A Pharmacokinetic Study Evaluating the Relationship Between Treatment Efficacy and Incidence of Adverse Events with Thalidomide Plasma Concentrations in Patients with Refractory Multiple Myeloma

Abstract Background Multiple myeloma (MM) is a clonal disorder of plasma cells, accounting for 10% of hematologic malignancies. Relapsed or refractory MM has a poor prsognosis. Thalidomide has been reported to be effective for these patients; however, high-dose thalidomide has induced many adverse events, including in the nervous, gastrointestinal, and hematopoietic systems in approximately 20%-50% of patients. Recently, low-dose thalidomide therapy has been used in many countries in order to reduce these adverse events. The objective of this study was to determine whether plasma concentration of thalidomide is related to the efficacy and the development of adverse events in patients with refractory MM treated with low-dose thalidomide plus low-dose dexamethasone. Patients and Methods A total of 66 patients (age range, 40-74 years) presenting with progressive disease after previous treatments were treated with low-dose thalidomide and low-dose dexamethasone. Thalidomide was administered orally at 100 mg/day for the first week. When severe adverse events did not develop, the dose was increased to 200 mg/day in the second week and was continued until progression. Dexamethasone was administered at a dose of 4 mg/day for the first 4 weeks, then decreased by 1 mg every week, and finally maintained at 1 mg/day. Plasma trough concentration of thalidomide 3 days after thalidomide treatment was analyzed by high-performance liquid chromatography in 45 patients (age range, 42-74 years) who agreed to participate in this study of thalidomide concentration analysis. Results The mean concentrations at 100 mg/day and 200 mg/day were 0.343 μg/mL (range, 0.05-1.45 μg/mL) and 0.875 μg/mL (range, 0.19-2.09 μg/mL), respectively. The overall response rate (near-complete response + partial response + minimal response) of this treatment was 73%. Five had stable disease, and 3 patients experienced progressive disease. There was no relationship between the concentration of thalidomide in the plasma and the efficacy ( P > .8). Severe adverse events, including grade > 2 nonhematologic and grade > 3 hematologic adverse events, were observed in 21 patients (46.6%). There was no significant difference in the concentration of thalidomide between the patients with and without severe adverse events ( P > .843). Conclusion The thalidomide concentration in the plasma does not predict treatment efficacy and the development of adverse events.