Document RJrLnBnEzy17jx7xdxKB6KMYn

EPIDEMIOLOGY OF MULTIPLE Linda M. Pottern Martha S. Linet Susan S. Devesa le myeloma, a plasma cell tumor arising in the w, is a rare cancer with a n elusive etiology. o 1994 estimates by the American Cancer 12,700 cases and 9,800 deaths from multia occumng annually in the United States r approximately 1.0 percent of all newly diaglignancies and 2.0 percent of all cancer DESCRIPTIVE EPIDEMIOLOGY LMortality Age-speclfic mortality data have shown that rates inara~eexponentially beginning at age 30 and pealung 0 age 80 and older among whites and blacks of both Mortality rates are consistently higher among *-than women and among blacks than whites in each @Oup,although the male/female ratio is greater at e r ages than at younger ages, and the black/white -0 is 3.0 among persons under age 50 compared with among older individuals.`*3 Since 1950, age-adjusted mortality rates have risen Onthously; in 1985 to 1989 such rates were approxilaatelY2.3 and close to 4.0 times those in 1950 to 1954 center whites and nonwhites, respectively (National for Health Statistics, unpublished data). These bases were among the highest observed for any can- this time interval.'.' Rates for blacks, moniseparately from data for nonwhites (consisting of `%S chapter was prepared by government employees ad is not subject to copyright. the combined group of American blacks, Asians, and Indians) since 1970, have shown the greatest proportional increase among all racial groups, increasing 30 percent for men and 16 percent for women between 1970 to 1974 and 1985 to 1989. During the last two decades, the highest age-adjusted myeloma rates have been observed in black men, followed by black women, and then white men, with the lowest rates occurring in white women.'.3 To further evaluate the increases in mortality during the past four decades, we examined rates according to age group and year of birth to determine whether (1) the increases were confined to certain age groups or were seen among adults of all ages, and ( 2 ) persons born in earlier time periods had a similar or different mortality experience than those born more recently. AS shown in Figure 24-1, the increase in mortality during the past four decades occurred primarily among older whites and blacks of both sexes, with little change among persons under age 50. The increases were progressively more rapid in the older age groups. The nsk for multiple mveloma rose among individuals born in the late 1800s and earlv 19OOs, with more recent birth cohorts experiencing little change in risk. International mortality data have revealed that the highest rates occur in northern Europe, North America, Australia, and New Zealand, with the lowest rates in Japan, Yugoslavia, and Greece.4 Based on 1960 to 1989 mortality data from the World Health Organization files, the rates of increase in myeloma mortality have diminished over the past three decades. The largest proportional increases have occurred in the older age groups for both women and men. Greater increases were also observed in countries with lower baseline death rates, and rates are now stable in most 441 442 Neoplastic Diseases of the Blood MALES FEMALES F 10 ...).e ...... ..... 55-64 D-----O ----n--- 45-54 I -'1 /-- 35-44 YEAR ...... *-0 0-U- ......A..... 85+ -------A- 75-84 65-74 ...... ..... 55-64 -35-44 Fig. 24-1. Trends in U.S.age-specific mortality rates for multiple myeloma by cohort year of birth: 1880-1960 by race and gender. Incidence Epidemiology of Multiple Myeloma 443 demonstrated asmall increase between 1945to 1977and 1978to 1990.' Similarly, between 1950and 1979,the incidence of myeloma rose only slightly in Malmo, Swe- st to the notable increases in national agertality rates, particularly for blacks, the in- om versus clinical characterization and/or death certif- icate only), and quality and availability of medical care, MALES FEMALES MALES FEMALES ,",', , ,- 0.1 1 I 1 I , ,II I 1 I I 0 10 20 30 40 50 60 70 80 90 100 AGE Fig. 24-2. Age-specific incidence rates for multiple myeloma by race and gender for nine SEER areas, 1975-1991. 444 Neoplastic Diseases of the Blood __ n u1 4 E o/O-O-O'\, -0 / . . ., ,2 - , 1 1 .