A Phase II Study of Bevacizumab and Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma
Rationale: With the identification of thalidomide as an active agent in Multiple Myeloma,
the role of angiogenesis in its pathogenesis has become a subject of much investigation.
Micro vessel density (neovascularization) is inversely related to prognosis in Multiple
Myeloma. Response to thalidomide was felt to correlate with a decline in microvessel density
(Singhal et al NEJM). While the mechanism of neovascularization is yet to be fully
elucidated, a number of models have shown VEGF to play a central role.
Thalidomide has been shown to synergize with a number of agents used to treat MM, including
bortezomib. (Wang et al ASH 2005) This would justify the use of other therapeutics with
known antiangiogenic activity in conjunction with established antimyeloma therapies.
Bortezomib, which has the precedence of known synergy with Thalidomide and has an extremely
well established optimal dose, schedule, response rate, event free survival, and overall
survival would make it an excellent candidate for combination therapy with other established
There have been several reports of the role of VEGF in multiple myeloma. It has been shown
that multiple myeloma cells secreteVEGF, which further promotes production of IL-6 in BMSCs,
as well as migration and proliferation of the tumor cells. Thus VEGF is both an autocrine
growth factor and trigger of IL-6-mediated paracrine multiple myeloma cell growth. Recent
reports have highlighted the major role of VEGF in multiple myeloma pathogenesis,
demonstrating the VEGF also increases microvessel density in the bone marrow. VEGF also
inhibits dendritic cells. Taken together, these preclinical reports make strong suggestion
for the promise of VEGF targeted agents in multiple myeloma (Le Gouill et al 2004).
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Time to Tumor Progression (TTP)
David S Siegel, MD, PhD
The Cancer Center at Hackensack University Medical Center
United States: Food and Drug Administration
|The Cancer Center at Hackensack University Medical Center||Hackensack, New Jersey 07601|