Multiple myeloma (MM) remains incurable, with a median survival of 3 to 4 years. This study shows direct effects of vascular endothelial growth factor (VEGF) upon NIM and plasma cell leukemia (PCL) cells. The results indicate that VEGF triggers tumor cell proliferation via a protein kinase C (PKC)-independent Raf-1-MEK-extracellular signal-regulated protein kinase pathway and migration via a PKC-dependent pathway. These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM. (C) 2001 by The American Society of Hematology.