Phase II Clinical Trial of Lenalidomide and Dexamethasone Therapy in Japanese Elderly Patients With Newly Diagnosed Multiple Myeloma to Determine Optimal Plasma Concentration of Lenalidomide

Background: The authors conducted a phase II clinical trial of lenalidomide and dexamethasone combination therapy in Japanese elderly patients with newly diagnosed multiple myeloma to evaluate its safety and efficacy and to determine whether safety and efficacy correlate with the plasma concentration of lenalidomide. Methods: Forty patients received oral lenalidomide on days 1-21 of a 28-day cycle in addition to weekly doses of dexamethasone. Plasma concentrations of lenalidomide were measured, and the area under the concentration-time curve from 0 to 24 hours (AUC(0) (24)) of lenalidomide was predicted using a formula the authors previously reported in this journal. Results: The median age was 75.5 years. Twenty-one patients had renal impairment severe enough to require dose adjustment of lenalidomide. The median initial doses of lenalidomide and dexamethasone were 12.5 and 20 mg, respectively. The overall response rate was 68.6%, and the 2-year overall survival rate was 88.5%. There was no correlation between the response rate and plasma concentration of lenalidomide. Grade 3-4 adverse events (AEs) were observed in 57.5% of patients. The AUC(0) (24) of lenalidomide was significantly higher in patients with grade 3-4 AEs than in those who did not suffer from AEs (median = 4852.0 versus 2464.9 ng . h(-l). mL(-1), P = 0.027). Receiver-operating characteristic curve analysis showed that the AUC(0) (24) of lenalidomide was a good predictor of grade 3-4 AEs, with an area under the receiver-operating characteristic curve of 0.758 (95% confidence interval, 0.572-0.943, P- 0.027). The cutoff value for best prediction of grade 3-4 AEs was 2613.5 ng. h(-1). mL(-1)(sensitivity 86.7%, specificity 54.5%). Multivariate logistic analysis confirmed the significance of this cutoff value. Conclusions: These data suggest that overexposure to lenalidomide could contribute to toxicity. Furthermore, the predicted cutoff value of AUC(0) (24) can be clinically used to prevent severe AEs.