MELISSE, a Large Multicentric Observational Study to Determine Criteria and Risk Factors of Thromboembolism for Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Immunomodulator drugs (IMiDs) are new and very promising oral agents for initial treatment and for treatment of relapse in Multiple Myeloma (MM); however, IMiDs are also associated with an increased risk of venous thromboembolism (VTE) which necessitates routine prophylaxis. Guidelines (Palumbo et al, Leukemia 2008) have proposed either aspirin or low weight molecular heparin (LWMH) for VTE prophylaxis based on a VTE risk stratification. Controversies remain regarding the best choice of VTE prophylaxis regimen in MM patients treated with IMiDs-based therapy and the criteria for the VTE risk definition. More studies are needed to better determine the criteria required for patients to receive either aspirin or LWMH as VTE prophylaxis. We designed a large multicentre observational study aimed at prospectively evaluating the incidence and risk factors of thromboembolism associated with IMiDs [either lenalidomide (Len) or thalidomide (Thal)] therapy in MM.

A total of 519 patients with MM treated with first to third line of therapy were included in this study. Patients were treated with IMiDs-based therapy at entry in the study, and those receiving VTE prophylaxis had to start this prior to start IMiDs (the choice was solely that of the clinician). Patients gave written informed consent according to the declaration of Helsinki. Various patient characteristics were recorded, such as age, sex, criteria of vascular complications, including adjuvant treatment such as EPO, bisphosphonates, radiotherapy, and previous history of either deep venous thrombosis (DVT) or pulmonary embolism (PE), or arterial vascular complications. The physicians were to record the risk of VTE occurrence, breakdown as low, mild and high, based on guidelines and their own appreciation of the risk. Occurrence of any thrombosis event (either venous or arterial) was to be recorded along with the descriptive characteristics of the event, how the event was managed and the outcome of the patient. The data were collected at entry in the study, and then at 4 and 12 months.

Out of the 519 patients, 35.66% had Thal-based and 64.34% had Len-based therapy. Overall, median age was 71, with 64.67% >65 years old and sex ratio was 249 male/268 female, similar in the 2 groups (data missing for n=2). One hundred and eighty patients were in first line therapy, 169 in second line therapy and 153 in third line therapy (data missing for n=17). Patients were treated with VTE prophylaxis as follow (data missing for n=8); 293 (57.34%) aspirin, 91 (17.81%) LWMH and 46 (9.00%) vitamin K antagonists. Surprisingly, 81 (15.85%) patients had no VTE prophylaxis. Aspirin was administered in 164 (69.79%) of low risk patients and LWMH in 33 (45.83%) of high risk patients.

Investigators recorded 13 (3.65%) VTE at the 3564-months visits currently completed, with 7 DVT, 2 PE and 4 DVT+PE. Of these 13 VTE, 8 patients had aspirin, 1 had LWMH and 4 had no prophylaxis treatment. Of the 13 VTE, 1 patient was considered to have high risk of vascular complication and 12 patients either low or moderate risk, according to guidelines. The occurrence of VTE was unrelated to the regimen-based IMiD therapy and the line of therapy.

This study further demonstrates that occurrence of VTE is low in IMiDs-based treated MM patients upon VTE prophylaxis, and that VTE prophylaxis is needed for patients treated with IMiDs-based therapy. However, despite VTE prophylaxis, we observed occurrence of VTE. These results question whether the current guidelines on VTE prophylaxis in MM patients treated with IMiDs-based therapy are accurate. Final results will be proposed with updated results at ASH 2010.

Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Daley:LEO Pharma: Employment. Lamblin:LEO Pharma: Employment. Natta:LEO Pharma: Employment.