AUTHORS: G.D. Roodman1,2, N. Kurihara2, Y. Hiruma2
1VA Pittsburgh Healthcare System, Medicine/Hematology-Oncology, Pittsburgh, PA, USA
2University of Pittsburgh, Medicine/Hematology-Oncology, Pittsburgh, PA, USA
By Lynne Lederman, PhD
Bone lesions in multiple myeloma occur only adjacent to myeloma cells. Over the course of the disease about 60% of patients will experience a pathologic fracture. In contrast with osteolytic solid tumors such as breast cancer, where osteoblasts are present in the normal or increased numbers, in myeloma, osteoblasts are decreased in number. Osteoclasts are increased, and their growth is stimulated by factors produced by myeloma cells, stromal cells, and the adhesive interactions between these cells. Because myeloma bone disease can be blocked by inhibiting any one factor involved in the process (e.g., DKK1, IL-3, or SFRP2), it appears that subcritical levels are involved. Agents that target one or more of the signaling pathways involved are in clinical trial. These include a humanized monoclonal antibody, AMG162 (denosumab) that binds RANKL specifically, that is being compared with pamidronate. Another agent, SCIO-469, that inhibited bone resorption by targeting p38 MAPK, which is downstream of RANKL, is no longer in development. p62, which is in the RANKL pathway and required for stromal cell support, is another potential target. Other potential therapeutic targets are MIP-1α (using a CCR1/5 antagonist), IL-3 and IL 7 (using siRNA or soluble receptors), and DK1/sSFRP-2 (using p62 or a protein kinase C antagonist). Although Wnt signaling is also involved, Dr. Roodman felt that a Wnt agonist might promote tumor growth, as might induction of osteoblast activity, although it has not been seen with PTHrb in clinical trials. In myeloma, osteoblast paralysis might occur. When plasmacytomas are cured with radiation, the bone lesions don’t heal, as is the case with myeloma, suggesting that there is a problem with stromal cells or the microenvironment is left in an inhospitable state. Although anabolic agents are active in mouse models, their safety hasn’t been tested in patients. However, therapies that disrupt the interaction between myeloma cells and stromal cells should have a major impact on myeloma bone disease.