Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

Bioequivalence study of single-dose lenalidomide capsule vs. Revlimid® capsule in healthy Chinese males.

OBJECTIVE: Lenalidomide is a 4-amino-glutaryl derivative of thalidomide and belongs to a new generation of immunomodulatory agents for the treatment of patients with myelodysplastic syndrome and multiple myeloma. The aim of this study is to evaluate the bioequivalence and safety of a capsule containing 25 mg of a test formulation of lenalidomide and a 25 mg Revlimid® capsule in healthy, Chinese adult males for good quality anti-cancer medicine with lower costs. METHODS: This was a single-center, randomized, open-label, single-dose, two-period, crossover pharmacokinetic study. Forty-eight healthy, adult Chinese males were administered a test lenalidomide or Revlimid® capsule, 24 in a fasted and 24 in a fed state, followed by crossover to the other capsule. RESULTS: Twenty-four subjects in the fasting group and 23 in the postprandial group completed the clinical trial. Subjects administered test lenalidomide and Revlimid® capsules in the fasting state had a Cmax of 564 ± 153 and 609 ± 121 ng/mL, respectively; an AUC0-t of 1660 ± 211 and 1660 ± 235 h ng/mL, respectively; and an AUC0-∞ of 1670 ± 210 and 1670 ± 237 h ng/mL, respectively. In the fed state, the subjects had a Cmax of 389 ± 105 and 383 ± 101 ng/mL, respectively; an AUC0-t of 1770 ± 314 and 1740 ± 360 h ng/mL, respectively; and an AUC0-∞ of 1800 ± 316 and 1760 ± 362 h ng/mL, respectively. Both capsules were well tolerated, with no serious adverse events observed. CONCLUSION: According to the criteria for bioequivalence, the test formulation of lenalidomide and Revlimid® was determined to be bioequivalent.

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 (AUC0-24) 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 AUC0-24 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·mL, P = 0.027). Receiver-operating characteristic curve analysis showed that the AUC0-24 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·mL (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 AUC0-24 can be clinically used to prevent severe AEs.