Document M42qGDevGRYrv5kxbVz0EJYxx

~~ ~ MULTIPLE MYELOMA ~ 08894588192 $0.00 + .20 THE EPIDEMIOLOGY OF MULTIPLE MYELOMA Denise A. Riedel, MPH, a n d Linda M. Pottern, PhD, MPH Multiple myeloma, a plasma cell tumor arising in the bone marrow, is a rare cancer with an elusive etiology. Mortality rates for myeloma were not readily available until 1950, at which time myeloma was removed from the general category of "lymphoreticular malignancies" and assigned a unique ICD code (203) in the Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death.ImThis recent ability to track myeloma rates provided a basis to study the descriptive epidemiology, which has since been well reported. However, risk factors for myeloma remain obscure. DESCRIPTIVE EPIDEMIOLOGY Incidence in the United States According to currently available US incidence data (1984 to 1988) from the Surveillance, Epidemiology, and End Results (SEER) Program, multiple myeloma accounts for 1.0% of all malignancies in whites and 2.0% in blacks.'" The average annual age-adjusted (1970 US standard) incidence rates per 100,OOO for whites are 4.7 in men and 3.2 in women, whereas for blacks, they are nearly double, at 10.2 in men and 6.7 in women.'u Socioeconomic factors, such as household size and family income, do not appear to explain this difference in rates between blacks and whites.", Of all the lymphoreticular neoplasms, multiple myeloma accounts for 31% among blacks and 13% among whites, whereas leukemias occur equally in blacks and whites at 31%.+' ' The incidence of multiple myeloma has been fairly stable among US whites since the early 1970s (Fig. 1);however, incidence among blacks increased from the 1970s into the early 1980s when it peaked, then decreased slightly." Poverty, as indicated by percent of persons with incomes below the poverty level, did not explain All material in this article ISin the public domain with the exception of any borrowed figures or tables. From the Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 6 NUMBER 2 APRIL 1992 225 226 IUEDEL & POTTERN 2 m a White males o White females Black males Black females the excess incidence among blacks, because the rates remained twice those for whites after adju~tment."~ SEER data for the period 1975 to 1985 indicate that other ethnic groups including native Hawaiians, female Hispanics and female American Indians from New Mexico,' and Alaskan nativesq5also experience higher myeloma rates relative to US whites from the same geographic region. Ethnic groups having lower incidence rates relative to their geographic white counterparts include Chinese and Japanese populations from Hawaii and San Francisco. Rates of the Filipino population of San Francisco and male Hispanics and male American Indians approximate those of whites.& A distinctive feature of myeloma is its late age of onset. Compared with the median age of diagnosis for all cancer in the United States for men and women, ages 68 and 66, respectively, the median age at diagnosis for myeloma is slightly higher, 69 for men and 71 for women.'* The average annual agespecific incidence rates increase sharply with age regardless of race or gender, and the rates for blacks are more than twice as high as those for whites at virtually every age (Fig. 2). A male predominance is seen in both races.'" Although definition of "urban" and "rural" vanes among geographic r e g i ~ n s , ~th~e.i'n~ci~dence for men in urban areas tends to exceed that in rural areas, whereas the rates for women are evenly distributed. However, differences by gender may seem small, because multiple myeloma incidence overall appears to be evenly distributed between urban and rural areas in 13 popula- tions from around the world, including the United States." '' I TP I: 7Myeloma incidence per 8o 20 0 20 30 40 = Dec: Black males 0White males Figure 2. Multiple myeloma average ar to 1988.Age plotted as the average of ! years. (From Ries LAG, Hankey BF, M Washington, OC,U S Government Prir 27891.) International Incidence Incidence of multiple rnyelc registries from around the world international cancer registry incic the populations served may vary (e.g., pathology versus death c diagnostic precision.'?' i'' In women. Incidence rates in nort American white populations, wht Kingdom, eastern Europe, and ! observed in Asian populations. Multiple myeloma incident, including Israel, the Scandinavia vakia, Australia, and New Zeala~ incidence over time. In Czecho myeloma incidence increased fro1 from 1955 to 1979,13' in Malmo, S from 1943 to 1962. In the Danisk 1963 to 1982, most likely due to I no increase in myeloma was ok 1 9 8 0 ~ .I'n~general, the increasin been followed recently by a le. observed among whites in the U Comprehensive incidence da able. The myeloma rates that underestimate, mainly owing tc case ascertainment.* Multiple 1960s and 1970s have suggested --Ef-----E3 White males 0 White females a Black males 0 Black females 1985 itandard population) incidence of multiple :o, Connecticut, Detroit, Iowa, and Atlanta) rom Devesa SS: Descriptive epidemiology ?ds):Epidemiology and Biology of Multiple 191, p 3.) se the rates remained twice those for '85 indicate that other ethnic groups ianics and female American Indians >sq5also experience higher myeloma le geographic region. Ethnic groups their geographic white counterparts Ins from Hawaii and San Francisco. ancisco and male Hispanics and male 4hites.* its late age of onset. Compared with er in the United States for men and median age at diagnosis for myeloma . women.'u The average annual agevith age regardless of race or gender, twice as high as those for whites at minance is seen in both races.Iu d "rural" varies among geographic an areas tends to exceed that in rural evenly distributed. However, differe multiple myeloma incidence overall I urban and rural areas in 13 popula- 'he United States.* '' THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 227 Myeloma incidence per 100,000 8 0 ll 60 40 I 20 0 20 30 40 SO 60 70 80 = Decade of age (years) Black males Black females 0White males White females Figure 2. Multiple myeloma average annual age-specific incidence for United States, 1984 to 1988. Age plotted as the average of two five-year age groups. Rates per 100,000 personyears. (From Ries LAG, Hankey BF, Miller EA, et al: Cancer Statistics Review 1973-1988. Washington, DC. US Government Printing Office, 1991 (DHHS publication (NIH) No. 91- 27891.) International Incidence Incidence of multiple myeloma from selected population-based cancer registries from around the world is shown in Figure 3.12'. i76. In Comparisons of international cancer registry incidence rates must be made cautiously because the populations served may vary with regard to accuracy of case ascertainment (e.g., pathology versus death certificate only), level of medical care, and diagnostic precision. 132 ITj In most countries, men have higher rates than women. Incidence rates in northern Europe are similar to those in North American white populations, whereas the rates are slightly lower in the United Kingdom, eastern Europe, and South America. Substantially lower rates are observed in Asian populations. Multiple myeloma incidence surveys conducted in different countries including Israel, the Scandinavian countries, Switzerland, France, Czechoslo- vakia, Australia, and New Zealand2*4.9 'm. i27. Irn also show increasing incidence over time. In Czechoslovakia" and Western Australia,iU multiple myeloma incidence increased from the 1960s to the mid 1980s, in New Zealand from 1955 to 1979,13' in Malmo, Swedenim from 1950 to 1979, and in Denmarkn from 1943 to 1962. In the Danish survey, however, the rates leveled off from 1963 to 1982, most likely due to changes in diagnostic criteria. In Switzerland, no increase in myeloma was observed between the late 1970s and the late 1 9 8 0 ~ .I'n~ general, the increasing incidence of myeloma over many years has been followed recently by a leveling off. This phenomenon has also been observed among whites in the United state^.^' Comprehensive incidence data for African populations are largely unavail- able. The myeloma rates that have been reported are thought to be an underestimate, mainly owing to limited diagnostic facilities and incomplete case ascertainment." * Multiple myeloma case series from Africa in the late 1960s and 1970s have suggested a younger median age at diagnosis than in the I 228 Tt United States, reflecting a younp These findings have persisted in Mortality in the United States Historically, mortality data ir longer period of time than in( monitored since the early 1950s incidence data since 1973. Rates i for mortality as well as for incidei has increased dramatically betwee over 55 have not been as great. i be due in part to improved medic populations,* or due to a true into the cohort of maximum risk mortality appears to have becor specific rates reveal that myelon in older age groups since the 19f (Fig. 4). Peak mortality has shifte International Mortality Multiple myeloma mortality ' and the increase has been most 1 Some view the increased mortali! and earlier diagnosis and increat increase to be reaLW The countries where death Japan, and Hungary) have had th This is in contrast to countries R New Zealand, and Finland, or cou and Wales, and France, where th percent increase in mortality dun Because men and women have sl environmental exposure, rather tt influence on multiple myeloma rr Survival The prognosis for multiple r nosed from 1981 to 1987, US blacL rate than whites, 28.37~and 26.2 \vere higher for women than for for blacks and 27.5% versus 25. favorable among those with high( , ii ,;- Other studies did not SUP study of US multiple myeloma p ability to travel to receive treatme had a more favorable survival 1- f CD Y) t (3 N mz I 0 THE EPIDEMIOLOGY 3 F MULTIPLE MYELOMA 2 9 United States, reflecting a younger population and a sizable male excess.". These findings have persisted in an update of a Kenyan case series.lZ Mortality in the United States Historically, mortality data in the United States have been available over a longer period of time than incidence data. Myeloma mortality has been monitored since the early 1950s, whereas the SEER program has provided incidence data since 1973. Rates among nonwhites exceed those among whites for mortality as well as for incidence. Among nonwhites over age 55, mortality has increased dramatically between 1950 and 1988, whereas increases for whites over 55 have not been as great. The dramatic increases in mortality rates may be due in part to improved medical technology, particularly in older, high-risk populations,", 170 or due to a true upward shift in the risk for individuals born into the cohort of maximum risk in the late ~ ~ O O OSve.r ~th~e past 20 years, mortality appears to have become more stable, as has the incidence. Agespecific rates reveal that myeloma mortality has increased disproportionately in older age groups since the 1950s, especially among those over age 60 years (Fig. 4). Peak mortality has shifted over time from age 60 to age 80. International Mortality Multiple myeloma mortality has been increasing in a number of countries, and the increase has been most pronounced in individuals age 55 and older.* Some view the increased mortality in the older age group as a result of better and earlier diagnosis and increased 10ngevity,l~w~hereas others consider the increase to be real." The countries where death rates have been lowest (including Greece, Japan, and Hungary) have had the largest increases for the period 1970 to 1985. This is in contrast to countries with traditionally high rates, such as Norway, New Zealand, and Finland, or countries with moderate rates, including England and Wales, and France, where the rate of increase is intermediate. The largest percent increase in mortality during the period was in the 70 to 74 age group." Because men and women have shown a similar pattern of increase, a common environmental exposure, rather than an occupational exposure, may have more influence on multiple myeloma mortality." Survival The prognosis for multiple myeloma is poor. Based on SEER cases diagnosed from 1981 to 1987, US blacks had a slightly higher 5-year relative survival rate than whites, 28.3% and 26.3%, respectively.lu The relative sunrival rates were higher for women than for men regardless of race: 29.3% versus 27.5% for blacks and 27.5% versus 25.0% for whites.lu Survival is generally more favorable among those with higher income and education, regardless of race.