Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy

Although thalidomide (Thal) was initially used to treat multiple myeloma (M M) because of its known antiangiogenic effects, the mechanism of its anti-M M activity is unclear. These studies demonstrate clinical activity of Thal against NIM that is refractory to conventional therapy and delineate mechan isms of anti-tumor activity of Thal and its potent analogs (immunomodulator y drugs [IMiDs]). Importantly, these agents act directly, by inducing apopt osis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex), Moreover, Th al and the IMiDs enhance the anti-MM activity of Dex and, conversely, are i nhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Tha l and the IMiDs is associated with activation of related adhesion focal tyr osine kinase, These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both t he tumor cell and the micro-environment, overcome classical drug resistance , and achieve improved outcome in this presently incurable disease. (C) 200 0 by The American Society of Hematology.