Study of circulating endothelial cells in multiple myeloma: biological aspects and effect of novel agents

Background. There is accumulating evidence from preclinical studies that circulating endothelial cells (CEC) and their precursors (CEP) (ie. mobilized EC from the BM in response to angiogenic cytokines) are involved in tumor angiogenesis. Rare in healthy individuals, CEC and CEP are increased in cancer patients (pts). CEC or CEP enumeration has been proposed as surrogate biomarker for (anti-angiogenic) treatment response and is currently being applied in multiple clinical studies. Preclinical studies also suggest a role of CEP in tumor regrowth after therapy. Cytotoxic agents administered at MTD induce a rapid CEP mobilization during therapy-free intervals, with possible paradoxal rebound angiogenesis. This CEP mobilization can be inhibited by anti-angiogenic agents, resulting into sustained EC suppression. In MM, angiogenesis is increased in the BM and the effect of novel agents such as Bortezomib (VEL) and Thalidomide (THAL) is partially mediated by inhibition of BM angiogenesis. Aims. In the present study, we evaluated CEC and CEP numbers in MM pts and monitored their kinetics during therapy with Melphalan (MEL)-, THAL- and VEL- based regimens. Methods. CEC (CD31+CD45-CD34+CD133-) and CEP (CD34+CD133+CD45dim cells) were enumerated among blood mononuclear cells by multicolor FACS at baseline and at multiple time points during treatment. Baseline levels and changes during treatment were correlated with response and survival. Results. At baseline, MM pts (n=71) show significant higher CEC and CEP levels vs. healthy controls (n=10) (7 and 2,5-fold increase, P