@. 133. 117 Other studies did not support this finding, however.". In a clinical study of US multiple myeloma patients," survival was related to the patient`s ability to travel to receive treatment, perhaps reflecting better prognosis. Blacks had a more favorable survival than whites after adjustment for potential mP P -.va-l) E 2 z0 P zm za 00, 0 41 0W 0%n 8 230 confounding variables including center." RADIATION EXPOSURES Exposure to ionizing radiatior: myeloma. DNA, and particularly is believed to be the target oi damage." Multiple myeloma occu survivors exposed to high dose> suggest a link with long-term, IOU Atomic Bomb Survivors The strongest evidence linkin by cancer mortality studies of aton bombed areas of Hiroshima City 1% greater risk of myeloma mortality of myeloma deaths between 1950 ai been attributed to the atomic radiat Radiation-Related Occupations Studies on the mortality experie have provided further information radiation. The excess of myeloma nearly 30 years ago.'"' In a more rc doses of long-term radiation had a t Increases in the incidence and who were ever employed in the US noted.'"' Large exposures to radium radium-containing paint to make fi were lacking. Greater incidence and length of employment than with intr Diagnostic and Therapeutic X-Rays Diagnostic x-ray exposure has myeloma. Some studies of diagnosl nonsignificant increased risk of myel whereas others have 4 1 . h Z Membe myeloma risk for more frequent x-r; Chinese diagnostic x-ray workers, no over a 30-year period when cornparel tions in which x-ray exposure was no The effects of therapeutic irradiat Studies of patients receiving therape have suggested an association with IT increased over time since first irradiz 0m (0D i? a0 I Q) a0, THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 231 confounding variables including age, sex, education, therapy, and treatment center.* RADIATION EXPOSURES Exposure to ionizing radiation is the most convincing risk factor for multiple myeloma. DNA, and particularly proto-oncogenes or "cancer genes" in DNA, is believed to be the target of potentially carcinogenic ionizing radiation damage." Multiple myeloma occurs after a long latent period in atomic bomb survivors exposed to high doses of radiation,155but studies of radiologists suggest a link with long-term, low-dose exposure to radiation.10'.II' Atomic Bomb Survivors The strongest evidence linking radiation to myeloma has been provided by cancer mortality studies of atomic bomb survivors.8'.155 Those who entered bombed areas of Hiroshima City within 3 days after the blast had nearly 60% greater risk of myeloma mortality than those not exposed.8' Nearly one third of myeloma deaths between 1950 and 1985 among atomic bomb survivors have been attributed to the atomic radiation in 1945.155 Radiation-Related Occupations Studies on the mortality experience of radiologists and radium dial painters have provided further information on the risk of multiple myeloma due to radiation. The excess of myeloma deaths among radiologists was observed nearly 30 years ago.Io1In a more recent study, radiologists exposed to lower doses of long-term radiation had a twofold excess myeloma risk."' Increases in the incidence and mortality from myeloma among women who were ever employed in the US radium dial painting industry have been noted.Ia Large exposures to radium resulted from licking brushes dipped into radium-containing paint to make fine tips." Accurate measures of exposure were lacking. Greater incidence and mortality were more strongly linked with length of employment than with internal radium intake. Diagnostic and Therapeutic X-Rays Diagnostic x-ray exposure has not been clearly linked with multiple myeloma. Some studies of diagnostic x-ray exposure have shown a small, nonsignificant increased risk of myeloma associated with this exposure,", 99. 61 whereas others have n ~ t . ~Me~mb. e~rs o~f a. p~rep~aid health plan had an excess myeloma risk for more frequent x-ray exposure.IBIn a study of over 27,000 Chinese diagnostic x-ray workers, no excess myeloma incidence was reported over a 30-year period when compared with workers in other medical occupations in which x-ray exposure was not likely.'" The effects of therapeutic irradiation on myeloma risk are inc~nsistent.'l~6 , Studies of patients receiving therapeutic radiation for ankylosing spondylitis have suggested an association with multiple rn~eloma.'~39. Myeloma mortality increased over time since first irradiation treatment among the spondylitics, 232 RIEDEL & POTTERN but the trend was not significant.]' A nested case-control study also reported a nonsignificant increase in myeloma risk for x-ray treatment. I' The mortality experience of US women, based on cancer registry data, who were initially irradiated for cervical cancer has shown no excess of myeloma.'5 Nuclear Facilities Several studies have indicated an increased risk of multiple myeloma mortality among workers in the nuclear i n d ~ s t r y , 'bb~. lI1. but not in another study.6 Most excesses of multiple myeloma mortality have been related to exposures between 10 to 15years prior to In an analysis of combined mortality data from the Hanford site, Oak Ridge National Laboratory, and Rocky Flats Nuclear Weapons Plant, multiple myeloma was the only cancer with a significantly increased risk.65The significance was mainly driven by the high risk among the Hanford workers. These studies suggest that chronic exposure in the workplace to low levels of radiation may be involved in the development of multiple myeloma. Investigations of residential proximity to nuclear facilities have provided little evidence of an increased risk of multiple myeloma. A recent US nationwide mortality survey found mortality from multiple myeloma among residents of counties with nuclear facilities similar to that among residents of counties without nuclear facilities.85Data on multiple myeloma incidence were not available in relation to the accident at the Three Mile Island nuclear power plant; however, increased rates were observed for lymphoma, especially non- Hodgkin's lymphoma."0 Mortality from myeloma was not elevated among residents living near a nuclear facility in France compared with those living farther away." Other studies that have inferred radiation exposure based on residential distance from the nuclear facility". have found no association with myeloma risk and proximity to the nuclear installations. A study of British participants in atmospheric nuclear weapons tests revealed increased risk for multiple myeloma among test participants when compared with unexposed controls.B More recently, a follow-up study among the New Zealand participanis in the same nuclear weapons tests revealed no incident myeloma cases over a 30-year period.'" Exposures incurred by British participants may have been greater, however, because the New Zealanders participated in at most 9 of 21 tests covered in the British study. OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES The role of occupational exposures on the risk of multiple myeloma remains unclear. The overwhelming majority of occupational associations with myeloma have been in agric~lture"a~nd have been most consistent for farming occupations. Nonspecific associations for metal, rubber, benzene, wood, leather, textile, petroleum, and miscellaneous occupations and industries have been reported in the epidemiologic literature. However, a very recent case-control study conducted in the Montreal area reported some elevation in myeloma risk based on detailed job descriptions."' Owing to the wide variety of potential exposures incurred in many of the occupations, causal associations with specific chemical agents or type of work are lacking. Some studies may also be of insufficient size to detect an association. Agriculture A number of epidemiologl, risk for multiple'myeloma in at 6.1 IZh 171. IO but a few have s h o w r been reported by some to be as$ sheep farming,')* exposure to b orchard farming. Agricultura myeloma risk include grain dusi exhaust5' from farm equipment. workers may encounter expos multiple myeloma.'" Because o studies, it is impossible to dett zoonotic viruses, animal insecti nation of these exposures are I mveloma. Increased risk of myeloma c e n t l y , l l 20 I17 1x1 particularly in change to modern chemical farn miologic studies of both case-cc have explored the association o and insecticides) and multiple m of multiple myeloma with pest] myeloma was not increased a p p ~ to farming or only to pesticide exposed to both farming and pes observed between pesticide use i cohort of licensed pesticide applii Few studies have evaluated I multiple myeloma. However, he include phenoxvacid herbicides elevated myeloma risk for exposL. rine and carbamate classes, and f~ classes of herbicides. Metals Exposures to various metals 1.11 li' 1% A significant increased I smelter and metallurgy workers"* nificant elevations in myeloma ris In a case-control study, myeloma arsenic, cadmium, and copper PO among whites but not among bl made it difficult to assess whether exposures explain the observed el( Workers at a Canadian nickel r mortality." In contrast, no apprec lymphoma mortality among Swei '\'ere potentially exposed to chrom been detected for trace levels of It mveloma mortality.' Lead exposL myeloma in a US hosp~tal-based cc , ted case-control study also reported a for x-ray treatment." The mortality cer registry data, who were initially IOexcess of myeloma.'. increased risk of multiple myeloma industry," butM Ill I i N not in another .oma mortality have been related to death.". liC In an analysis of combined 3 a k Ridge National Laboratory, and ultiple myeloma was the only cancer significance was mainly driven by the These studies suggest that chronic , of radiation may be involved in the Ity to nuclear facilities have provided iple myeloma. A recent US nationwide nultiple myeloma among residents of to that among residents of counties .ultiple myeloma incidence were not the Three Mile Island nuclear power ,served for lymphoma, especially nonI myeloma was not elevated among in France compared with those living inferred radiation exposure based on ility"-" have found no association with 2ar installations. I atmospheric nuclear weapons tests ieloma among test participants when ore recently, a follow-up study among me nuclear weapons tests revealed no ieriod.'" Exposures incurred by British owever, because the New Zealanders ired in the British study. 'AL EXPOSURES In the risk of multiple myeloma remains xcupational associations with myeloma en most consistent for farming occupa:tal, rubber, benzene, wood, leather, occupations and industries have been !. However, a very recent case-control :ported some elevation in myeloma risk >wing to the wide variety of potential ,ations, causal associations with specific lacking. Some studies may also be of THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 233 Agriculture A number of epidemiologic studies have indicated a significant increased risk for multiple myeloma in agriculture (predominantly farming),'). '. ~ 6 3.5. y). n2 137 '7' IW but a few have shown no association.".25,142.169 Multiple myeloma has been reported by some to be associated with hog production,z6dairy farming,'" sheep farming," exposure to beef cattle,'" working with farm animals,'16and orchard farming. 'I7 Agriculturally related exposures linked to an increased myeloma risk include grain dust,' dusty occupations," aflatoxins,'m and engine exhaustJ9from farm equipment. A study in Sweden suggested that agriculture workers may encounter exposures that evoke both allergic reactions and multiple myeloma.'" Because of the variety of associations reported in these studies, it is impossible to determine from these studies whether oncogenic zoonotic viruses, animal insecticides, agricultural chemicals, or some combination of these exposures are responsible for the increased risk of multiple myeloma. Increased risk of myeloma has occurred among farmers born more recently,ll. 26. 137. 1.10 particularly in industrialized countries, which may reflect a change to modern chemical farming methods over the past 40 yeamZ7Epide- miologic studies of both case-control". 