--0- WHITE MALES -0- WHITE FEMALES - - - BLACK MALES - -0- - BLACK FEMALES Epidemiology of Multiple Myeloma 445 8 NORTH AMERICA US Los Angeles: black (318) US SEER: black 17491 Canada, Ontario (2:290) US Los Angeles: Sp surname white (200) US SEER: white (4,006) CARIBBEAN, CENTRAL & SOUTH AMERICA Martinique (116) Puerto Rico (538) Costa Rica (145) Cuba (247) RATE PER 100,000 PERSON-YEARS MALES FEMALES Israel, All Jews (517) Hong Kong (444j Japan, Osaka (603) China, Shanghai (289) Philippines, Rital (45) India, Bombay (197) EUROPE Norway (1,298) Sweden (2,711) UK England 8 Wales (11,324) Denmark (1,199) France, Calvados (90) Italy, Torino (114) German Dem Reo f2.139) OCEbtNlA New Zealand, Maori (41) New Zealand, non-Maori (703) Australia, NSW (1,087) Fig. 24-4. International variation in multiple myeloma incidence (age-adjusted. world standard) by gender, 1983- 1987. (Data from Parkin et id.") findings of an increased myeloma risk associated with atomic bomb irradiation have been refuted in a recent report of myeloma incidence data for the years 1950 to 1987; no evidence of an excess risk of myeloma or a significant dose response was observed." Differences between the earlier data sets and the present data were evaluated to determine the reasons for this disparity. In the most recent report,'' it was determined that the change in the risk estimates was due to more complete follow-up (an additional 12 years of incidence data), more stringent diagnostic criteria, and the exclusion of myeloma cases classified as second primaries. The I-elationshipbetween atomic bomb radiation and multiple myeloma is still under investigation. Radiation-Related Occupations The mortality experience of radiologists and other radiation-exposedworkers has provided additional information on multiple myeloma risk due to radiation. An of myeloma deaths among American radiolomsts was first reported over 30 years ago.I7 More recendymyelomarisk was reported to be two times higher among radiologists exposed to lower doses of radiation than among physicians in other specialties." Among over 27,000 Chinese diagnostic x-ray workers, however, no excess incidence of myeloma was observed over a 30year period when compared with medical workers unlikely to have had occupational x-ray exposure.'' Employment in nuclear facilities and risk of myeloma has been investigated in several studies. Although mortality from myeloma was lower than that observed in the general population (probably due to the healthy worker effect), an association between this cancer and radiation exposure was seen in two nuclear facilities2",2'and among a large cohort of British radiation workers from many facilities.22 No myeloma deaths (with a I0-year lag) were observed among workers in the Oak Ridge National Laboratory or in the Rocky Flats Nuclear Weapons Plant.23 Residential and Atmospheric Radiation Exposures Investigations of the relation of residential proximity to nuclear facilities have provided little evidence of an increased risk of multiple m y e l ~ m a . I~n~ad- d~it~ion, a a 446 Neoplastic Diseases of the Blood recent U.S. nationwide mortality survey reported similar myeloma mortality among residents of counties with and without nuclear f a ~ i l i t i e s . ~ ~ Increases in multiple myeloma incidence and mortality have been observed among British military men who participated in atmospheric nuclear weapons tests when compared with unexposed controkZ8 Among New Zealand military participants in the same nuclear weapons tests, no incident myeloma cases were seen over a 30-year period.29Exposures incurred by the New Zealanders may have been lower since they participated in fewer tests than the British subjects. Diagnostic and Therapeutic X-Rays Diagnostic x-ray exposure has not been clearly linked with multiple myeloma. Most epidemiologic studies have reported no association with diagnostic x- Among members of a prepaid health plan, no excess risk of myeloma associated with diagnostic xrays was observed, although a trend with increasing number of x-rays received was seen regardless of the lagging interval.36 Of historic interest is the significantly increased risk of myeloma observed among women who had received injections of Thorotrast (aemitting x-ray contrast medium) for cerebral arteriography3'; fortunately Thorotrast has not been used for many years because of the recognized health risks. Studies of the effects of therapeutic irradiation on