![]() ![]() By 1965, there were at least 10 published reports of families with 2 or more affected members and families with many combinations of affected members were described. In 1954, the first detailed case report of two sisters with proven MM was published by Mandema and Wildervanck. In a review of MM published in 1928, Geshickter and Copeland briefly mention a case in which two siblings both died of myeloma. In 1925, Meyerding highlighted 13 cases of MM in his series, one patient with myeloma had an aunt with a bone disease with a fractured leg. The idea of a potential familial predisposition to MM was first advanced in the 1920s. Here we focus on available data in this area and highlight future research directions. Several lines of direct and indirect evidence also suggest the existence of inherited factors, which may predispose individuals to development of MM, MGUS and other related cancers. While the causes of MM remain poorly understood, factors affecting risk for development of the disease include age, gender, racial and ethnic background, underlying immunodeficiency, exposure to radiation, exposure to dioxin-related compounds, and family history of MM and other hematolymphoid neoplasms. Alternatively, the risk of MM is very low in individuals of Asian descent. Striking racial differences in MM have long been noted, with the incidence in the black population being approximately twice that of the white population in the US. The incidence of MM varies widely, ranging from 0.4 to 5 cases per 100,000 persons, with the highest rates in Australia, New Zealand, North America and parts of Europe, and the lowest rates in Asia. It is estimated that in 2012, 21,700 people will be diagnosed and 10,710 people will die of MM in the US. About 75% of MM cases are diagnosed in persons over 50 years of age. Surveillance Epidemiology and End Results (SEER) data indicate that, in the United States, the median age at diagnosis of MM is 69 years, with an age-adjusted incidence of 5.8 cases per 100,000 persons per year. MM may be preceded by a monoclonal gammopathy of undetermined significance (MGUS), which is present in about 3% of the general population over the age of 50 years, and carries a risk of progression to MM of about 1% per year. Common clinical manifestations include lytic bony lesions, renal impairment, anemia, hypercalcemia and immune dysfunction. The disease is characterized by infiltration of the bone marrow, bones and sometimes other tissues by malignant plasma cells, which typically produce a monoclonal paraprotein. ![]() Multiple myeloma (MM) is a plasma cell neoplasm that accounts for 0.8% of cancer cases worldwide and comprises about 13% of hematologic malignancies. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. In addition, several targets of paraproteins (so called ‘paratargs’) in MM have been identified. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma.
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