Abstract
Abstract
Background: Based on bone marrow (BM) biopsies, increased angiogenesis has been reported in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients compared with individuals with monoclonal gammopathy of undetermined significance (MGUS). In this prospective clinical trial open for MGUS, SMM and MM patients, we conducted BM biopsies and used immunohistochemistry to define microvessel density (MVD) in every patient; results were compared to results obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and multiplex ELISA-based serum angiogenic cytokine assays.
Patients and Methods: We included 10 MGUS, 10 SMM and 10 MM patients. We performed DCE-MRI of entire lumbosacral spine to compare exchange rate constants (contrast agent transit from the extravascular compartment to the intravascular compartment, Kep; movement of contrast agent from plasma to extravascular extracellular space, Ktrans) with bone marrow biopsies immunostained with CD34 as measures of MVD, and serum angiogenic markers By ELISA to include EGF, Ang2, GCSF, BMP9, endoglin, Leptin, Follistatin, IL8, HGF, HBEGF, PLGF, VEGFC, VEGFD, FGF2, VEGFA. The association among continous parameters was determined by Spearman rank correlation. Trends in continuous parameters according to ordered categorical parameter were determined by Jonckheere-Terpstra test for trend. The parameters between two groups were compared using an exact Wilcoxon rank sum test.
Results: Both MVD and Kep increased along the myeloma spectrum (MGUS < SMM < MM). MVD and Kep were strongly correlated (r=0.93 and p=0.002). Ktrans was weakly to moderately well correlated with MVD (r=0.43 p=0.03). Higher Kep values were seen in MM/SMM vs. MGUS patients (median 7.1 vs. 3.9; p=0.08). Similarly, higher MVD values were seen in MM/SMM patients versus MGUS (median 20 vs. 15; p=0.01). As regards serum angiogenic markers, levels of HGF (r=0.45; p=0.02), Ang2(r=0.37 and p=0.06), and VEGFD (r=-0.35 and p=0.07), correlated with Kep. The levels of Ang2 (p=0.02), GCSF (p=0.06), follistatin (p=0.06), HGF (p=0.01), and VEGFA (p=0.02), were elevated in MM/SMM patients in comparison to MGUS. Other angiogenic cytokines did not correlate with MVD or Kep.
Conclusions: MVD and Kep (measured by DCE-MRI) were highly statistically correlated. MVD increased along the disease spectrum from MGUS to SMM to MM (p=0.008). Some, but not all, angiogenic biomarkers detected in peripheral blood were associated with increased vascularity in the bone marrow.
Citation Format: Manisha Bhutani, Esther Mena, Irina Maric, Esther Tan, Neha Korde, Alexandra R. Berg, Alex R. Minter, Brendan M. Weiss, Liza Lindenberg, Baris Turkbey, Omer Aras, Seth Steinberg, Troy Kemp, Katherine R. Calvo, Peter L. Choyke, Karen Kurdziel, Ola Landgren. Role of bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2013-369