Novel Imaging Modalities to Characterize Angiogenesis in the Bone Marrow Microenvironment in Multiple Myeloma (MM) and Its Precursor Disease

Background:

• Multiple myeloma (MM) is a plasma cell neoplasm with a median survival of 3-4 years.
• Monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are premalignant plasma cell proliferative disorders characterized by elevated monoclonal protein and bone marrow plasma cells. MGUS affects 3.2% of Caucasians over the age of 50 and has a 1% annual risk of progression to MM. Approximately 3,000 cases of SMM are diagnosed annually with a 10% annual risk of progression to MM.
• Currently, it is not possible to predict which patients will progress to MM, and the biological changes occurring in those precursor states remain poorly understood.
• Angiogenesis is a hallmark of multiple myeloma and its precursor disease.

Angiogenesis has been measured using microvessel density. In a prior study, we have demonstrated increased microvessel density using CD34 immunohistochemistry in patients with multiple myeloma, compared to SMM or MGUS, suggesting that there is increased vascular density as the disease progresses. A correlation between MM disease stage and prognosis has been reported for several serum angiogenic factors and myeloma cells and bone marrow endothelial cells have been shown to secrete and respond to angiogenic modulators.

• Dynamic contrast-enhanced (DCE)-MRI is a noninvasive way to evaluate angiogenesis. In a prior NIH study, we have demonstrated that the kep (a measure of contrast influx in vessels in the bone marrow microenvironment) to be gradually higher in MM>SMM>MGUS, however it was limited to imaging a single field of view (i.e. the lumbar spine). This is also highly correlated with microvessel density.
• Fluciclatide is a small cyclic peptide containing the RGD tri-peptide, which preferentially binds with high affinity to Alpha(v)Beta(3) integrins, which are up-regulated in angiogenesis.
• Alpha(v)Beta(3) integrins are also expressed on certain types of tumor cells and on activiated osteoclasts.
• (18)Fluciclatide (previously known (18)F-AH111585) is a new radiopharmaceutical developed for PET imaging, which targets Alpha(v)Beta(3) receptors.
• Novel imaging modalities using tracers specific for angiogenesis, using (18)F-Fluciclatide whole-body PET/CT imaging may improve our ability to predict patients who are at high risk of progression.

Objectives: