Lenalidomide was approved by the US Food and Drug Administration (FDA) for 
treatment of transfusion-dependent lower-risk myelodysplastic syndrome patients 
with deletion (del) (5q) alone or with additional karyotype abnormalities. The 
approval was based on high rates of prolonged transfusion independence and 
complete cytogenetic response in this subset. In lower-risk non-del(5q) 
patients, meaningful erythroid responses also were reported with a low frequency 
of cytogenetic improvement, although inferior to that observed in the del(5q) 
patients. There is now a better understanding of the mechanism of the 
karyotype-dependent drug action, explaining the disparate response rates and 
frequency of myelosuppression. In del(5q) patients, lenalidomide suppresses the 
clone by inhibiting the nuclear sequestration of the haplodeficient cell cycle 
regulatory protein cdc25c, thereby promoting selective G2 arrest and apoptosis. 
In non-del(5q) patients, lenalidomide enhances erythropoietin receptor 
signaling. Future directions include use of biologic and molecular markers as 
predictive tools to select patients and use of combination strategies to 
overcome resistance to lenalidomide in del(5q) patients or enhance 
erythropoiesis in non-del 5 patients.