26. 27. w, 138 and prospectiveln designs have explored the association of agricultural pesticides (including herbicides and insecticides) and multiple myeloma. Morns et allu reported a 2%-fold risk of multiple myeloma with pesticide use. Boffetta et all' found that risk for myeloma was not increased appreciably among those who were exposed only to farming or only to pesticides, but that risk rose dramatically for those exposed to both farming and pesticides (odds ratio = 4.3).No association was observed between pesticide use and myeloma in an Italian study" or among a cohort of licensed pesticide applicators.Im Few studies have evaluated links between specific pesticide exposures and multiple myeloma. However, herbicides potentially associated with myeloma include phenoxyacid herbicides and chlorophenoIs.l3. BurmeisteP found elevated myeloma risk for exposure to the crop insecticides of the organochlorine and carbamate classes, and for the dinitroaniline, thiocarbamate, and urea classes of herbicides. Metals Exposures to various metals have been linked with myel~ma.'~57., 67. 123. 157. I59 A significant increased risk of myeloma has been observed among smelter and metallurgy workers'I6 and sheet metal workers,Lnwhereas nonsig- nificant elevations in myeloma risk have been noted for foundry I6l In a case-control study, myeloma was associated with lead vapors and liquid, arsenic, cadmium, and copper powder and fumes.'= These excesses occurred among whites but not among blacks. Insufficient exposure information has made it difficult to assess whether particular metal fumes, metal dusts, or other exposures explain the observed elevations in risk. Workers at a Canadian nickel refinery had a significant increase in myeloma morta1ity.j' In contrast, no appreciable associations were found for myeloma/ lymphoma mortality among Swedish workers grinding stainless steel, who were potentially exposed to chromium and nickel.lS A positive correlation has been detected for trace levels of lead and cadmium in US water supplies and myeloma mortality.' Lead exposure was not found to be a risk factor for myeloma in a US hospital-based case-control study.Im 234 RIEDEL & POTTERN Rubber Manufacturing Employment in the rubber manufacturing industry may be a risk factor for multiple mye10ma.'~Excess mortality rates of myeloma have been observed among white and nonwhite female rubber workers.'. A majority of these women worked in the industrial products division where rubber bands, hoses, belts, and molded rubber goods were made.Ix A slight increase in myeloma incidence was observed among Swedish male and female rubber w ~ r k e r s . ' ~ Increased incidence was particularly associated with individuals who had a longer exposure time to the chemical weighing and mixing process, because their period of employment encompassed a time when dust control was minimal. Results are inconsistent among white male rubber workers. Greater mortality was observed in one study,45but not in another."' A slight excess, based on small numbers, occurred among black male reclaim w ~ r k e r s . `I~n a mortality study of male British rubber industry workers, no link with multiple myeloma was detected.lM Benzene and Other Chemicals Benzene has been suggested as a possible etiologic agent of multiple myeloma42because its metabolites are known bone marrow toxins. Myeloma incidence has been found to be statistically higher among benzene exposed cohorts," and a statistically significant excess of myeloma and leukemia mortality has been observed among workers exposed to benzene in the manufacture of rubber hydrochloride.145 In a nested case-control study of chemical workers,131there was a trend association with benzene exposure of 5 years or more, although another caseconhol study reported no as~ociation.'A~~cohort of firefighters was found to have a significant increase in myeloma mortality; however, benzene exposure is only one of the myriad of chemicals present in most structural fires.8J An excess of deaths from myeloma and malignant lymphomas combined was noted in a Swedish study of chemical factory workers who were exposed to a variety of established or suspected carcinogens including piperazine, urethane, formaldehyde, benzyl chloride, ethylene oxide, and epichlorohyd r i n n Risk of myeloma was markedly elevated in a cohort of chemical workers exposed to epichlorohydrin and chemical groups including antioxidants and nitriles."' A significant increase in myeloma mortality was observed among male aircraft maintenance workers exposed to methylene chloride, and female workers exposed to chlorinated and aromatic hydrocarbons including perchloroethylene.I6' A mortality study of Canadian metal workers revealed a significant increase of multiple myeloma among machinists,- who were potentially exposed to hard metallic alloys, cutting oils, and mineral oil lubricants in the production of machine parts. A mortality study of metal fabrication workers with similar exposures in New York state found no myeloma excess.Ia Among embalmers and funeral directors potentially exposed to formaldehyde, funeral directors had a significant excess of lymphatic and hematopoietic cancer mortality, but embalmers did not.82The excess occurred among blacks but not among whites. Wood, Leather, and Textile Industries and Occupations Associations between myeloma risk and employment in the wood industry have been mostly with the pulp and paper making processes. A nonsignificant increased risk of mortality from 1 has been noted among paper anc paper factory workers in Sweden.. between work in wood-related indL Myeloma has been observed I the leather tanning industry had a of myeloma," and a study of shc increase among men and greater tl An assoaation with myelom;: linkage study of Swedish cancer in, revealed a nearly threefold increast textile workers in the wool indusi nonsignificant risks for Danish wo published data). On the other han North Carolina textile workers and no significant multiple myeloma mc Petroleum Industry and Fuel Comt An excess of deaths due to c observed in several petroleum refi others.w iR A case-control study of thc work history records did not find sp product exposure.lMA recent study tially exposed to asphalts, tars, gas report elevated myeloma mortality. Exposures to carbon monoxide a fuel, or automobile exhausts, coal ft myeloma risk.35j9 However, anoth, of myeloma cases among subjects ex1 products, or chemical solvents. Hair Dyes Epidemiologic studies of multiple or cosmetologist have reported both (unpublished data).16'One potential wt Hair dyes contain aromatic, nitro, and to be mutagenic in laboratory anima multlple myeloma have specifically a both found an elevated risk among M `"mmunication, 1991) who dyed their Permanent hair color than for semi- or among users of dark hair-coloring PI Increased with longer duration of hair nication, 1991). Miscellaneous Environmental and Occ Positive associations between mu1 hcl\'c' been reported in case-control and iring industry may be a risk factor for es of myeloma have been observed Jer workers.' I" A majority of these I division where rubber bands, hoses, ade.'" A slight increase in myeloma I male and female rubber workers.Th ociated with individuals who had a 2ighing and mixing process, because jed a time when dust control was white male rubber workers. Greater Jut not in another."' A slight excess, ig black male reclaim workers.'j In a iustry workers, no link with multiple possible etiologic agent of multiple nown bone marrow toxins. Myeloma :ally higher among benzene exposed xcess of myeloma and leukemia mor!xposed to benzene in the manufacture qemical workers,"' there was a trend years or more, although another caseA cohort of firefighters was found to nortality; however, benzene exposure resent in most structural fires.'' and malignant lymphomas combined :a1 factory workers who were exposed ed carcinogens including piperazine, l e , ethylene oxide, and epichlorohyevated in a cohort of chemical workers :a1 groups including antioxidants and =loma mortality was observed among sed to methylene chloride, and female matic hydrocarbons including perchloidian metal workers revealed a signifimg machinists,"' who were potentially oils, and mineral oil lubricants in the ity study of metal fabrication workers te found no myeloma excess.'" ictors potentially exposed to formaldeexcess of lymphatic and hematopoietic The excess occurred among blacks and Occupations and employment in the wood industry per making processes. A nonsignificant THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 235 increased risk of mortality from lymphoma and multiple myeloma combined has been noted among paper and pulp workers in New Hamp~hire''a~nd in paper factory workers in Sweden.%Other studies have not shown a relationship between work in wood-related industries and muliple myeloma.".35. 92. Myeloma has been observed in studies of the leather industry. Workers in the leather tanning industry had a nearly twofold nonsignificant increased risk of m ~ e l o m a , 'a~nd a study of shoe manufacturing workers noted a twofold increase among men and greater than a threefold increase among ~ o m e n . ~ " An association with myeloma and textile processing is contradictory. A linkage study of Swedish cancer incidence data and occupational census dataIl6 revealed a nearly threefold increased risk of multiple myeloma among women textile workers in the wool industry, whereas Pottem et a1 found elevated, nonsignificant risks for Danish women employed in the textile industry (unpublished data). On the other hand, proportional mortality studies of female North Carolina textile workers and male Rhode Island textile workers revealed no significant multiple myeloma mortality." 55 Petroleum Industry and Fuel Combustion Products An excess of deaths due to cancers of the lymphatic tissue has been observed in several petroleum refinery populations5'. m. IO5 '**. Is2 but not in others.3.78A case-control study of the petroleum industry that utilized company work history records did not find specific associations with work category and product exposure.IMA recent study of highway maintenance workers potentially exposed to asphalts, tars, gasoline, engine exhaust, and lead did not report elevated myeloma m ~ r t a l i t y . ~ Exposures to carbon monoxide as a consequence of exposure to diesel, jet fuel, or automobile exhausts, coal fumes, and smoke have been linked with myeloma risk.35j9. However, another study" did not find a significant excess of myeloma cases among subjects exposed to gasoline or diesel exhausts, coal products, or chemical solvents. Hair Dyes Epidemiologic studies of multiple myeloma and employment as a beautician or cosmetologist have reported both positive7' Ib1 and negative associations (unpublished data).I6' One potential workplace exposure is hair dye application. Hair dyes contain aromatic, nitro, and amino compounds that have been shown to be mutagenic in laboratory animals.* Two recent case-control studies of multiple myeloma have specifically assessed hair dye usage, however, and both found an elevated risk among women185and men (LM Brown, personal communication, 1991) who dyed their hair. Risk among women was higher for permanent hair color than for semi- or nonpermanent color, and it was higher among users of dark hair-coloring products.1n5Among men, myeloma risk increased with longer duration of hair dye use (LM Brown, personal communication, 1991). Miscellaneous Environmental and Occupational Exposures Positive associations between multiple myeloma and exposure to paint have been reported in case-control and prospective studies.I01F 'lo. A recent 236 RIEDEL h POTERN study in New Zealand reported higher myeloma risk among car, spray, and sign painters than general painters.'O Risk for spray painters may be higher because of increased exposure to nonvolatile components in the paints. The association between multiple myeloma and exposure to asbestos has been reported in some case-control studies35.I m and one prospective but not in other studies.l`.%.lU. A significant exposure-response gradient was reported for individuals with multiple myeloma who were exposed to asbestos for at least 10 years as compared with hospital control^.'