myeloma risk have been inconsistent. A few case control interview studies have shown an excess risk of myeloma with radiation therapy, and others have not.34*35,3A8 follow-up study of approximately 14,000 patients with ankylosing spondylitis who received a single course of x-ray treatment revealed a nonsignificant elevated risk of myeloma.39 Among over 180,000 women treated for cervical cancer, no overall excess risk of myeloma was associated with radiation therapy; however, a trend analysis revealed significantly increased risks after the first 10 years of treatment.40 Occupational Exposures The role of occupational exposures on the risk of multiple myeloma is not clear. In case control studies, evaluation of occupational associations is often based on employment in a specific industry or occupation. Because of the small number of individuals employed in any single occupation, statistical power is often insufficient for analysis by job title. Although analysis by industry type has provided some etiologic clues, such information is usually not specific enough to identify particular workplace exposures. Similarly, cohort studies of specific occupational groups have infrequently reported occupational associations with multiple myeloma, because of the rarity of this malignancy. The few studies demonstrating excess risks among occupational cohorts have generally identified small numbers of cases, sometimes as few as three. Most case-control and cohort studies have not included detailed exposure assessments or measurements; thus, specific workplace exposures associated with increased myeloma risk have not been thoroughly evaluated. Agricultural Occupations and Exposures A number of epidemiologic studies have evaluated the risk of myeloma among agricultural workers with positive associations reported by many but not all of the s t u d i e ~ . ~S'u-g~g~ested agriculturally related exposures that may be associated with an increased myeloma risk include grain d ~ s t s ,e~ng~in.e ~ex~hausts and fuels,38 contact with farm ani mal^,^^,^^ and p e ~ t i c i d e s .N~u~merous studies have investigated the association between potential pesticide exposure and multiple myeloma; some have reported elevated risks and others have not.41-43Only a feu. studies have evaluated use of specific pesticide^.^'-^^ In a case-control study of white men in Iowa, nonsignificantlv increased risks of myeloma were associated with handling certain pestic i d e ~ . ~E'xposure to phenoxv herbicides was significantly linked with myeloma risk in a Swedish but this finding was not confirmed in the Iowa Metal Workers Workers in various metal occupations and industries have been reported to have increased mveloma ri although these findings have not been c o n s i ~ t e n t . ~ ~ Significantly elevated risks have been observed am smelter and metallurgy workers,5' machinists nickel refinery workers.49 By contrast, other have reported no appreciable associations with tional metal exposure^.^^-^^ Inadequate exposure have made it difficult to assess the specific metal e sures that could explain the observed elevations in Rubber Manufacturing Some epidemiologic studies have suggested an as tion between multiple myeloma and employment rubber manufacturing i n d ~ s t r y . ~R~ub*b~er~wo- ~ ~ can be exposed to a myriad of substances, incl organic solvents, plastic monomers, and rubber tives. The specific exposure(s) linked with excess o rence of myeloma has not been identified in any of studies. Other Industries At least a dozen studies have investigated the ass tions between myeloma risk and employme wood, lumber, or paper manufacturing in Most of the studies showed little or no elevat eloma risk.30,31~34,38~A6n3-e6x8cess of deaths cancers of the lymphatic tissue has been obse several petroleum refinery population^^^-^^ but not other^.^^!^^ An association between myel ployment in textile processing has been two linkage studies of cancer incidence tional census or pension data.55,75By cont cohort studies of textile workers revealed no Epidemiology of Multiple Myeloma 447 increase in deaths due to multiple m y e l ~ m a . ~E~x,- ~ ~ "served an increased risk of multiple myeloma among cess risks of myeloma among workers employed in the woman who dye for 20 years o r greater,Io3however, the paint manufacturing industry have been noted in sev- Nurse's Health Study did not confirm this finding.lo4 eral s t ~ d i e s . ~ ~ , ~ ~ . ~ ~ , ~ ~ Epidemiologic studies investigating the association between employment as a beautician or cosmetologist [ Specific Occupational Exposures I have been inconsistent, with some reporting excess risk^'^^.'