Embryo-fetal Exposure and Developmental Outcome of Lenalidomide Following Oral Administration to Pregnant Cynomolgus Monkeys

Lenalidomide is an immunomodulatory drug and is very effective in the management of a number of malignancies, including multiple myeloma. Like thalidomide, lenalidomide interacts with the cereblon E3 ligase complex, which results in targeted destruction of proteins. This study was conducted to study the teratogenic potential of lenalidomide when administered to pregnant cynomolgus monkeys. Lenalidomide was administered orally on gestation days 20-50 at dosages of 0 (vehicle control), 0.5, 1, 2 and 4 mg/kg/day. Thalidomide was used as a positive control and was administered orally at 15 mg/kg/day on gestation days 26-28. Each group consisted of 5 pregnant monkeys. Pregnancy was terminated on gestation day 100 +/- 1 by cesarean section and fetuses examined for external, internal and skeletal changes. Intrauterine loss was 40% in the thalidomide group and 20 % in each of the lenalidomide 2 and 4 mg/kg/day groups. Treatment with lenalidomide and thalidomide resulted in no effects on placental weights, fetal body weights and body measurements. External fetal examination revealed malformations in fetuses of all lenalidomide-treated groups, including malformations of upper and lower extremities. These external malformations had correlated skeletal findings and were similar to those seen in the thalidomide-treated group, where two of three fetuses showed the classic thalidomide syndrome of malformed upper and lower extremities. A no-observed-adverse-effect level was not identified in this study, and the mean maternal exposures at the lowest dosage, where fetal malformations were observed, were 5-folder lower than the exposures observed in the MM patients treated with 25 mg of lenalidomide.