Myeloma aetiology and epidemiology.

Recently there have been substantial improvements in our understanding of the biology of myeloma. These findings have important implications for aetiological studies aimed at defining the causative factors for myeloma. Myeloma is closely related to monoclonal gammopathy of unknown significance (MGUS), which is now recognized to be very common in the older population. The epidemiology of these conditions is presented and discussed in the context of the genetic factors governing both the risk of developing MGUS or of transformation to myeloma. Biological studies support a role for aberrant class switch recombination early in the natural history of myeloma suggesting that factors in the environment may interact with this mechanism to increase myeloma risk. Case-control and cohort studies have identified several known and suspected environmental exposures. These exposures include high doses of ionizing radiation, and occupational exposure in the farming and petrochemical industries. The data supporting these associations are presented and discussed in the context of the molecular mechanisms underlying these exposures. In particular DNA damage occurring as a consequence could readily interact with the class switch recombination process to increase the risk of chromosomal translocations, oncogene deregulation and malignant transformation. A further hypothesis, which has been extensively investigated, is the role of chronic immune/antigenic stimulation and the risk of myeloma. This concept is difficult to explain in the context of our current immunological concepts. The data supporting the association and how molecular epidemiological studies using genetic variants in cytokine genes are allowing us to revisit this concept are discussed in detail.