^^ and others describing no association^.^^,'^^ , Benzene has been suggested as a possible etiologic agent for multiple myeloma.80-82Although an elevated Medication Use 1 of myeloma has been observed among some ben- I zene-exposed populations of workers ranging in size Prescription and over-the-counter medications have from 250 to 1,165,80.82a cohort study of over 74,000 been evaluated as myeloma risk factors in several stud- . Chinese benzene-exposed workers demonstrated no ex- ies.33.58.'0S7ignificant associations have been observed cess of for myeloma with the use of laxatives5' and erythromy- 1 Some cohort investigations of chemical workers have cin.'07 Nonsignificantly elevated risks have been re- revealed excess myeloma m ~ r t a l i t y , w~ h~il,e~ o~ther ported for phenobarbital, diazepam, propranolol, ibu- studies have Chemical workers have been ex- profen, diet drugs, and stimulant^.'^^ posed to a variety of established or suspected carcino- gens such as piperazine, urethane, ethylene oxide, and epichlorohydrin," as well as antioxidants and ni- Precursor Medical Conditions t r i l e ~A. ~m~ong aircraft maintenance workers, a signifi- Several precursor medical conditions have been in- cant increase in myeloma mortality was observed for vestigated as possible risk factors for myeloma, includ- men exposed to methylene chloride and for women ex- ing monoclonal gammopathy of undetermined signifi- posed to chlorinated and aromatic hydrocarbons, in- cance (MGUS). A wide variety of other nonmalignant cluding perchloroethylene."A positive association be- medical conditions, postulated to cause repeated or tween mveloma and asbestos exposure has been chronic antigenic stimulation, have also been suspected reported in some,3'~58~bu8t9not all, s t ~ d i e s . ~ ~ * ~ ~to.p~la~y ,an~ e' tiologic role. Life-style Factors Several studies of multiple myeloma have evaluated the role of personal life-style factors, including cigarette and alcohol consumption, hair dye application, and medication use. To date, the possible role of diet has not been fullv evaluated. Cigarette Smoking and Alcohol Consumption Based on the study findings to date, cigarette smoking and alcohol consumption do not appear to be risk factors for multiple myeloma.30~34~58~O92nl-y99one study, a follow-up of Seventh Day Adventists, observed an increased myeloma risk among smokers.98No epidemiologic study has reported a relation between alcohol consumption and myeloma.30~34~58*96 Hair Dyes Personal use of hair dyes was evaluated as a risk factor for myeloma in three recent case control studies and two prospective ~ t u d i e s . " ~ - " ~Elevated myeloma risk was observed among women who dyed their hair, with the highest risk among users of permanent hair dyes and dark hair coloring products.99In another case-control study, no excess risk was found; however, this finding was based on the answer to a single question on regular hair dye use.1o2Men who use hair dye have also been reported to have an elevated risk of myeloma that increases with duration of hair dye use."' The Amencan Cancer Society prospective mortality study ob- Monoclonal Gammopathy of Undetermined Significance MGUS, considered to be a potential precursor condition for multiple myeloma, is a typically asymptomatic, benign disorder involving proliferation of plasma cells and production of M components.'08 In one of the largest series of MGUS patients followed to date, 19percent of the 241 MGUS patients developed multiple myeloma within 2 to 29 years.'" Alterations of interleukin-6 (a growth factor) expression or mutations in oncogenes or tumor suppressor genes (or both) may play a role in the malignant transformation of MGUS (see Ch. 28). However, the factors that may initiate or promote these changes are unknown at the present time. Chronic Antigenic Stimulation Based on results from animal studies of induced plasm a c y t o m a ~a' n~d~on clinical reports,"o-"2 it has been postulated that repeated or chronic antigenic stimulation (CAS) of the immune system may lead to mye10ma.