^ Also associated with a nonsignificant excess risk of myeloma was photography and exposure to electric cable.35An increased risk was reported for janitors and cleaners, and for exposure to cleaning agents and disinfectant~.'~A'n association between occupational exposure to electromagnetic fields and multiple myeloma was not shown in two studies attempting to evaluate this relationship.I'*. A cohort study of Swedish chimney sweeps reported a marginally significant increase in multiple myeloma incidence.= Potential occupational exposures included polycyclic aromatic hydrocarbons (formed by combustion of coal, wood, coke, and oil) and metals such as arsenic, nickel, and chromium." A nonsignificant excess of multiple myeloma was reported among a cohort of abrasive manufacturing workers whose potential work exposures included dusts from aluminum oxide and silicon carbide processing.% Nonoccupational Exposures Prescription and over-the-counter medications have been suggested as myeloma risk factors in several case-control studies. Friedmanb1found propoxyphene use to be predictive for multiple myeloma. A possible association with prior use of phenytoin, phenobarbital, diazepam, propranolol, ibuprofen, diet drugs, stimulants, and laxatives has been suggested.105A mortality study of health plan members in California found a significant elevation in myeloma for prior use of erythromycin, chlorpheniramine, gentamicin sulfate, sulfamethoxazole, and terpin hydrate.'" It is unclear whether the responsible factor for the increased myeloma risk was the prescription drug or the medical condition that was being treated with the drug; however, the probability of chance findings cannot be ruled out. Multiple myeloma has not been found to be strongly related to either cigarette smoking or alcohol consumption. One Swedish case-control study reported inconsistent results; ex-smokers had an elevated risk, but current smokers did not.9 Several other case-control studies", 21. IO5 have found ~~ no increased risk for tobacco use. An increased myeloma risk for ever having smoked cigarettes has been reported in a follow-up study of Seventh Day Adventists, with significant trend associations for number of cigarettes smoked and years smoked.'MNo such pattern was observed in a cohort study of US veterans.8" Previous case-control studies have found no appreciable association between alcohol consumption and myeloma'46.2, IO5 A recent case-control study of white men found a significant increased risk for myeloma and alcohol consumption, particularly among those who consumed combinations of beer, wine, and hard liquor (LM Brown, personal communication, 1991). Biologc mechanisms linking myeloma etiology to alcohol consumption have not been adequately explored. TI Familial and Genetic Factors Familial occurrence of myelor has been no conclusive evidence I disease. Recent research has for human leukocyte antigen (HLA), environmental vari'ables that corrc Case Reports Among Family Me! Previous reports documented and spouses. Of 37 families witfcancer occurred among siblings Northern Ireland had multiple m rently, although the monoclonal t. within each family.'IrIn another fa and two brothers both had monc studies have also reported the occu members." '' "*Associations with I history of autoimmune disorders' diseases," and a nonsignificant e, among first-degree relatives. l9 An suggested by cases of multiple my( Genetic Marker Studies Over the last decade, several been conducted to determine the cases have with respect to immuno tested 68 myeloma patients and 3 differences in HLA type; however, studies revealed a significant incre; controls. An HLA typing of two si. antigens; however, the sisters had did they share a common M-prc myeloma in nontwin brothers whg monoclonal immunoglobulin of the Early studies of HLA and mult~ 8 locus"'; however, more recent ass An association of multiple myeloi allotype was reported in a study of 2 '* As part of a popula myeloma among US blacks and wk of HLA-Cw2 was observed for cases white men.!* Although myeloma 1 for both black and white men, it dc cancer among black men. Chromosomal Abnormalities One important cytogenetic abn myeloma is the l l q + abnormality, myeloma risk among car, spray, and sk for spray painters may be higher itile components in the paints. yeloma and exposure to asbestos has jies35. lLl5 and one prospective study"' licant exposure-response gradient was veloma who were exposed to asbestos >spital controls.'5 Also associated with a was photography and exposure to !ported for janitors and cleaners, and jinfectants. 157 An association between I fields and multiple myeloma was not uate this relationship.""sweeps reported a marginally signifin ~ e . P' ~otential occupational exposures qons (formed by combustion of coal, IS arsenic, nickel, and chromium.-' A ]ma was reported among a cohort of 2 potential work exposures included 2arbide processing." medications have been suggested as trol studies. Friedmad' found propox' myeloma. A possible association with liazepam, propranolol, ibuprofen, diet !en suggested.105A mortality study of i a significant elevation in myeloma for amine, gentamicin sulfate, sulfamethlear whether the responsible factor for scription drug or the medical condition ; however, the probability of chance ound to be strongly related to either tion. One Swedish case-control study 2rs had an elevated risk, but current ontrol studies1' LL. 'I. have found ncreased myeloma risk for ever having in a follow-up study of Seventh Day ations for number of cigarettes smoked was observed in a cohort study of US found no appreciable association bena" *?. Ius A recent case-control study of 2d risk for myeloma and alcohol convho consumed combinations of beer, ,rsonal communication, 1991). Biologic to alcohol consumption have not been THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 237 Familial and Genetic Factors Familial occurrence of myeloma has been well established; however, there has been no conclusive evidence implicating multiple myeloma as an inherited disease. Recent research has focused on various genetic markers including human leukocyte antigen (HLA), chromosomal abnormalities, oncogenes, and environmental variables that correlate with multiple myeloma. Case Reports Among Family Members and Spouses Previous reports documented multiple myeloma occurring among siblings and spouses. Of 37 families with at least two members with myeloma, the cancer occurred among siblings in 25 of the families.'% Three families in Northern Ireland had multiple myeloma in two first-degree relatives concurrently, although the monoclonal type of immunoglobulin varied in both cases within each family.IL5In another family, a sister had kappa light chain myeloma and two brothers both had monoclonal IgG kappa myeloma.% Case-control studies have also reported the occurrence of multiple myeloma in related family rnembers.l9.'I. IO6 Associations with myeloma include significant links with family history of autoimmune disorders'* and degenerative central nervous system diseases,') and a nonsignificant elevated risk for family history of myeloma among first-degree relatives. l9 An environmental role in myeloma etiology is suggested by cases of multiple myeloma occurring among spouses.*'. 88. w.91. Genetic Marker Studies Over the last decade, several genetic studies of multiple myeloma have been conducted to determine the similarities and differences that myeloma cases have with respect to immunogenetic markers.R.IO8. IOp Ludwig and M a y F tested 68 myeloma patients and 3000 controls for HLA types and noted no differences in HLA type; however, a larger analysis including data from other studies revealed a significant increase of HLA-B5 among cases compared with controls. An HLA typing of two sisters with myeloma revealed identical HLA antigens; however, the sisters had no common chromosomal abnormality, nor did they share a common M-protein.'08 Grosbois et alR reported multiple myeloma in nontwin brothers who were identical for the HLA genotype of monoclonal immunoglobulin of the IgG kappa isotype variety. Early studies of HLA and multiple myeloma found a n association with the B locus"); however, more recent associations have been found with the C locus. An association of multiple myeloma with HLA-Cw5 antigen and G3m(g5) allotype was reported in a study of 22 black myeloma patients and 138laboratory 41 As part of a population-based case-control study of multiple myeloma among US blacks and whites, a significantly higher gene -frequency of HLA-Cw2 was observed for cases compared with controls for both black and white men.'% Although myeloma risk appears to be enhanced by HLA-Cw2 for both black and white men, it does not explain the higher incidence of the cancer among black men. Chromosomal Abnormalities One important cytogenetic abnormality of etiologic relevance to multiple myeloma is the 14q+ abnormality, first reported by Wurster-Hill et all% in 238 RIEDEL h POTERN 1973. Gould et a170examined 115 myeloma patients for karyotypic abnormalities and found that the translocation t(8;14)(q24;q32) was statistically associated with IgA myeloma protein. The same translocation has been associated with 80%of all Burkitt's lymphoma cases.151Another translocation, t(11;14)(q13;q32), has been observed in various B-cell abnormalities including multiple myeloma, chronic lymphocytic leukemia, and plasma cell leukemia.a B-lymphoproliferative disorders are often associated with chromosomal abnormalities of the light chain immunoglobulin loci, on chromosomes 2 and 22, and the heavy chain immunoglobulin locus on chromosome 14." A recent case review of the cytogenetic literature from the 1960s through the 1980s" revealed 453 myeloma patients of whom 124 had a complete karyotype analysis. Of these 124 patients, 32% had various chomosomal abnormalities involving chromosome 14. Other structural and numerical chromosomal aberrations in myeloma patients have been reportedIo2;however, at this time no specific chromosomal abnormality has been linked to multiple myeloma. Oncogenes Recent studies have implicated malignant transformation by oncogenes in the pathogenesis of multiple myeloma.J. Ig, 70. I". Is) Increased levels of c-myc mRNA have been detected in myeloma plasma cells in 9 of 37 myeloma patients, and two of these patients had c-myc gene rearrangement^.'^) A case series from Japan found 4 of 11 advanced myeloma patients had high c-mnyc RNA expression that in turn correlated with high levels of myeloma cellular proliferation.'" This suggests that transformation of myeloma cells occurs only in response to increased expression and activation of the c-myc gene. Coamplification of c-myc and the pvt-locus in myeloma is rare,4 and the role of other genes in tumor development remains unknown. One investigation noted an activated m s " gene in a myeloma cell line that had a rearranged myc allele.58 Other oncogenes that so far have an undefined role in myeloma etiology include the B-cell lymphomafleukemia genes bcl-1 and bcl-2." PRE-EXISTING MEDICAL CONDITIONS Because multiple myeloma is a plasma cell tumor, the role of the immune system in the cancer's etiology is of primary interest. An excess of certain preexisting immune-stimulating medical conditions has been observed in myeloma cases, suggesting that chronic antigenic stimulation (CAS) of the immune system may be an important factor in the development of myeloma. However, not all studies have reported the same findings owing to inconsistencies in defining CAS, differences in the lag time between the medical condition and the diagnosis of myeloma, and the quality of medical information obtained. Recent epidemiologic StudieS14.31. 35. 62. 71, 93. 