Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma

Departments of ¹Hematology and Immunology and ²Pathology, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium; ³Ortho Biotech Oncology Research & Development, Johnson & Johnson Pharmaceutical R&D, Beerse, Belgium; and ⁴Section of Musculoskeletal Science, University of Sheffield Medical School, Sheffield, United Kingdom

^* To whom correspondence should be addressed. E-mail: Karin.Vanderkerken{at}vub.ac.be.

	Abstract

The proteasome inhibitor bortezomib (Velcade) is currently approved as second-line treatment of multiple myeloma (MM). MM-related bone disease is one of the most debilitating complications of MM. Besides supportive care with biphosphonates, which have proven efficacy in reducing and delaying skeletal-related events, there is no specific treatment of lytic bone lesions. The present study investigated the effect of bortezomib alone or in combination with a hydroxamate-based histone deacetylase inhibitor, JNJ-26481585 on tumor burden, and MM bone disease in the 5T2MM model. Injection of 5T2MM cells into C57Bl/KaLwRij mice resulted in MM bone disease, characterized by an increase in the percentage osteoclasts, a decrease in osteoblasts, trabecular bone volume, trabecular number, and the development of bone lesions. Treatment of 5T2MM-bearing mice with bortezomib significantly reduced tumor burden, angiogenesis, and MM bone disease. More importantly, the combination of bortezomib with JNJ-26481585 resulted in a more pronounced reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib as single agent. These data suggest that bortezomib has bone remodeling properties that can be improved in combination with low dose JNJ-26481585. The study indicates that this combination therapy could be a useful strategy for the treatment of MM patients, especially in those patients with skeletal complications. [Cancer Res 2009;69(13):5307–11]

Key Words: multiple myeloma, 5TMM model, histone deacetylase inhibitor, JNJ-26481585, bortezomib