Risk Factors of Thromboembolic Events in Multiple Myeloma Treated with IMiDs-Based Therapy While on LMWH Prophylaxis,

Immunomodulator drugs (IMiDs) are promising oral agents in Multiple Myeloma (MM); and MM that cannot benefit from novel agents, including IMiDs, only have 9 months survival. On the other hand IMiDs are associated with an increased risk of thromboembolic events (TE) in MM, and must be stopped when TE occurs with a potential shortened life expectancy. Although DVT (Deep Venous Thrombosis), including PE (Pulmonary Embolism), was primarily observed, arterial events were also described. Guidelines have proposed LWMH for VTE prophylaxis for patients that displayed greater than 2 risk factors of VTE. Studies have showed a decrease incidence of TE since a prophylaxis was mandatory; however TE remained despite use of LMWH. We sought to characterize and study the incidence of TE in MM treated with an IMiDs-based regimen and having LMWH as TE prophylaxis, and to determine risk factors for patients to develop TE.

MMVAR/IFM 2005–04 is a large multicenter, prospective, randomized, open-label, phase 3, EBMT and IFM combined study that compared VTD to TD for MM patients in first progression after autologous transplantation. Treatment comprised 8 cycles of bortezomib 1.3 mg/m² IV bolus on days 1, 4, 8 and 11 of a 21-days cycle and then on days 1, 8, 15 and 22 of a 42-days cycle for 4 more cycles. In both arms, oral thalidomide was administered at 200 mg/day for 1 year with dexamethasone at 40 mg/day for 4 days every 3 weeks for 1 year. A TE prophylaxis was mandatory in both arms using enoxaparin 40 mg/day during one year. TTP was the primary end point. Response was assessed by EBMT criteria. Adverse events were graded by the NCI-CTCAE, Version 3.0.

The MMVAR trial was stopped because of superiority of VTD over TD at first interim analysis, as 157 relapsed were recorded out of 267 patients randomized in arm VTD (n=135) and arm TD (n=132), respectively. With a median follow-up of 27 months, the probability of achieving CR and CR+PR during the first year, the median TTP and PFS were greater in the VTD arm, although it did not translate into a better OS, yet. In the VTD and TD arms, the mean number of treatment cycles for the 12 cycles was 7.56 vs 9.93, respectively. Treatment was discontinued due to toxicity in 48 patients, including 8 (17%) related to occurrence of TE, and 33 patients died during the treatment period. There were 24 (8.9%) TE recorded, 12 in either arm; we have then decided to pool the 2 groups for the subsequent analysis. The characteristics of the MM with TE were not different from the overall population, 14 male/10 female, median age (range) was 63 (42–76) with 25% patients older than 65. The median (min-max) time from start of MMVAR to occurrence of TE was 3.4 months (0.3–11.9), not different in either arm. TE occurred in 16 (66%) vs. 8 (33%) patients in the first 4 months and after 4 months, respectively. 15 (62.5%) pts had at least some tumor burden reduction (minor response and better) at time of occurrence of TE, while 12.5% had progression of MM, 12.5% stable disease, and 12.5% were non evaluable. All TE occurred while pts were on LMWH prophylaxis since the initiation of the study treatment but one. The occurrence of TE impacted the treatment of MM as 16 (67%) pts did stop their IMiDs-based treatment, either transiently for 8 (33%) pts or definitely for 8 (33%) pts. The doses of the IMiDs were reduced for 5 pts when IMiDs were reintroduced. Overall only 5 pts had no change applied to their MM treatment while TE occurred. The occurrence of TE might have impacted response rate, CR rate, and the survival end points, TTP, PFS and OS. An update of this sub analysis will be presented at ASH with multivariate analysis to determine risk factors for occurrence of TE while on LMWH prophylaxis.

Although LMWH is recommended to patients with high risk of TE, the optimal dose and duration of LMWH remains to be determined. More studies are needed to determine risk factors of TE in MM patients treated with IMiDs-based regimen, and to guide physician in their routine practice with the optimal TE prophylaxis.

On behalf of the Myeloma Subcommittee of the Chronic Leukemia Working Party of the EBMT (European Group for Blood and Marrow Transplantation) and the IFM (Intergroupe Francophone du Myélome).

Leleu:Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; LeoPharma: Honoraria, Research Funding; Novartis: Research Funding. Masszi:Centocor Ortho Biotech Research & Development: Research Funding. Hajek:Merck:; Janssen: Honoraria; Celgene: Honoraria.