105 1x3 181 have explored the CAS hypothesis by utilizing medical history information, namely, past exposures to viral or bacterial illnesses, immunizations, allergies, or autoimmune disorders. A number of case-control studies have examined the relationship between myeloma and history of certain medical conditions. A study in Italy" found that scarlet fever, BCG vaccination, and chronic bacterial disease were significant risk factors for multiple myeloma. Risk rose with increasing number of bacterial illnesses. A nonsignificant twofold risk was observed for history of herpes zoster, pyelonephritis, tuberculosis, and malaria. In contrast, no increase in risk was found for scarlet f l malaria in a British study and , No association between myelomi $vas observed in a study conduc based case-control study in four myeloma risk was found for irstudy also reportgd significantl!, mononucleosis, and rheumatic tuherculosis, urinary tract infectic for gonorrhea.'" A separate anal! a nonsignificant increase in risk f c and hepatitis. Risk was not elev. chain cases, unlike for the more c Three case-control studieso2 allergy-related conditions. Risk 01 fever,IW"any allergic condition," but nonsignificant, risks were de! and food allergies, whereas no allergies."" Risk was also increa conditions among light chain m y of the other autoimmune disease: icant increase in risk in one of t either allergic conditions or autoii case-control studies.l.` 3i ;I IC". A nested case-control study medical conditions reported an e> contrast, no association between n two other case-control studies." *2 The following medical condit with myeloma in at least two ca2 chickenpox and mumps)," '` vac -1 "1 previous lymphoid tissue s bronchitis,'.` v3 tuberculosis,l.` hZ h( myeloma diagnosis.". u3 In a recent data from the two US prepaid hea risk were detected for disc dise, eczema, and bronchitis (for plan o 1991). Twofold nonsignificant elei infection, and herpes zoster. Mod urinary tract infection, hay fever, a rheumatic fever, and degenerative tencies in the medical conditions rt CAS, when evaluated in this man1 to adequately-evaluate the role of multiple myeloma. Multiple myeloma in relation t( A LOS Angeles population-based st in multiple myeloma incidence." 1 myeloma occurring in patients at Epstein-Barr virus genome incorp association may suggest that dereg: could predispose one to B-cell neoF nts for karyotypic abnormalities 132) was statistically associated :ation has been associated with translocation, t(11;14)(q13;q32), es including multiple myeloma, 1 leukemia.` B-lymphoprolifera)soma1abnormalities of the light 2 and 22, and the heavy chain A recent case review of the l e 1980s- revealed 453 myeloma I analysis. Of these 124 patients, ivolving chromosome 14. Other tions in myeloma patients have ecific chromosomal abnormality transformation by oncogenes in !'In Increased levels of c-myc sma cells in 9 of 37 myeloma gene rearrangements."' A case yeloma patients had high c-myc high levels of myeloma cellular on of myeloma cells occurs only ivation of the c-myc gene. Coyeloma is rare,4 and the role of known. One investigation noted tat had a rearranged myc allele.u fined role in myeloma etiology cl-1 and bcI-2." I1 tumor, the role of the immune nterest. An excess of certain preIS has been observed in myeloma nulation (CAS) of the immune zlopment of myeloma. However, ngs owing to inconsistencies in ween the medical condition and I f medical information obtained. ' 13R have explored the CAS ation, namely, past exposures to rgies, or autoimmune disorders. amined the relationship between iitions. A studv in Italy" found iic bacterial disease were signifirose with increasing number of risk was observed for history of d malaria. In contrast, no increase THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 239 in risk was found for scarlet fever or for tuberculosis, BCG vaccination, or malaria in a British study and a US population-based case-control study.'), 93 No association between myeloma and the category of chronic bacterial infections was observed in a study conducted in Baltimore, Maryland.'05In a population* based case-control study in four areas of the United States, a trend of increased myeloma risk was found for increased number of bacterial illne~ses.~T'his study also reported significantly elevated risks for fever blisters, contact with mononucleosis, and rheumatic fever, and nonsignificant increased risks for tuberculosis, urinary tract infections, and syphilis. No increased risk was found for g ~ n o r r h e a . ~A' separate analysis of the light chain myeloma cases revealed a nonsignificant increase in risk for medical implants, infectious mononucleosis, and hepatitis. Risk was not elevated for having fever blisters among the light chain cases, unlike for the more common form of myeloma.'Sl Three case-control studiesb2I,yI. reported elevated risks of myeloma with allergy-related conditions. Risk of myeloma was significantly increased for hay fever,IW"any allergic condition," allergy treatment, and Elevated, but nonsignificant, risks were detected for asthma, use of asthma medication, and food allergies, whereas no excess was observed for eczema or drug allergies.'" Risk was also increased for childhood eczema and any allergic conditions among light chain myeloma cases.18'Rheumatoid arthritis, but none of the other autoimmune diseases evaluated, was associated with a nonsignif- icant increase in risk in one of the studies.IyI No association was found for either allergic conditions or autoimmune disorders and myeloma in the other case-control studies.". 'I. 3s, IO5 A nested case-control study that ascertained previous history of various medical conditions reported an excess of diabetes among myeloma cases." In contrast, no association between myeloma and diabetes was reported in at least two other case-control s t ~ d i e s . ' ~ . The following medical conditions have not been shown to be associated with myeloma in at least two case-control studies: childhood illnesses (e.g., chickenpox and mumps),'`. 93 vaccinations for childhood and other disease^,'^, 71. 93 previous lymphoid tissue s~rgery,'~. IO5 kidney disease,". b2 chronic bronchitis," y3 tuberculosis,". b2 hepatitis,62.93 and blood transfusion prior to myeloma diagn~sis.'9~3 .In a recent case-control study based on medical record data from the two US prepaid health plans, significant elevations in myeloma risk were detected for disc disease and other musculoskeletal conditions, eczema, and bronchitis (for plan only) (MM Doody, personal communication, 1991). Twofold nonsignificant elevations were found for tuberculosis, pelvic infection, and herpes zoster. Moderately elevated risks were noted for boils, urinary tract infection, hay fever, asthma, rheumatoid arthritis, psoriasis, gout, rheumatic fever, and degenerative joint disease arthritis. The overall inconsis- tencies in the medical conditions reported by case-control studies suggest that CAS, when evaluated in this manner, does not provide sufficient information to adequately evaluate the role of immune stimulation in the development of multiple myeloma. Multiple myeloma in relation to the AIDS epidemic has also been studied. A Los Angeles population-based study did not reveal an AIDS-related increase in multiple myeloma incidence.* However, there have been case reports of myeloma occurring in patients at risk for AIDS,IR IiJ one of whom had the Epstein-Barr virus genome incorporated into the B-cell tumor tissue. This association may suggest that deregulation of the immune system, as in AIDS, could predispose one to B-cell neoplasia. 240 RIEDEL & POTTEW' CONCLUSION Although myeloma incidence and mortality have been increasing until recently, multiple myeloma remains a relatively rare cancer. In the United States, myeloma rates in blacks continue to outpace those in whites. Internationally, incidence is highest in industrialized countries and lowest in developing countries. The differences in rates reflect the presence of cancer registries, usually in industrialized countries, that cover a larger proportion of the total population within a country and reflect greater access to medical care. The causes of multiple myeloma are largely unknown; however, potential risk factors include radiation and certain occupational exposures such as farming and pesticide use. The strongest association between multiple myeloma risk and radiation exposure has been observed among atomic bomb survivors, radiologists, and radium dial workers. Risk associated with exposure to diagnostic and therapeutic x-rays is contradictory. With the advent of nuclear power, concern for elevated cancer risks has increased among power plant workers and local residents. There is some evidence for elevated risks among nuclear plant workers, but risk among residents near nuclear facilities does not appear to be increased. Although associations of myeloma with farming and other occupations have been reported in some studies, it is not yet clear what specific agricultural or workplace exposures might be etiologically involved. The strongest candidates include pesticides, benzene, and other organic solvents. Nonoccupational exposures including smoking and alcohol consumption d o not seem to be strongly related to myeloma. Associations between myeloma and previous use of prescription drugs have not been well clarified. The role of chronic antigenic stimulation (CAS) in multiple myeloma is incon ,usive, mainly because of inconsistencies in the definition of CAS, varying quality of medical history information, and the subsequent contradictory study results. In addition to environmental risk factors, epidemiologic research of multiple myeloma should focus on potential genetic determinants. Research on chromosomal aberrations, HLA type, and oncogenes will continue to shed light on the pathogenic mechanism of myeloma, as well as provide genetic information that may be useful in the prediction and prognosis of this cancer and other Bcell malignancies. Incorporation of laboratory-based measures of genetic aberrations and immune function in future epidemiologic studies may be instrumental toward understanding the role of genetics and immune deregulation in the etiology of multiple myeloma. ACKNOWLEDGMENTS The authors wish to thank Dr. Susan Devesa for assistance in updating SEER incidence rates and mortality rates, and Drs. Shelia Zahm, Aaron Blair, and Ms. Patricia Stewart for their excellent editorial comments. References 1. Alavanja MCR, Rush GA, Stewart P, Blair A: Proportionate mortality study of workers in the grain indust?. J Natl Cancer Inst 78:247. 1987 2. Ames BN, Kammen HO, Yamasaki E: Hair dyes are mutagenic: Identification of a variety of mutagenic ingredients. Proc Natl Acad Sci USA 72~2423,1975 3. Andlelkovich D. Taulbee J, ! manufacturing plant J Occup 4. Bakkus MHC, Brakel-van Peer and the pvt-like region in hum 5. Bender AP, Parker DL, Johnso: study: Cancer mortality. Am j 6 . Beral V, lnskip H, Fraser P, t'i Atomic Energy Authority, 19% 7 . Berg JW, Burbank F: Correlatior and cancer mortality. Ann NY S. Bernstein L, Levin D, Menck k Los Angeles County men: A co 9. Bertazzi PA, Zocchetti C, Pe. population involved in the Sei.,. 10. Bethwaite PB, Pearce S , Fraser Zealand Cancer Registn. Br J I: 11. Blair A, Malker H, Cantor KP, Health 11:397, 1983 12. Blair A, Zahm SH: Cancer anReviews 6:335, 1991 13. Blair A, Zahm SH: Herbicides a. issues. Recent Results Cancer R 14. Boffetta P, Stellman SD, Garfii nested in the American Cancer 15. Boice JD Jr, Day NE, Andersen 2 for cervical cancer. An internat Cancer Inst 74:955, 1985 16. Boice JD Jr, Engholm G. Kleint risk in patients treated tor canct 17. Boice JD Jr, Land CE, Preston [ JF Jr (eds): Cancer Epidemiolog. Press, in press 18. Boice JD Jr, Morin MM, Glass leukemia, lymphoma, and multi 19. Bourguet CC, Grufferman 5, Dt of cancer. A case-control study. 