Paraproteinaemias: pathophysiology

Paraproteinaemias may be associated with benign or malignant proliferations of lymphocytes or plasma cells, including multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and Waldenström's macroglobulinaemia. Primary amyloidosis may be associated with multiple myeloma and rarely with lymphoid malignancies, but most cases can be considered as a particular form of monoclonal gammopathy of undetermined significance, where the paraprotein causes damage by virtue of its amyloidogenic properties. This article discusses recent advances in understanding of the biology of multiple myeloma. Multiple myeloma is now known to arise from a post-germinal centre B cell in the lymph node which homes to the bone marrow. Interactions with stromal cells in the marrow facilitate homing and growth of the myeloma cells. The stromal cells produce IL-6, which is an important growth factor for myeloma cells, while the myeloma cells produce factors such as TNF-alpha and IL-1 beta that activate osteoclasts, resulting in myeloma bone disease. Myeloma cells also produce vascular endothelial growth factor which results in increased microvessel formation in the marrow, promoting tumour growth. There has been interest in the possible role of the Kaposi's sarcoma associated herpes virus (HHV8) in multiple myeloma, following the demonstration of viral gene sequences in multiple myeloma marrow. However, results of further studies have been conflicting and at present there is no clear evidence for an aetiological role of HHV8 in multiple myeloma. Cytogenetic studies using modern techniques have demonstrated that almost all multiple myeloma cases are cytogenetically abnormal, the predominant abnormalities being various translocations involving chromosome 14q and deletions of chromosome 13. 14q translocations are equally common in monoclonal gammopathy of undetermined significance, but deletions of chromosome 13 seem to be associated with progression to multiple myeloma, and also have powerful prognostic significance for survival in multiple myeloma patients.