Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.