20. Brown LM, Everett GD. Gibsc lymphoma and multiple myelon 21. Brownson RC: Cigarette smokin 1991 22. Brownson RC. Reif IS: A can, lymphoma. multiple myeloma a 23. Brownson RC, Reif IS, Chang J( Cancer 64:2381, 1989 24. Brugiatelli M, Comis M, lacopin Acta Haematol &:227, 1980 25. Burmeister LF: Cancer in Iowa t, 26. Burmeister LF, Everett GD. V a r farm practices in Iowa. Am J Ep! 27. Cantor KP, Blair A: Farming an( study with the use of death certi 28. Carli I'M, Bailly F, Tavernier C, in a well-defined population in t 29. Carli PM, Milan C, Lorenzini j L a well defined population in Fral 30. Chen VW, Craig JF, Fontham El in Louisiana: An opportunity for 1990 31 Cohrn HJ, Bernstein Rj, Grufterl of multiple myeloma. A case-con ortality have been increasing until Iatively rare cancer. In the United o o u t p a c e those in whites. Interna- zed countries and lowest in devel- iect t h e presence of cancer registries, ,ver a larger proportion of t h e total aater access to medical care. rgely unknown; however, potential upational exposures such a s farming o n between multiple myeloma risk ?d a m o n g atomic b o m b survivors, k associated with exposure to diag:tory. With the a d v e n t of nuclear h a s increased among power plant :evidence for elevated risks among ients n e a r nuclear facilities does not ith farming and other occupations it yet clear what specific agricultural .ally involved. The strongest candi- r organic solvents. Nonoccupational I consumption do not seem to be oetween myeloma and previous use x i f i e d . The role of chronic antigenic is inconclusive, mainly because of varying quality of medical history :ory study results. s, epidemiologic research of multiple ic d e t e r m i n a n t s . Research on chrosenes will continue to shed light on well a s provide genetic information rognosis of this cancer a n d o t h e r B- !asures of genetic aberrations a n d ;tudies may b e instrumental toward nune deregulation i n t h e etiology of rvesa for assistance in updating SEER Zlia Zahm, Aaron Blair, and Ms. Patricia lir A: Proportionate mortality study of 'r Inst 78:247, 1987 . dyes are mutagenic: Identification of a Acad Sci USA 72:2423. 1975 THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 241 3. Andjelkovich D, Taulbee J, Blum S: Mortality of female workers in a rubber manufacturing plant. J Occup Med 20409, 1978 4. Bakkus MHC, Brakel-van Peer KMJ, Michiels JJ, et al: Amplification of the c-niyc and the pvt-like region in human multiple myeloma. Oncogene 51359, 1990 5. Bender AP, Parker DL, Johnson RA, et al: Minnesota highway maintenance worker study: Cancer mortality. Am J Ind and Med 15:545, 1989 6 . Beral V, Inskip H, Fraser P, et al: Mortality of employees of the United Kingdom Atomic Energy Authority, 1946-1979. Br Med J 291:440, 1985 7. Berg JW, Burbank F: Correlations between carcinogenic trace metals in water supplies and cancer mortality. Ann NY Acad Sci 199:249, 1972 8. Bernstein L, Levin D, Menck H, Ross RK: AIDS-related secular trends in cancer in Los Angeles County men: A comparison by marital status. Cancer Res 49:466, 1989 9. Bertazzi PA, Zocchetti C, Pesatori AC, et al: Ten-year mortality study of the population involved in the Seveso incident in 1976. Am J Epidemiol 129:1187, 1989 10. Bethwaite PB, Pearce N, Fraser J: Cancer risks in painters: Study based on the New Zealand Cancer Registry. Br J Ind Med 47:742, 1990 11. Blair A, Malker H, Cantor KP, et al: Cancer among farmers. Scand J Work Environ Health 11:397, 1985 12. Blair A, Zahm SH: Cancer among farmers. Occupational Med: State of the Art Reviews 6:335, 1991 13. Blair A, Zahm SH: Herbicides and cancer: A review and discussion of methodologic issues. Recent Results Cancer Res 120132, 1990 14. Boffetta P, Stellman SD,Garfinkel L: A case-control study of multiple myeloma nested in the Amencan Cancer Society prospective study. Int J Cancer 43:554, 1989 15. Boice JDJr, Day NE, Andersen A, et al: Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries. J Natl Cancer Inst 74:955, 1985 16. Boice JD Jr, Engholm G, Kleinerman RA, et al: Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 116:3, 1988 17. Boice JD Jr, Land CE, Preston DL: Ionizing radiation. In Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention, ed 2. Oxford, Oxford University Press, in press 18. Boice JD Jr, Morin MM. Glass AG, et al: Diagnostic X-ray procedures and risk of leukemia, lymphoma, and multiple myeloma. JAMA 2651290, 1991 19. Bourguet CC, Grufferman S, Delzell E, et al: Multiple myeloma and family history of cancer. A case-control study. Cancer 562133, 1985 20. Brown LM, Everett GD, Gibson R, et al: Smoking and risk of non-Hiodgkin's lymphoma and multiple myeloma. Cancer Causes Control 3:49, 1992 21. Brownson RC: Cigarette smoking and risk of myeloma. J Natl Cancer Inst 83:1036, 1991 22. Brownson RC. Reif JS: A cancer registry-based study of occupational risk for lymphoma, multiple myeloma and leukaemia. Int J Epidemiol 1727, 1988 23. Brownson RC, Reif JS, Chang JC, Davis JR: Cancer risks among Missouri farmers. Cancer 642381, 1989 24. Brugiatelli M, Comis M, Iacopino P, et al: Multiple myeloma in husband and wife. Acta Haematol 64227, 1980 25. Burmeister LF: Cancer in Iowa farmers: Recent results. Am J Ind Med 18:295, 1990 26. Burmeister LF, Everett GD, Van Lier SF, Isacson P: Selected cancer mortality and farm practices in Iowa. Am J Epidemiol 118:72, 1983 27. Cantor KP, Blair A: Farming and mortality from multiple myeloma: A case-control study with the use of death certificates. J Natl Cancer Inst 72251, 1984 28. Carli PM, Bailly F, Tavernier C, et al: Multiple myeloma: Epidemiological features in a well-defined population in Burgundy, France. Int J Epidemiol 18:330, 1989 29. Carli PM, Milan C, Lorenzini JL, et al: Incidence of hematopoietic malignancies in a well defined population in France. Oncology 43:354, 1986 30. Chen VW, Craig IF. Fontham ETH, Correa P: Excessive cancer rates among blacks in Louisiana: An opportunity for physician intervention. J La State Med Soc 14218, 1990 31. Cohen HJ, Bernstein RJ, Grufferman S: Role of immune stimulation in the etiology of multiple myeloma: A case-control study. Am J Hematol 24:119, 1987 242 RIEDEL & POTTERN 32. Cook-Mozzaffari PJ, Darby SC, Doll R, et al: Geographical variation of mortality from leukemia and other cancers in England and Wales in relation to proximity to nuclear installations, 1969-78. Br J Cancer 59:476, 1989 33. Croce CM, Shander M, Martinis J, et al: Chromosomal location of the genes for human immunoglobulin heavy chains. Proc Natl Acad Sci USA 7 6 3 1 6 . 1979 34. Cuzick J: International time trends for multiple myeloma. Ann NY Acad Sci 609:205, 1990 35. Cuzick J, De Stavola 8: Multiple myeloma-a case-control study. Br J Cancer 57516, 1988 36. Cuzick J, Velez R, Doll R: International variations and temporal trends in mortality from multiple myeloma. Int J Cancer 32:13, 1983 37. Darby SC, Doll R, Gill SK, Smith PG: Long term mortality after a single treatment course with x-rays in patients treated for ankylosing spondylitis. Br J Cancer 55:179, 1987 38. Darby SC, Kendall GM, Fell TI,' et al: A summary of mortality and incidence of cancer in men from the United Kingdom who participated in the United Kingdom's atmospheric nuclear weapons tests and experimental programmes. Br Med J 296:332, 1988 39. Darby SC, Nakashima E, Kat0 H: A parallel analysis of cancer mortality among atomic bomb survivors and patients with ankylosing spondylitis given x-ray therapy. J Natl Cancer Inst 75:l. 1985 40. Davis DL, Hoe1 D, Fox J, Lopez A: International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 2:474, 1990 41. Davis FG, Boice JD Jr, Hrubec Z, Monson RR: Cancer mortality in a radiationexposed cohort of Massachusetts tuberculosis patients. Cancer 49:6130, 1989 42. Decoufle P, Blattner WA, Blair A: Mortality of workers exposed to benzene and other agents. Environ Res X 1 6 , 1983 43. DelzeU E, Grufferman S: Cancer and other causes of death among female textile workers, 1976-78. J Natl Cancer Inst 71:735, 1983 44. Delzell E, Grufferman S: Mortality among white and nonwhite farmers in North Carolina, 19761978. Am J Epidemiol 121:391, 1985 45. Delzell E, Monson RR: Mortality among rubber workers: X. Reclaim workers. Am J Ind Med 7:307, 1985 46. Devesa SS: Descriptive e3idemiology of multiple myeloma. In Obrams GI, Potter M (eds): Epidemiology ana Biology of Multiple Myeloma. Berlin, Springer-Verlag, 1991, p 3 47. Devesa SS, Silverman DT, Young J L Jr, et al: Cancer incidence and mortality trends among whites in the United States, 1947-84. J Natl Cancer Inst 79:701, 1987 48. Dewald GW, Jenkins RB: Cytogenetic and molecular genetic studies of patients with monoclonal gammopathies. In Wiernik PH, Canellos GP, Kyle RA, Schiffer CA (eds): Neoplastic Diseases of the Blood, ed 2. New York, Churchill Livingstone, 1991, p 427 49. Dimitrova E, Plesko I, Somogyi J, Kiss J: Trends and patterns in cancer incidence in Czechoslovakia, 1968-1985. Neoplasma 36:245, 1989 50. Divine BJ,Barron V: Texaco mortality study: 111. A cohort of producing and pipeline workers. Am J lnd Med 11:189, 1987 51. Divine BJ, Barron V, Kaplan SD: Texaco mortality study: I. Mortality among refinery, petrochemical, and research workers. J Occup Med 27445, 1985 52. Doll R: Urban and rural factors in the aetiology of cancer. Int J Cancer 47:803, 1991 53. Dolphin GW: A comparison of the observed and the expected cancers of the haematopoietic and lymphatic systems among workers at Windscale: A first report. Hanuell, England, National Radiation Protection Board NRPB-R54, 1976 54. Dousset M: Cancer mortality around La Hague nuclear facilities. Health Phys 56:875, 1989 55. Dubrow R, Gute DM: Cause-specific mortality among male textile workers in Rhode Island. Am J Ind Med 13:439, 1988 56. Edling C, Jarrholm 8, Anderson L, Axelson 0: Mortality and cancer incidence among workers in an abrasive manufacturing industry. Br J Ind Med 4457, 1987 57. Egedahl RD, Coppock E, Homik R: Mortality expenence at a hydrometallurgical nickel refinery in Fort Sash Med 41:29, 1991 58. Ernst TJ, Gazdar A, h t z J, ras', in a human multiple 72:1163, 1988 59. Flodin U, Fredriksson M, r wood, and creosote: A cast 60. Forman D, Cook-Mozaffar! Commentary. Nature 329:4. 61. Friedman GD: Multiple rr radiation and occupation. 11 62. Gallagher RE', Spinelli JJ, exposure and risk factors fo 63. Gallagher RP, Threlfall WJ. 129:1191, 1983 64. Gardner M: Cancer among J 296:309, 1988 65. Gilbert ES, Fry SA, Wiggs Hanford Site, Oak Ridge I\ Plant. Radiat Res 120:19, 19, 66. Gilbert ES, Petersen GR, B 194.5-1981. Health Physics 5 67. Giles GG, Lickiss JN, Baiki, disorders in Tasmania, 1972 Inst 72:1233, 1984 68. Glover CS, Horm J, Christt multiple myeloma survival. , of Multiple Myeloma. Berlin 69. Goldstein BD: Is exposure I NY Acad Sci 6 0 9 2 5 , 1990 70. Gould J, Alexanian R, Good; Blood 71:453, 1988 71. Gramenzi A, Buttino I, D A myeloma. Br J Cancer 63:76' 72. Grosbois B, Gueguen M, F;i immunochemical and immu 73. Grufferman 5, Cohen HI, Dt and central nervous system 74. Guidotti S, Wright WE. Pet1 Med 3:169, 1982 75. Gustavsson P, Gustavsson sweeps. Br J Ind Med 45:777 76. Gustavsson P, Hogstedt C, Swedish rubber workers, 19 77. Hagmar L, Bellander T, Eng! in a chemical factory. Scand 78. Hanis NM, Shallenberger L study of workers in three Comparisons with U.S. pop' 79. Hensen NE, Karle H, Olser Denmark 194S1982: A stud! 80. Hatch MC, Beyea J , Nieves J ' plant: Radiation emissions. 61. Hayakawa N, Ohtaki M, Uec among atomic bomb survivor J Med Sci 38:53, 1989 82. Hayes RB, Blair A, Stewart directors. Am J Ind Med 16:r 82a. Heineman EF, Zahm SH, h! 11 Geographical variation ot mortalitv and Wales in relation to proximity to 176, 1989 hromosomal location of the genes for Uatl Acad Sci USA 76 3416, 1979 le myeloma Ann NY Acad Sci 609 205, case-control study. Br J Cancer 57516, :ions and temporal trends in mortality 983 erm mortality after a single treatment -losing spondylitis. Br J Cancer 55179, mmary of mortality and incidence of participated in the United Kingdom's .mental programmes. Br Med J 296:332, I analysis of cancer mortality among losing spondylitis given x-ray therapy. rl trends in cancer mortality in France, les, and the USA. Lancet 2:474, 1990 RR Cancer mortality in a radiationpatients. Cancer 49:6130, 1989 of workers exposed to benzene and auses of death among female textile j83 lite and nonwhite farmers in North 1985 r workers: X. Reclaim workers. Am J le myeloma. h i Obrams GI, Potter M Myeloma. Berlin, Springer-Verlag, ancer incidence and mortality trends Vat1 Cancer Inst 79:701, 1987 cular genetic studies of patients with h e l l o s GP, Kyle RA, Schiffer CA New York, Churchill Livingstone, j and patterns in cancer incidence in 1989 A cohort of producing and pipeline y study: I. Mortality among refinery, d e d 27:445, 1985 of cancer. Int J Cancer 47303, 1991 and the expected cancers of the uorkers at Windscale: A first report. 1 Board NRPB-R54, 1976 uclear facilities. Health Phys 56375, nong male textile workers in Rhode 0: Mortality and cancer incidence d u s t y . Br J Ind Med 14:57, 1987 experience at a hydrometallurgical THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 243 nickel refinery in Fort Saskatchewan, Alberta between 1954 and 1984. J SOCOccup Med 1129, 1991 38. Ernst TJ, Gazdar A, Ritz j, Shipp MA: Identification of a second transforming gene, ras", in a human multiple myeloma line with a rearranged c-myc allele. Blood 72:1163, 1988 59. Flodin U,Fredriksson M, Persson B: Multiple myeloma and engine exhausts, fresh wood, and creosote: A case-referent study. Am J Ind Med 12519, 1987 60. Fonnan D, Cook-Mozaffari P, Darby S, et al: Cancer near nuclear installations.