The cytotoxic effect of cnicin was evaluated in multiple myeloma. Cnicin treatment revealed potent antiproliferative effects and induced cell death in cell lines and primary myeloma cells even in the presence of survival cytokines and the tumor microenvironment. Other cell lines of hematopoietic origin also succumb to cell death whereas stromal cells and endothelial cells were unaffected. Combining cnicin with current standard or experimental therapeutics leads to enhanced cell death. The activation of caspases, accumulation of reactive oxygen species and downregulation of nuclear factor kappa-light-chain-enhancer of activated B cell contribute to the cytotoxic effects of cnicin. Microarray analysis reveals downregulation of Pim-2, a serine/threonine kinase. Pim-2 constitutes a new survival kinase for myeloma cells in vitro and is highly expressed in malignant but not in normal plasma cells in vivo. The authors concluded that cnicin induces myeloma cell death via several pathways and revealed Pim-2 as a novel target .