Treatment with lenalidomide enhances the activation of calpains (CAPNs), a family of Ca2+-dependent cysteine proteases, that is dependent on the expression of CRBN and GPR68, and CAPN inhibitor PD150606 completely reverses the tumoricidal effect of lenalidomide on MDSL cells and TF-1 cells (an AML cell line with del(5q)), indicating that lenalidomide activates a GPR68/Ca2+/CAPN pro-apoptotic pathway in MDS/AML cells. Here, CTSB is linked to acute myeloid leukemia.