text: The role of angiogenesis in the support of myeloma was first discovered by Vacca in 1994. They discovered increased bone marrow angiogenesis correlates with myeloma growth and supporting stromal cells are a significant source for angiogenic molecules in myeloma. This is believed to be a main component of the mechanism in vivo by which thalidomide inhibits multiple myeloma.
  Additionally, inflammatory responses within the bone marrow are believed to foster many hematological diseases. The secretion of IL-6 by bone marrow stromal cells (BMSC) and the secretion of the adhesion molecules VCAM-1, ICAM-1 and LFA, is induced in the presence of TNF-α and the adhesion of MM cells to BMSC. In vitro proliferation of MM cell lines and inhibition of Fas-mediated apoptosis is promoted by IL-6. Thalidomide and its analogs directly decrease the up-regulation of IL-6 and indirectly through TNF-α, thereby reducing the secretion of adhesion molecules leading to fewer MM cells adhering to BMSC. Osteoclasts become highly active during MM, leading to bone resorption and secretion of various MM survival factors. They decrease the levels of adhesion molecules paramount to osteoclast activation, decrease the formation of the cells that form osteoclasts and downregulate cathepsin K, an important cysteine protease expressed in osteoclasts.