Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, and Division of Hematology/Oncology, Veterans Administration Pittsburgh Healthcare System, Research and Development, PA 15232, USA.
Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. The multiple myeloma-induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions. Recently the biologic mechanism involved in the imbalance between osteoclast activation and osteoblast inhibition induced by multiple myeloma cells has begun to be clarified. In this article, the pathophysiology underlying the imbalanced bone remodeling and potential new strategies for the treatment of bone disease in multiple myeloma are reviewed.
"Bone abnormalities such as osteoporosis, compression fractures, and lytic lesions are characteristic of MM and are present in approximately 80% of patients at the time of diagnosis.22 MM cells secrete osteoclast activating factors such as RANKL, IL-3, macrophage inflammatory protein, and IL-6, while levels of the RANKL decoy receptor osteoprotegrin, which regulates osteoclast activity, are decreased in patients with the disease.23 In addition, increased levels of osteoblast inhibitors dickhofp-1 (DKK1), IL-7, and IL-3 in MM diminish bone anabolism.24 "
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy characterized by clonal expansion of plasma cells within the bone marrow, the presence of a serum and/or urine monoclonal protein, lytic bone lesions, and anemia. On a cellular level, the disease is characterized by complex interactions between tumor cells and the surrounding bone marrow microenvironment. Understanding of the relationship between malignant plasma cells and the microenvironment has sparked ongoing efforts to develop targeted therapeutic agents for treatment of this disease. The successful development of the first-in-class small-molecule proteasome inhibitor bortezomib occurred as a result of these efforts. This review focuses on the rationale for bortezomib therapy in the treatment of patients with newly diagnosed and relapsed MM, important treatment-related side effects, and future directions for use of bortezomib and other, emerging proteasome inhibitors.
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