Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine.Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 55–60% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.These constitutive genetic alterations in multiple myeloma cells and changes in gene-expression profiles mediate the protective effects of the bone marrow microenvironment on multiple myeloma cells.Multiple myeloma cells that home to the bone marrow have important functional sequelae. Specifically, the adhesion of multiple myeloma cells to extracellular matrix proteins confers cell adhesion-mediated drug resistance (CAMDR), and the binding of multiple myeloma cells to bone marrow accessory cells triggers the secretion of cytokines, which not only promote growth, survival and migration of multiple myeloma cells, but also confer resistance to conventional chemotherapy. Targeting these mechanisms offers a potential therapeutic strategy to overcome drug resistance.Several factors, including MIP1α and RANKL, stimulate osteoclast activity; on the other hand, DKK1 inhibits osteoblastogenesis in multiple myeloma. This imbalance between bone formation and resorption results in osteolytic lesions, which are a hallmark of multiple myeloma.New agents that target multiple myeloma cells, tumour–bone marrow interactions, or the bone marrow milieu, used alone or in combination, have shown promise in overcoming conventional drug resistance and improving patient outcome in multiple myeloma. Oncogenomics will allow for both patient selection and rational combination therapeutics.