Maintenance Therapy with Thalidomide/Prednisone Post Autologous Stem-Cell Transplant for Patients with Multiple Myeloma Elevates D-Dimer and Possibly Factor VIII Levels.

Abstract Background: Thalidomide is commonly used for the treatment of multiple myeloma (MM). Several studies have observed that venous thromboembolism (VTE) is a complication for up to 10% of patients receiving thalidomide therapy, especially when used as combination chemotherapy as part of primary treatment. Elevated Factor VIII and D-dimer levels are well described markers of thrombin generation and for an increased risk of VTE. The purpose of this study was to assess whether MM patients allocated to receive maintenance therapy with thalidomide and prednisone (thal/pred) post stem cell transplant for MM have increased levels of Factor VIII and D-dimer as laboratory confirmation for the reported increased clinical occurrence of VTE with thalidomide therapy. Methods: This is a correlative sub-study of NCIC CTG MY.10 which is an open-label randomized multicentre trial assessing the efficacy (time to progression) of maintenance therapy with the combination of thalidomide 200mg/day and prednisone 50mg every other day compared to no maintenance therapy post stem cell transplant. No clinical outcomes are available at this time as the study is ongoing. This laboratory companion study was incorporated in MY.10 a priori. Eligible patients were registered and randomized 60–100 days post transplantation. All consenting patients had plasma samples collected and frozen at baseline and two months post study enrollment. An unmatched comparison by MY.10 treatment arm was performed to assess the change in D-dimer and Factor VIII from baseline to two months for the first 79 patients entered into the trial. Results: There were 37 patients allocated to thal/pred (28 males, 76%) and 42 on observation (29 males, 69%). The mean ages were 56.6 and 55.8 years respectively. Based on continuous log D-dimer and log Factor VIII using two-way ANOVA, the results are shown in Table 1. Since D-dimer is also reported as positive or negative (<200 or =/>200μg/l) this was also assessed and the results as shown in Table 2. D-dimer results were significantly different (Bonferroni, p = 0.05) at two months compared with baseline for patients allocated to thal/pred rather than observation alone. At two months there were also significantly more patients allocated to thal/pred who had elevated D-dimers, 13 (72%) versus 5 (28%), (Bonferroni p < 0.05). There was a trend towards higher Factor VIII levels in patients allocated to thal/pred than on observation. Conclusion: These results provide clinical laboratory evidence of thrombin activation with the use of thal/pred post autologous transplant in patients with MM, and offer a potential mechanism, as well as, potential predictive markers for the clinical observations to date that patients receiving treatment with thalidomide for MM have an increased risk of VTE. Table 1 Mean Unadjusted Baseline 2 months p-value thal/pred Observation thal/pred Observaton (D-dimer μg/l) 119 101 137 75.6 0.03 FVIII (units/ml) 1.25 1.30 1.60 1.26 0.09 Table 2 D-dimer # ≥200(μg/l) Unadjusted p-value N thal/pred Observation Pearson Exact Chi-square Fisher Baseline 23 10 (43%) 13 (57%) 0.70 0.81 At 2 months 18 13 (72%) 5 (28%) 0.01 0.02