. Thirty-one percent of patients were treated with prophylactic dose of LMWH (45 patients) or full-dose of VKA (14 patients) and 57% of patients received a median dose of 75 mg per day of aspirin. The median age of the study population was 75.5 years old, with 57% of patients being over 75 years old. The sex ratio was 1.21 (104 males/86 females). The characteristics of patients and VTE risk factors are presented in table on Supporting Information material. In this analysis, we reported VTE events, defined as pulmonary embolism (PE) and/or deep vein thrombosis (DVT), at 12 months in 18 patients (10.1%; 95% CI 6.1–15.5; 9 PE and 12 DVT); 10 patients with events (5.3%; 95% CI 2.6–9.5) were reported at 4 months (5 PE and 7 DVT) and 8 patients with events (4.5%; 95% CI 2.0–8.7) were reported between 4 and 12 months (4 PE and 5 DVT). The median age of these 18 patients with VTE was 76.5 years, the sex ratio was 2 (12 males/6 females), 13 received thalidomide and 5 lenalidomide, associated with rEPO in 9 patients. Concerning thromboprophylaxis, 2 patients received LMWH, 14 received aspirin, and two patients had no thromboprophylaxis. Using multivariate logistic regression model to identify risk factors predicting TE events at 12 months (two-sided level 5%), only the treatment with rEPO was found to be an independent VTE risk factor (OR 3.7, 95% CI = 1.34 − 10.20; P = 0.01; Table 1). Thus, while usual VTE risk factors were recorded in this observational study, none of them except rEPO were identified as predictor of VTE in newly diagnosed MM patients treated with IMIDs. Therefore, it seems that higher-risk IMID treated patients are only those receiving rEPO and all these patients should be treated with prophylactic LMWH. Neither the retrospective study 2 nor this prospective register, allow to conclude about other VTE risk factors. This lack of data on additional risk factors makes the use of guidelines difficult. The use of hyperviscosity, high-dose dexamethasone, and the following factors as stated above are potential areas of future study. In addition, as it was already reported 2, 6, 7, this analysis could not show that the choice of VTE prophylaxis had an impact on the occurrence of VTE, but these studies were not designed or powered to assess the efficiency of thromboprophylaxis. Considering the risks and costs associated with the different type of antithrombotic treatments and the fact that different impact of different risk factors is not taken into account, society guidelines recommending thromboprophylaxis in patients with MM should be revisited. Moreover, as high level recommendations cannot exist, it is important to develop recommendations in this field on the basis of experience. Data on rEPO have to be added to all guidelines and we need prospective studies to propose a reliable VTE risk stratification in such patients. Emilie Chalayer,1* Céline Chapelle,2,3 Xavier Leleu,4 Ismail Elalamy,5 Silvy Laporte,1,2,3 and Bernard Tardy1,2,3 1Centre d'investigation Clinique CIC 1408, CHU Saint Etienne, France 2Unité de Recherche Clinique, Innovation, Pharmacologie, CHU Saint-Etienne, France 3INSERM UMR 1059, Equipe DVH, Université J Monnet, Saint Etienne, France 4Haematology department clinique, CHU de Poitiers, France 5Hôpital Tenon, APHP, France Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.