- Commentary. Nature 329:499, 1987 61. Friedman GD: Multiple myeloma: Relation to propoxyphene and other drugs, radiation and occupation. Int J Epidemiol 15:424, 1986 62. Gallagher RP, Spinelli JJ, Elwood JM, Skippen DH: Allerges and agricultural exposure and risk factors for multiple myeloma. Br J Cancer 48:853, 1983 63. Gallagher RP, Threlfall WJ: Cancer mortality in metal workers. Can Med Assoc J 129:1191, 1983 64. Gardner M: Cancer among participants in tests of British nuclear weapons. Br Med J 296:309, 1988 65. Gilbert ES, Fry SA, Wiggs LD, et al: Analyses of combined mortality data at the Hanford Site, Oak Ridge National Laboratory, and Rocky Flats Nuclear Weapons Plant. Radiat Res 120:19, 1989 66. Gilbert ES, Petersen GR. Buchanan JA: Mortality of workers at the Hantord Site: 1945-1981. Health Physics 56:11, 1989 67. Giles GG, Lickiss J N , Baikie MJ, et al: Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-1980: Occupational and familial aspects. J Natl Cancer lnst 72:1233, 1984 68. Glover CS, Horm J, Christenson G: Race and socioeconomic stalus differences in multiple myeloma survival. In Obrams GI, Potter M (eds): Epidemiology and Biology of Multiple Myeloma. Berlin, Springer-Verlag, 1991, p 55 69. Goldstein BD: Is exposure to benzene a cause of human multiple myeloma? Ann NY Acad Sci 609225, 1990 70. Gould J, Alexanian R, Goodacre A, et al: Plasma cell karyotype in multiple myeloma. Blood 71:453, 1988 71. Gramenzi A, Buttino I, DAvanzo B, et al: Medical history and the risk of multiple myeloma. Br J Cancer 63:769, 1991 72. Grosbois B, Gueguen M, Fauchet R, et al: Multiple myeloma in two brothers. An immunochemical and immunogenetic familial study. Cancer 582417, 1986 73. Grufferman S, Cohen HJ, Delzell ES, et al: Familial aggregation of multiple myeloma and central nervous system diseases. J Am Geriatr SOC37:303, 1989 74. Guidotti S, Wright WE, Peters JM: Multiple myeloma in cosmetologists. Am J Ind Med 3:169, 1982 75. Gustavsson,'I Gustavsson A, Hogstedt C: Excess of cancer in Swedish chimney sweeps. Br J Ind Med 45777, 1988 76.Gustavsson P, Hogstedt C, Holmberg 8: Mortality and incidence of cancer among Swedish rubber workers, 1952-1981. Scand J Work Environ Health 12:538, 1986 77. Hagmar L, Bellander T,Englander V, et al: Mortality and morbidity among workers in a chemical factory. Scand J Work Environ Health 1 2 3 5 , 1986 78. Hanis NM, Shallenberger LG, Donaleski DL, Sales EA: A retrospective mortality study of workers in three major U.S. refineries and chemical plants. Part 1: Comparisons with U.S. population. J Occup Med 27383, 1985 79. Hensen NE, Karle H, Olsen JH: Trends in the incidence of multiple myeloma in Denmark 1943-1982: A study of 5500 patients. Eur J Haematol42:72, 1989 80. Hatch MC, Beyea J, Nieves JW, Susser M: Cancer near the Three Mile Island nuclear plant: Radiation emissions. Am J Epidemiol 132:397, 1990 81. Hayakawa N, Ohtaki M, Ueoka H, et al: Mortality statistics of major causes of death among atomic bomb survivors in Hiroshima Prefecture from 1968 to 1982. Hiroshima J Med Sci 3853, 1989 82. Hayes RB, Blair A, Stewart PA, et al: Mortality of U.S. embalmers and funeral directors. Am J Ind Med 18:641, 1990 82a. Heineman EF, Zahm SH, McLaughlin JK, et al: A prospective study of tobacco use '1 244 RIEDEL h POlTERN and multiple myeloma: Evidence against an association. Cancer Causes Control 3:31, 1992 83. Heyer N, Weiss NS, Demers P, Rosenstock L: Cohort mortality study of Seattle fire fighters: 19451983. Am J Ind Med 17:493, 1990 84. Horwitz LJ, Levy RN, Rosher F: Multiple myeloma in three siblings. Arch Intern Med 145:1449, 1985 85. Jablon S, Hrubec Z, Boice JDJr, Stone BJ: Cancer in Populations Living Near Nuclear Facilities, vol 1: Report and Summary (DHHS pub1 (NIH) no. 90-874). Washington, DC, US Govt Printing Office, 1990 86. Jacobson RA: Multiple myeloma in sub-Sahara Africa. In Obrams GI, Potter M (eds): Epidemiology and Biology of Multiple Myeloma. Berlin, Springer-Verlag, 1991, p 69 87. Johnston JM, Grufferman S, Bourguet CC, et al: Socioeconomic status and risk of multiple myeloma. J Epidemiol Community Health 39:175, 1985 88. Kanoh T Multiple myeloma in spouses (letter). Eur J Haematol 41:397, 1988 89. KapIan S D Update of a mortality study of workers in petroleum refineries. J Occup Med 28:514, 1986 90. Kardinal CG: Multiple myeloma in a husband and wife. ] M A 23922. 1978 91. Kat0 I, Tajima K, Hirose K, et al: A descriptive epidemiological study of hemato- poietic neoplasms in Japan. Jpn J Clin Oncol 15:347, 1985 92. Kawachi I, Pearce N, Fraser J: A New Zealand cancer registry-based study of cancer in wood workers. Cancer 64:2609, 1989 93. Koepsell TD, Daling JR, Weiss NS, et al: Antigenic stimulation and the occurrence of multiple myeloma. Am J Epidemiol 126:1051, 1987 94. Kyle RA, Greipp PR: Multiple myeloma. Houses and spouses. Cancer 51:735, 1983 95. Lanier AP, Bulkow LR, Ireland B: Cancer in Alaskan Indians, Eskimos, and Aleuts, 1969-83:Implications for etiology and control. Public Health Rep 104:658, 1989 96. La Vecchia C, Negri E, DAvanzo B, Franceschi S Occupation and lymphoid neoplasms. Br J Cancer 60:385, 1989 97. Leech SH, Brown R, Schanfield MS: Genetic studies in multiple myeloma. 11. Immunoglobulin allotype associations. Cancer 55:1473, 1985 98. Leech SH, Bryan CF, Elston RC, et al: Genetic studies in multiple myeloma. I. Association with HLA-Cw5. Cancer 51:1408, 1983 99. Lenhard RE, Enterline JP, Crowley I, Ho GYF: The effects of distance from primary treatment centers o n survival among patients with multiple myeloma. J Clin Oncol 5:1640, 1987 100. Levi F, Te VC, La Vecchia C: Changes in cancer incidence in the Swiss canton of Vaud, 1978-87. Ann Oncol 1:293, 1990 101. Lewis EB: Leukemia, multiple myeloma and aplastic anemia in American radiologists. Science 142:1492, 1963 102. Lewis JP, MacKenzie MR: Non-random chromosomal aberrations associated with multiple myeloma. Hematol Oncol 2307, 1984 103. Lickiss JN, Giles GG, Baikie MJ, et al: Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-80: Patterns in space and time. J Natl Cancer Inst 721223, 1984 104. Linet MS: Chronic lymphocytic leukemia and multiple myeloma in husband and wife. Am J Med Sci 288:21, 1984 105. Linet MS, Harlow SD, Mcbughlin JK: A case-control study of multiple myeloma in whites: Chronic antigenic stimulation, occupation, and drug use. Cancer Res 472978, I 1987 106. Linet MS, McLaughlin JK, Harlow SD, Fraumeni JR Jr: Family history of autoimmune disorders and cancer in multiple myeloma. Int J Epidemiol 17:512, 1988 107. Lopez AD: Competing causes of death. A review of recent trends in mortality in industrialized countries with special reference to cancer. Ann NY Acad Sci 60958, 1990 108. Loth TS, Whiteaker RS, Perrotta AL, et al: Genetic aspects of familial multiple myeloma. Milit Med 156:430, 1991 109. Ludwig H, Mayr WR: Genetic aspects of susceptibility to multiple myeloma. Blood 59:1286. 1982 110. Lundberg I: Mortality and cancer inadence among Swedish paint industry workers with long-term exposure to i 1986 111. Mancuso TE. Stewart A, Kn, from cancer and other cause' 112. Marsh GM, Enterline PE, Mc and chemical plant workers. 113. Marshall M: Experts clash 01'' 114. Matanoski GM: Risk of cance and other radiation workers. ments, Challenges, and Prosp D 241 115. McCrea AI', Morris TCM: COI 58:394, 1986 116. McLaughlin JK, Malker HS, 1 Sweden. Arch Environ Health 117. McWhorter WP, Schatzkin AC status to blackiwhite differenc 118. Milham S Jr: Mortality in work Perspect 62297, 1985 119. Miller 8, Blair AE, Raynor HI United States furniture worker 120. Mills PK, Newell GR, Beeson leukemia and myeloma: Resul Inst 82:1832, 1990 121. Monson RR, Nakano KK: Mol employees in Akron, Ohio. An 122. Monson RR, Nakano KK: Mor Am J Epidemiol 103:297, 1976 123. Morris PD, Koepsell TD, D a h myeloma: A case-control study 124. Muir C, Waterhouse J, Mack 7 (IARC pub1 no. 88). Lyon, Fra 1987 125. Mukiibi JM, Kyobe J: Pattern ( 40:20, 1988 126. Nandakumar A, Armstrong 3 Australia: A case-control stud socioeconomic status and count 127. Nandakumar A, Dougan LE, E of multiple myeloma in Western 128. Nishida K, Taniwaki M, Misaw mosome 14 at band q32.33 in ! phenotype. Cancer Res 49:1275, 129. Nobuyoshi M, Kawano M, Tana may be related to the aggressi Haematol 77523, 1991 130. OIsen JH, Dragsted L, Autmp H: in Denmark. Br J Cancer 58:392, 131. ott MG. Teta MJ, Greenberg HI chemical manufacturing environr 132. Parkin DM: Cancer Occurrence I I France, International Agency for 133. Pasqualetti P, Colantonio D, C sopravvivenza ne1 mieloma multl 134. Pearce N, Prior 1, Methven D, British atmospheric nuclear weap 133. Pearce N, Reif J, Fraser J: Case-ct workers. Int J Epidemiol 18:5j, 15 136. Pearce NE, Howard JK: Occupatit Zealand, 1974-78. Int J Epidemiol association Cancer Causes Control Cohort mortality study of Seattle fire I -loma in three siblings. Arch Intern r in Populations Living Near Nuclear wbl (NIH) no. 9C-874). Washington, Africa. In Obrams GI, Potter M (eds): I . Berlin, Springer-Verlag, 1991, p 69 al: Socioeconomic status and risk of ,alth 39:175, 1985 Eur J Haematol 41:397, 1988 ters in petroleum refineries. J Occup ind wife. JAMA 239:22, 1978 e epidemiological study of hematoi:347, 1985 ancer registry-based study of cancer ,enic stimulation and the occurrence , 1987 's and spouses. Cancer 51:735, 1983 Iskan Indians, Eskimos, and Aleuts, Public Health Rep 104:658, 1989 w h i S: Occupation and lymphoid . studies in multiple myeloma. 11. i5:1473, 1985 tic studies in multiple myeloma. I. 83 The effects of distance from primary .ith multiple myeloma. J Clin Oncol er incidence in the Swiss canton of Aastic anemia in American radiolo- osomal aberrations associated with roliferative and lymphoproliferative pace and time. J Natl Cancer Inst multiple myeloma in husband and introl study of multiple myeloma in 1, and drug use. Cancer Res 47:2978, )R Jr:Family history of autoimmune Epidemiol 17:512, 1988 .-w of recent trends in mortality in I cancer. Ann NY Acad Sci 60958, enetic aspects of familial multiple tibility to multiple myeloma. Blood ig Swedish paint industry workers THE EPIDEMIOLOGY OF MULTIPLE MYELOMA -1245 with long-term exposure to organic solvents. Scand J Work Environ Health 12:108, 1986 111. Mancuso TE, Stewart A, Kneale G: Radiation exposure of Hanford workers dying from cancer and other causes. Health Phys 33:369. 1977 112. Marsh GM, Enterline PE, McCraw D: Mortality patterns among petroleum refinery and chemical plant workers. Am J Ind Med 19:29, 1991 .113. .Marshall M: Experts clash over cancer data. Science 250:900, 1990 114. Matanoski GM: Risk of cancer associated with occupational exposure in radiologists and other radiation workers. In Burchenal JH, Ottegen HF (eds): Cancer, Achievements, Challenges, and Prospects for the 1980s. New York, Grune & Stratton, 1982, p 241 115. McCrea AP, Morris TCM: Concurrent familial myeloma in northern Ireland. Cancer 58~394,1986 116. McLaughlin jK, Malker HS, Linet MS, et ai: Multiple myeloma and occupation in Sweden. Arch Environ Health 43:7, 1988 117. McWhorter WP, Schatzkin AG, Horm JW, Brown CC: Contribution of socioeconomic status to blackiwhite differences in cancer incidence. Cancer 63:982, 1989 118. Milham S Jr: Mortality in workers exposed to electromagnetic fields. Environ Health Perspect 62:293. 1985 119. Miller B. Blair AE, Raynor HL, et al: Cancer and other mortality patterns among United States furniture workers. Br j Ind Med 46:508, 1989 120. Mills PK, Newell GR, Beeson WL, et al: History of cigarette smoking and risk of leukemia and myeloma: Results from the Adventist Health Study. J Natl Cancer Inst 82:1832, 1990 121. Monson RR, Nakano KK: Mortality among rubber workers. I. White male union employees in Akron, Ohio. Am J Epidemiol 103:284, 1976 122. Monson RR, Nakano KK: LMortality among rubber workers. 