Anti-Angiogenic Effect of Bortezomib Treatment in Multiple Myeloma is Associated with Lower NF-κB and OPN Expression

Abstract

Background: Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. It proliferates by inducing neovascularization of the bone marrow stroma. Both nuclear factor kappa B (NF-κB) and osteopontin (OPN) pathways are considered crucial in the development of various tumors, including MM. Bortezomib is a proteasome inhibitor well established as a first-line treatment in MM. This study aimed to demonstrate in vivo anti-angiogenic effects of bortezomib in MM patients who responded to therapy by analyzing whether the expression of NF-κB was associated with OPN and microvessel density (MVD) as well as overall survival (OS). Methods: Thirty patients who were newly diagnosed MM were enrolled in a study to investigate possible associations between neovascularization, expressed as microvessel density, NF-κB, and osteopontin expression in myeloma cells from bone marrow biopsy (BMB) pretreatment and posttreatment samples. This study used paraffin-embedded BMB before and after therapy with bortezomib. Immunohistochemical staining was performed to analyze the samples. Results: After bortezomib treatment, BMB samples showed significantly fewer plasma cell infiltrates (PCI) (p < 0.001), lower percentages of NF-κB (p < 0.001), and OPN (p = 0.023) in plasma cells, and reduced MVD (p = 0.009) compared to pretreatment. A significant positive correlation was observed between NF-κB and OPN expression in plasma cells before and after bortezomib treatment in BMB samples (r_s = 0.57, p = 0.002; and r_s = 0.50, p = 0.007; respectively). Additionally, significant positive correlations were observed between NF-κB and OPN with MVD in pretreatment BMB samples (r_s = 0.500, p = 0.018; and r_s = 0.502, p = 0.017; respectively). Patients with higher MVD posttreatment had significantly shorter overall survival (OS) rates (p = 0.025). Conclusions: Bortezomib treatment results in a significant decrease of MVD (angiogenesis) and PCI in BMBs of MM patients who responded to treatment. Furthermore, lower posttreatment MVD is associated with a longer OS. It seems that NF-κB and OPN inhibition could be the new therapeutic targets for MM patients, whilst MVD assessment before and after treatment with bortezomib (and other proteasome inhibitors) should be incorporated into routine diagnostic procedures.