Efficacy and tolerability of PTK787/ZK 222584 in a phase II study of post-transplant maintenance therapy in patients with multiple myeloma following high-dose chemotherapy and autologous stem cell transplant.

摘要

Elevated serum levels of vascular endothelial growth factor (VEGF) have been reported in patients with multiple myeloma (MM) [1] and correlate with both increased angiogenesis in MM bone marrow [2-5] and a higher plasma cell labeling index [3,4]. Binding of MM cells to bone marrow stromal cells markedly up-regulates VEGF secretion [6]. Moreover, VEGF secreted by MM cells triggers interleukin-6 (IL-6) production from bone marrow stromal cells [7], thereby augmenting paracrine MM cell growth. Importantly, VEGF acts directly on MM cells. Specifically, VEGF receptor-1 protein (Flt-1), but not the VEGF receptor-2 (Flk-1, or KDR), is expressed on MM cell lines and patient cells. Exogenous VEGF has been shown to stimulate in vitro proliferation and migration of MM cells through an extracellular matrix [8,9]. Recent reports have demonstrated that bone marrow angiogenesis and microvessel density (MVD) are significantly increased in MM, and may play an important role in the pathophysiology and prognosis of MM [10] and hematological malignancies in general [11]. This provides the framework for targeting VEGF and Flt-1 as a novel therapeutic target in MM.