~*A number of case-control studies have explored the CAS hypothesis by evaluating myeloma risk associated with past history of chronic infectious, inflammatory, connective tissue, autoimmune, and al- lergy-related disorder^.^^!^^ Although elevated myeloma risks have been observed in some investigations among persons with specific medical conditions (e.g., allergic conditions,34,l'3 musculoskeletal disorders and disc disease, I4 and rheumatoid arthritis"5*116)o, ther stud- ies of individuals with these conditions have shown no excess of m y e l ~ m a . " ~ ~ ~S~u"c'h inconsistencies sug- 448 Neoplastic Diseases of the Blood gest that evaluation of CAS, with this approach does Chromosomal Abnormalities not provide sufficient information to assess the role of immune stimulation adequately in the development of multiple myeloma."3*1'8Even when the CAS hypothesis is evaluated by grouping medical conditions according to their biologically or immunologically related immune response mechanisms, the findings do not support a causal relationship between CAS and myeIorna.'l3 The role of viruses in the etiology of multiple myeloma is currently unknown.' l9 Several patients with the acquired immunodeficiency syndrome (AIDS) have been reported to have multiple myeloma;'20~12h1o,wever, a population-based study did not observe an AIDSrelated increase in multiple myeloma incidence. 122 Data from two large case series investigating cytoge- netic abnormalities in plasma cell disorders have indi- cated frequent involvement of chromosomes 1 and 14.'36*'3T7he 14q+ abnormality occurred in 20 to 25 percent of the The t( 11;14) and t( 1 1:18) translocations have been observed in myeloma and other B-cell disorders.138Other structural and numeri- cal chromosomal aberrations in myeloma patients have also been reported (see Ch. 27).j3' Cytogenetic studies have been a useful aid in predicting prognosis and mon- itoring remission of myeloma patients.'37 The estab- lishment of etiologic associations with specific chromo- somal abnormalities is difficult and has yet to be pursued in epidemiologic investigations. Cytogenetic investigations have led to the identification of the Familial and Genetic Factors tumor-related genes, thereby providing new informa- tion about the pathobiology of myeloma. Familial aggregation of myeloma among first-degree relatives has been documented in numerous case re- Oncogenes and Tumor Suppressor Genes p o r t ~ , 'a~nd~ epidemiologic studies have reported higher frequencies of mveloma and other hematopoi- Several oncogenes and tumor suppressor genes occur etic cancers among cases compared with cont r o l ~ . ' ~R~ec-e'n~t r~esearch has focused on various genetic markers including human lvmphocyte antigens (HLA),chromosomal abnormalities, and oncogene and tumor suppressor gene mutations. at sites of some of the known breakpoints associated with myeloma and other B-cell disorders. Chromosome 14 with the 14q breakpoint is associated with the heavy chain immunoglobulin locus. Chromosome I includes the N-vas oncogene, which has been implicated in the pathogenesis of multiple mveloma.136High levels of c- Familial Cancer MYC gene expression have been reported in 25 percent of myeloma patients, although only a few cases pre- sented with rearrangement of the c-MYClocus.'3sOverReviews of the published literature on familial aggrega- expression of the BCL-2 oncogene has also been ob- tion of multiple myeloma from 1957 to 1987 have re- served in some myeloma cases, although cytogenetic vealed a total of 104 cases in 49 f a m i l i e ~ . ' ~M~ofre' ~ ~ breakpoints have not been identified.137In addition to recent case-control studies have reported a higher fre- oncogene activation, abnormalities in tumor suppres- quency of multiple myeloma in related family members sor genes are evident among myeloma patients. Altera- among cases compared with controls; however, the tions in the p53 gene on chromosome 17 and the RB- numbers were too small to reach statistical signifi- I gene on chromosome 13 have been reported in my- ~ a n c e . ' ~E~xc-e's~se~s of nonmalignant conditions such eloma studies.I3' Identification of the factors that con- as autoimmune disorders'27 and degenerative central tribute to oncogene expression is an important step in nervous system diseases.12' have also been observed predicting which individuals are at highest risk for deamong relatives of myeloma patients. By contrast, re- veloping myeloma. ports of cases of myeloma among spouses of myeloma patients suggest an environmental role in the etiology of this m a l i g n a n ~ y . ' ~ ~ - ' ~ ~ CONCLUSIONS Genetic Marker Studies Early studies investigating the relationship between HLA and multiple myeloma reported a link with the B 10cus.