11. Other employees. Am J Epidemiol 103:297, 1976 123. Morris PD, Koepsell TD, Daling JR, et al: Toxic substance exposure and multiple myeloma: A case-control study. j Natl Cancer Inst 76:987, 1986 124. Muir C, Waterhouse J, Mack T, et al: Cancer Incidence in Five Continents, vol 5. (IARC pub1 no. 88). Lyon, France, International Agency for Research on Cancer, 1987 123. Mukiibi JM, Kyobe J: Pattern of multiple myeloma in Kenyans. Trop Geogr Med 40:20, 1988 126. Nandakumar A, Armstrong BK. de Klerk NH: Multiple myeloma in Western Australia: A case-control study in relation to occupation, father's occupation; socioeconomic status and country of birth. Int J Cancer 3 7 3 3 , 1986 127. Nandakumar A, Dougan LE, English OR, Armstrong BK: Incidence and outcome of multiple myeloma in Western Australia 1960 to 1984. Aust NZ J Med 18974, 1988 128. Nishida K, Taniwaki M, Misawa W, Abe T: Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res 49:1275, 1989 129. Nobuyoshi M, Kawano M, Tanaka H, et al: Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells. Br J Haematol 77523, 1991 130. Olsen JH, Dragsted L. Autrup H: Cancer risk and occupational exposure to aflatoxins in Denmark. Br J Cancer 38:392, 1988 131. Ott MG, Teta MJ. Greenberg HL: Lymphatic and hematopoietic tissue canceiin a chemical manufacturing environment. Am J Ind Med 16:631, 1989 132. Parkin DM: Cancer Occurrence in Developing Countries. (IARC pub1 no. 75) Lyon, France, International Agency for Research on Cancer, 1986 133. Pasqualetti P, Colantonio D. Collacciani A, Casale R: Stato socioeconomico e sopravvivenza ne1 mieloma multiplo. Minerva Med 81:713, 1990 134. Pearce N, Prior I, Methven D, et al: Follow up of New Zealand participants in British atmospheric nuclear weapons tests in the Pacific. Br J Med 300:1161, 1990 135. Pearce N, Reif J, Fraser j: Case-control studies of cancer in New Zealand electrical workers. Int J Epidemiol 18:55, 1989 136. Pearce NE, Howard JK: Occupation, social class and male cancer mortality in New Zealand, 1974-78. Int J Epidemiol 15:156, 1986 246 RIEDEL & P07-TERN 137. Pearce NE, Smith AH, Fisher DO: Malignant lymphoma and multiple myeloma linked with aaricultural occupations in a New Zealand cancer registry-based study. ~~ Am J Epidemyol 121:225, 1985 138. Pearce NE, Smith AH, Howard JK, et al: Case-control study of multiple myeloma and farming. Br J Cancer 54:493, 1986 138a. Pottern LM,Gart JJ, Nam J , et al: HLA and multiple myeloma among black and white men: Evidence of a genetic association. Cancer Epidemiol Biomarkers Prevention, in press, 1992 139. Raffn E, Lynge E, Juel K, Korsgaard B: Incidence of cancer and mortality among employees in the asbestos cement industry in Denmark. Br J Ind Med 46:90, 1989 140. Reif J, Pearce N, Fraser J: Cancer risks in New Zealand farmers. Int J Epidemiol 18768, 1989 141. Reif J, Pearce N, Kawachi I, Fraser J: Soft-tissue sarcoma, non-Hodgkin's lymphoma and other cancers in New Zealand forestry workers. Int J Cancer 43:49, 1989 142. Reif JS, Pearce NE, Fraser J: Cancer risks among New Zealand meat workers. Scand J Work Environ Health 15:24, 1989 143. Riedel DA, Pottern LM, Blattner WA: Epidemiology of multiple myeloma. In Wiemik PH, Canellos GP, Kyle RA, Schiffer CA (eds): Neoplastic Diseases of the Blood, ed @ 2. New York, Churchill Livingstone, 1991, p 347 Ries LAG, Hankey BF, Miller BA, et al: Cancer Statistics Review 197S1988 (DHHS publ [NIH] no 91-2789). Washington, DC, US Govt Printing Office, 1991 145. Rinsky RA, Smith AB, Hornung R, et al: Benzene and leukemia. An epidemiologic risk assessment. N Engl J Med 316:1044. 1987 146. Rushton L, Alderson MR: Epidemiological survey of oil distribution centres in Britain. Br J Ind Med 40:330, 1983 147. Savage D, Lindenbaum J, Van Ryzin 1, et al: Race, poverty and survival in multiple myeloma. Cancer 54:3085, 1984 148. Schwartz DA, Vaughan TL, Heyer NJ, et al: B cell neoplasms and occupational asbestos exposure. Am J Ind Med 14:661, 1988 149. Schwartz E A proportionate mortality ratio analysis of pulp and paper mill workers in New Hampshire. Br J Med 45:234, 1988 150. Schwartz J: Multinational trends in multiple myeloma. Ann NY Acad Sci 609:215. 1990 151. Secker-Walker LM, Goldman JM: Cytogenetics and leukaemogenesis. In Hoffbrand AV, Lewis SM (eds): Postgraduate Haematology. Oxford, Heinemann Professional Publishing, 1989, p 372 152. Selby JV, Friedman GD, Fireman BH: Screening prescription drugs for possible carcinogenicity: Eleven to fifteen years of follow-up. Cancer Res 495736, 1989 153. Selvanayagam P, Blick M, Narni F, et al: Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma. Blood 71:30, 1988 154. Shapira R, Carter A: Multiple myeloma in northem Israel, 1970-1979. Cancer 58:206, 19& 155. Shimizu Y, Kat0 H, Schull W: Studies of the mortality of A-bomb survivors. 9. Mortalih. 195C-1985: Part 2. Cancer mortality based on the recently revised doses (Ds86).Radiat Res 121:120, 1990 156. Shoenfeld Y, Berliner S, Shaklai M, et al: Familial multiple myeloma. A review of thirty-seven families. Postgrad Med J 58:12, 1982 157. Siemiatvcki J: Risk Factors for Cancers in the Workplace. Boca Raton, Florida, CRC Press, 1'991 158. Smith PG, Douglas AJ: Mortality of workers at the Sellafield plant of British Nuclear Fuels. Br Med J 2932345, 1986 159. Sorahan T, Cooke MA: Cancer mortality in a cohort of United Kingdom steel foundry workers: 194685. Br J Ind Med 46:74. 1989 160. Sorahan T, Parkes HG, Veys CA, et al: Mortality in the British rubber industry 194645, Br J Ind Med %:1, 1989 161. Spinelli JJ, Gallagher RP, Band PR, Threlfall WJ: Multiple myeloma, leukemia, and cancer of the ovary in cosmetologsts and hairdressers. Am J Ind Med 6:97, 1984 162. Spirtas R, Stewart PA, Lee JS, et al: Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br J Ind Med 483515, 1991 163. Stebbings JH, Lucas HF, Stet1 radium dial workers. Am J I r 164. Steineck G, Wiklund K: M u Epidemiol I5:321. 1986 165. Svensson BG, Englander if, grinding stainless steel. Am 1 166. Teta MJ. Ott MG: A mortalit!, facility in western New York 167. Teta MI, Waliath J, Wister-M, ogists. J Natl Cancer Inst 72:i 168. Thomas TL, Waxweiler RJ, ( Texas oil refineries. Am J Ind 169. Tollerud DJ, Brinton LA, Sto, North Carolina furniture wori 170. Turesson I, Zettervall 0 , CUZ multiple myeloma in Malmo, ! 310:421, 1984 171. Vagero D, Persson G: Occur Scand J SOCMed 14:131, 1986 172. Voelkerding KV, Sandhaus t acquired immune deficiency 5 Clin Pathol 92:222, 1989 173. von Keyserlingk H, Baur R, St AIDS. Cancer Detect Prev 1 1 : ~ 174. Walrath J, Decoufle P, Thomas company. Am J Ind Med 12:61 175. Wang J-X, Boice JD Jr, Li 6-X, , in China. J Natl Cancer Inst 8C 176. Waterhouse JA, Muir C, Corre (IARC pub1 no. 15). Lyon, Fran, 177. Waterhouse JA, Muir C, Sh; Contents (IARC publ no. 42). Cancer, 1982 178. Weston 6,Grufferman 5 , Mac clinical factors on survival in m 179. Wiklund K, Dich J, Holm L-E, Swedish agriculture. Br J Ind k 180. Wiklund K, Holm L-E: Trends J Natl Cancer Inst 77:657, 1986 181. Williams AR, Weiss NS, Koeps in the etiology of light chain my, 182. Wong 0, Raabe GK: Critical re employees, with a quantitative 1989 183 World Health Organization. M, Diseases, Injunes, and Causes I 181 Wurster-Hill DH, Mclntyre 01 multfple myeloma and plasma I 183. Zahm 5. Weisenburger D, Bab Hodglun's lymphoma and multl use (abstract 1024) / t i Prograr Amencan Society of Clinical Or: nt lymphoma and multiple myeloma ;Zealand cancer registry-based study. Ise-control study of multiple myeloma d multiple myeloma among black and Cancer Epidemiol Biomarkers Preven- idence of cancer and mortality among n Denmark, Br J Ind Med 46:90, 1989 \lew Zealand farmers. Int J Epidemiol ue sarcoma, non-Hodgkin's lymphoma vorkers. Int J Cancer 43:49, 1989 m g New Zealand meat workers. %and iiology of multiple myeloma. In Wiernik ,): Neoplastic Diseases of the Blood, ed 347 cer Statistics Review 1973-1988 (DHHS S Govt Printing Office, 1991 nzene and leukemia. An epidemiologic .7 1 survey of oil distnbution centres in : Race, poverty and survival in multiple al: 5 cell neoplasms and occupational analysis of pulp and paper mill workers e myeloma. Ann NY Acad Sci 609:215, tics and leukaemogenesis. fn Hoffbrand Aogy. Oxford, Heinemann Professional eening prescription drugs for possible How-up. Cancer Res 495736, 1989 teration and abnormal expression of the la. Blood 71:30, 1988 xthern Israel, 1970-1979. Cancer 58:206, the mortality of A-bomb survivors. 9. lity based on the recently revised doses familial multiple myeloma. A review ot 1982 ie Workplace. Boca Raton, Florida, CRC i at the Sellafield plant of British Nuclear in a cohort of United Kingdom steel :74, 1989 vlortality in the British rubber industry II WJ: Multiple myeloma, leukemia, and iairdressers. Am J Ind Med 6:97, 1984 >ectivecohort mortality study of workers miological results. Br J Ind Med 48515. THE EPIDEMIOLOGY OF MULTIPLE MYELOMA 247 163. Stebbings JH, Lucas HF. Stehney AF: Mortality from cancers of major sites in female radium dial workers. Am J Ind Med 5435, 1984 164. Steineck G, Wiklund K: Multiple myeloma in Swedish agricultural workers. Int J Epidemiol 15:321, 1986 165. Svensson BG, Englander V, Akesson B. et al: Deaths and tumors among workers. grinding stainless steel. Am J Ind Med 1551. 1989 166. Teta MJ, Ott MG: A mortality study of a research, engineering, and metal fabrication facility in western New York state. Am J Epidemiol 127540, 1988 167. Teta MJ, Walrath J. Wister-Meigs J , Flannery JT: Cancer incidence among cosmetologists. J Natl Cancer lnst 72:1051, 1984 168. Thomas TL, Waxweiler RJ, Crandall MS, et al: Cancer mortality patterns in three Texas oil refineries. Am J Ind Med 6:3, 1984 169. Tollerud DJ, Brinton LA, Stone BJ, et al: Mortality from multiple myeloma among North Carolina furniture workers. J Natl Cancer lnst 74:799, 1985 170. Turesson I, Zettervall 0, Cuzick J, et al: Comparison of trends in the incidence of multiple myeloma in Malmo, Sweden and other countries, 195C-1979. N Engl J Med 310:421, 1984 171. Vagero D, Persson G: Occurrence of cancer in socieconomic groups in Sweden. Scand J SOCMed 14:151, 1986 172. Voelkerding KV. Sandhaus LM, Kim HC, et al: Plasma cell malignancy in the acquired immune deficiency syndrome. Association with Epstein-Barr virus. Am J Clin Pathol 92222, 1989 173. von Keyserlingk H. Baur R, Stein H, et al: Multiple myeloma in a patient at risk for AIDS. Cancer Detect Prev 14:403, 1990 174. Walrath J, Decoufle P. Thomas TL: Mortality among workers in a shoe manufacturing company. Am J Ind Med 12:615, 1987 175. Wang J-X, Boice JD Jr, Li 5-X, et al: Cancer among medical diagnostic x-ray workers in China. J Natl Cancer lnst 80:344,1988 176. Waterhouse JA, Muir C, Correa P, et al: Cancer Incidence in Five Continents, vol 3 (IARC pub1 no. 15). Lyon, France, International Agency for Research on Cancer, 1976 177. Waterhouse JA, Muir C, Shanmugaratnam K, et al: Cancer Incidence in Five Contents (IARC pub1 no. 42). LyonT France, International Agency for Research on Cancer, 1982 178. Weston 5, Grufferman S, MacMillan JP, Cohen HJ: Effects of socioeconomic and clinical factors on survival in multiple myeloma. J Clin Oncol 51977, 1987 179. Wiklund K, Dich J , Holm L-E, Eklund G: Risk of cancer in pesticide applicators in Swedish agriculture. Br J Ind Med 46:809, 1989 180. Wiklund K, Holm L-E: Trends in cancer risks among Swedish agricultural workers. J Natl Cancer Inst 77:657, 1986 181. Williams AR, Weiss NS, Koepsell TD, et al: Infectious and noninfectious exposures in the etiology of light chain myeloma: A casecontrol study. Cancer Res 494038, 1989 182. Wong 0, Raabe GK: Critical review of cancer epidemiology in petroleum industry employees, with a quantitative meta-analysis by cancer site. Am J Ind Med 15:283, 1989 183. World Health Organization: Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death. Geneva, WHO, 1949, 1959, 1969, 1979 184. Wurster-Hill DH, Mclntyre OR, Cornwell GG, et al: Marker-chromosome 14 in multiple myeloma and plasma ceII leukemia. Lancet 2:1031, 1973 185. Zahm S, Weisenburger D, Babbitt P, et al: An increased risk of developing nonHodgkin's lymphoma and multiple myeloma is associated with hair coloring product use (abstract 1024). In Program/Proceedings of the 26th Annual Meeting of the American Society of Clinical Oncology, Washington, DC,1990, p 264 Address reprint requests to Denise A. Riedel, MPH National Institutes of Health National Cancer Institute Executive Plaza North, Room 418 Bethesda, MD 20892