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Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial

Leukemia volume 28, pages 413–416 (2014)Cite this article

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In multiple myeloma (MM), increased angiogenesis of the bone marrow (BM) involves a complex interplay of proangiogenic and antiangiogenic molecules induced by plasma cells (PCs) within the BM microenvironment, with eventual balance tipped in favor of an ‘angiogenic switch,’ as the disease transitions to MM from preceding monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM).1, 2 The dynamic nature of angiogenesis can be exploited by highly active anti-myeloma agents, such as thalidomide, its derivatives, the immunomodulatory drugs (IMiDs™) and proteasome inhibitors, which not only interfere with tumor vessel growth, but also cause significant regression of the tumor vasculature both in vitro and in vivo. Therefore, there is great interest in studying the role of angiogenesis in MM to define therapeutic targets, prognostic and predictive biomarkers, as well as monitor disease activity longitudinally.

The results showed that while MVD was low in samples of BM obtained from patients with MGUS (median, 15.0), it increased in those with SMM (median, 19.4) and MM (median, 20.9; Table 1A). MVD linearly increased along the myeloma spectrum (MGUS<SMM<MM; Table 1A); P=0.008. DCE-MRI obtained kep and Ktrans values are listed in Table 1A. Higher kep and MVD were seen in MM/SMM vs MGUS patients (kep median 7.1 vs 3.9; P=0.08; MVD median 20.30 vs 15.00; P=0.01; Table 1B). MVD and kep were moderately strongly correlated in all patients (r=0.59; P=0.001). Ktrans was weakly-to-moderately well correlated with MVD (r=0.43; P=0.03). Circulating levels of Ang2 (P=0.02), granulocyte-colony stimulating factor (G-CSF; P=0.06), follistatin (P=0.06), hepatocyte growth factor (HGF; P=0.01) and vascular endothelial growth factor-A (P=0.02) were elevated in MM/SMM patients in comparison to MGUS (Table 1B). The levels of HGF (r=0.45; P=0.02), Ang2 (r=0.37; P=0.06) and VEGFD (r=−0.36; P=0.07) were weakly-to-moderately well correlated with kep. However, there was no correlation between any of the tested angiogenic biomarkers and MVD.

Table 1A Comparison of MVD, kep and Ktrans among patients with MGUS, SMM and MM
Full size table
Table 1B Comparison of MVD, kep and serum angiogenic markers between MGUS and SMM/MM groups
Full size table

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, NCI. The study is listed at ClinicalTrials.gov, identifier NCT01237054.

Author Contributions

O Landgren, K Kurdziel and E Tan, designed the study. E Tan coordinated the enrollment of patients and collected clinical data for the patients on this trial. N Korde, AR Minter, BM Weiss and O Landgren saw the patients in clinic. I Maric and A Berg did the main analysis by immunohistochemistry to define MVD. B Turkbey did the main analysis by DCE-MRI. P Choyke and K Kurdziel reviewed the imaging data. M Purdue and J Hofmann performed preliminary quality control analyses for the serum angiogenesis markers and developed the protocol for measurements in selected patients. T Kemp and L Pinto did the ELISA cytokine analysis. M Bhutani and A Berg compiled clinical, imaging, serum marker and bone marrow data for statistical analysis. S Steinberg did the statistical analysis. M Bhutani, I Maric and O Landgren wrote the manuscript. All the authors were involved in the interpretation of the results. All authors read, gave comments and approved the final version of the manuscript. All the authors had full access to the data in the study and take responsibility for the accuracy of the data analysis.

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Author notes

  1. B Turkbey & O Aras

    Present address: 7Current address: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA,

  2. B M Weiss

    Present address: 8Current address: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA,

  3. M Bhutani and E Tan: These authors contributed equally to this work.

  4. I Maric, K Kurdziel and O Landgren: These authors contributed equally to this work.

Authors and Affiliations

  1. Multiple Myeloma Section, CCR, NCI, NIH, Bethesda, MD, USA

    M Bhutani, E Tan, A R Berg, N Korde, A R Minter, B M Weiss & O Landgren

  2. Molecular Imaging Program, CCR, NCI, NIH, Bethesda, MD, USA

    B Turkbey, E Mena, L Lindenberg, O Aras, P L Choyke & K Kurdziel

  3. HPV Immunology Laboratory, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    T J Kemp & L A Pinto

  4. Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, MD, USA

    M P Purdue & J N Hofmann

  5. Biostatistics and Data Management Section, CCR, NCI, NIH, Bethesda, MD, USA

    S M Steinberg

  6. Hematology Section, CCR, DLM, NIH, Bethesda, MD, USA

    K R Calvo & I Maric

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Correspondence to O Landgren.

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Bhutani, M., Turkbey, B., Tan, E. et al. Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. Leukemia 28, 413–416 (2014). https://doi.org/10.1038/leu.2013.268

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