~'More recently, associations have been found with the C locus: HLA-Cw5 antigen was increased among 22 myeloma cases compared with laboratory and HLA-Cw2 was linked with myeloma in a large population-based case control interview study.135The environmental and other potential risk factors that may increase myeloma risk among this subset of potentially susceptible individuals have yet to be identified. Multiple myeloma is an intriguing malignancy from epidemiologic, biologic, and clinical perspectives. It is one of only two hematopoietic cancers (the other is chronic myeloid leukemia) characterized by higher incidence among blacks than whites, and to date epidemiologic investigations have been unable to determine the reasons for these racial differentials. In general, the causes of multiple myeloma are largely unknown. Several occupations and workplace exposures have been suggested as potential risk factors, but the epidemiologic evidence has been inconclusive^ The strongest associations have been with agricultural occupations and those involving exposures to ionizing radiation and organic solvents. Recently, the use of hair dyehas been linked with myeloma, although additional studies are needed to clarify the risk. Nonoccupational En,OSureSincluding diagnostic and therapeutic radiacigarette smoking, and alcohol consumption do not appear to be related to myeloma. T~ date, epidemiologic research has primarily fo- cused on the possible role of environmental risk factors io h e Occurrence of multiple myeloma. The role of on- cogene and tumor suppressor gene of multiple myeloma is mutations in the a n emerging area of investigation. Incorporation of laboratory-based measures of genetic aberrations in future epidemio- logic studies will be instrumental in understanding the ctions between genetics and environ- e risk factors on the development of mul- REFERENCES 1. Boring CC, Squires TS, Tong T, Montgomery S: Cancer statistics, 1994. CA Cancer J Clin 44:18, 1994 2. Devesa SS: Descriptive epidemiology of multiple myeloma. p. 3. In Obrams GI, Potter M (eds):Epidemiology and Biology of Multiple Myeloma. Springer-Verlag, Berlin, 1991 3. Miller BA, Ries LAG, Hankey BF et a1 (eds): SEER Cancer Statistlcs Review: 1973-1990, National Cancer Institute. NIH Pub. No. 93-2789, Bethesda, 1993 le mveloma. p. 455. In Doll R, uir CS (eds):Trends in Cancer Incity. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1994 5. Devesa SS, Silverman DT, Young JL Jr et al: Cancer incidence and mortality trends among whites in the United States, 1947-84. J Natl Cancer Inst 79:701, 6. Ries LAG, Miller BA, Hankey BF et al: SEER Cancer Statistics Review, 1973-1991: Tables and Graphs, National Cancer Institute. NIH Pub. No. 94-2789. Bethesda, 1994 7. Kyle RA, Beard CM, O'Fallon WM, Kurland LT: Incidence of multiple myeloma in Olmsted County, Minnesota: 1978through 1990,with a review of the trend since 1945. J Clin Oncol 12:1577, 1994 8. Turesson I, Zetterval 0, Cuzick J et al: Comparison of trends in the incidence of multiple myeloma in Malmo, Sweden, and other countries, 1950-79. N Engl J Med 310:421, 1984 9. Parkin DM, Muir CS, Whelan SL et a1 (eds): Cancer Incidence in Five Continents. Vol. VI. IARC Scientific Publications No. 120. International Agency for Research on Cancer, Lyon, 1992 lo. Glover CS, Horm J, Christenson G: Race and socioeconomic status differences in multiple myeloma survival. p. 55. In Obrams GI, Potter M (eds): Epidemiology and Biology of Multiple Myeloma. SpringerVerlag, Berlin, 1991 `1. Pasqualetti P, ~ o ~ a n t o nDi ,oCollacciani A, Casale R: Stato socioeconomico e soprawivenza ne1 mieloma muhiplo. Minerva Med 81:713, 1990 12. Savage D. Lindenbaum J, Van Ryzin J et al: Race, poverty and survival in multiple myeloma. Cancer 54: 3085, 1984 l3. Lenhard R E Enterline JP. Crowlev J. Ho GYF: The Epidemiology of Multiple Myeloma 449 effects of distance from primary treatment centers on survival among patients with multiple myeloma. J Clin Oncol 5:1640, 1987 14. Shimizu Y, Kato H, Schull W: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121:120, 1990 15. Ichimaru M, Ishimaru T, Mikami M: Multiple myeloma among atomic bomb survivors in Hiroshima and Nagaski, 1950-76:relationship to radiation dose absorbed by marrow. J Natl Cancer Inst 69:323,1982 16. Preston DL, Kusumi S, Tomonaga M: Cancer incidence in atomic bomb survivors. Part 111:Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res 137:S68, 1994 17. Lewis EB: Leukemia, multiple myeloma and aplastic anemia in American radiologists. Science 142:1492, 1963 18. Matanoski GM: Risk of cancer associated with occupational exposure in radiologists and other radiation workers. p. 241. In Burchenal JH, Ottegen HF (eds): Cancer, Achievements, Challenges, and Prospects for the 1980's.Grune & Stratton, New York, 1982 19. Wang J-X, Boice JD Jr, Li B-X et al: Cancer among medical diagnostic X-ray workers in China. J Natl Cancer Inst 80:344, 1988 20. Gilbert ES, Petersen GR, Buchanan JA: Mortality of workers at the Hanford Site: 1945-1981. Health Phys 56:11, 1989 21. Smith PG, Douglas AJ: Mortality of workers at the Sellafield plant of British Nuclear Fuels. BMJ 293: 845, 1986 22. Kendall GM, Muirhead CR, MacGibbon BH: Mortality and occupational exposure to radiation: first analysis of the National Registry for radiation workers. BMJ 304:225, 1992 23. 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 24. Cook-Mozaffari PJ, Darby SC, Doll Ret 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 25. Dousset M: Cancer mortality around La Hague nuclear facilities. Health Phys 562375, 1989 26. Forman D, Cook-Mozaffari P, Darby S et al: Cancer near nuclear installations. Commentary. Nature 329: 499, 1987 27. Jablon S, Hrubec Z, Boice JD Jr, Stone BJ: Cancer in Populations Living Near Nuclear Facilities. Vol. 1: Report and Summary. NIH Pub. No. 90-874, Washington, DC, 1990 28. Darby SC, Kendall GM. Fell TP 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. BMJ 296:332, 1988 29. Pearce N, Prior I, Methven D et al: Follow up of New Zealand participants in British atmospheric nuclear weapons tests in the Pacific. BMJ 300:1161, 1990 30. Boffetta P, Stellman SD, Garfinkel L: A case-control study of multiple myeloma nested in the American Cancer Society prospective study. Int J Cancer 43: 554, 1989 450 Neoplastic Diseases of the Blood 31. Cuzick J, De Stavola B: Multiple myeloma-a casecontrol study. Br J Cancer 57:516, 1988 32. Davis FG, Boice J D Jr, Hrubec Z, Monson R R Cancer mortality in a radiation-exposed cohort of Massachusetts tuberculosis patients. Cancer 49:6130, 1989 33. Friedman GD: Multiple myeloma: relation to propoxyphene and other drugs, radiation and occupation. Int J Epidemiol 15:424, 1986 34. Gallagher RP, Spinelli JJ, Elwood JM, Skippen DH: Allergies and agricultural exposure and risk factors for multiple myeloma. Br J Cancer 482353, 1983 35. Eriksson M: Rheumatoid arthritis as a risk factor for multiple myeloma: a case-control study. Eur J Cancer 29:25, 1993 36. Boice JD Jr, Morin MM, Glass AG et al: Diagnostic X-ray procedures and risk of leukemia, lymphoma, and multiple myeloma. JAMA 265:1290, 1991 37. Andersson M, Storm HH: Cancer incidence among Danish Thorotrast-exposed patients. J Natl Cancer Inst 84:1318, 1992 38. Flodin U, Fredriksson M, Persson B: Multiple mveloma and engine exhausts, fresh wood, and creosote: a case-referent study. Am J Ind Med 12:519, 1987 39. Darby SC, Doll R, Gill SK, Smith PG: Long term mortality after a single treatment course with X-rays in patients treated for ankvlosing spondylitis. Br J Cancer 55:179, 1987 40. Boice J D Jr, 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 41. Riedel DA, Pottern LM, Blattner WA: Epidemiology of multiple myeloma. p. 347. In Wiernik PH, Canellos GP, Kyle RA, Schiffer CA (eds): Neoplastic Diseases of the Blood. 2nd Ed. Churchill Livingstone, New York, 1991 42. Riedel DA, Pottern LM: The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 6:225, 1992 43. Hemnton L, Weiss NS, Olshan AF: Epidemiology of multiple myeloma. p. 127. In Malpas JS, Bergsagel DE, Kyle RA (eds):Myeloma-Biology and Management. Oxford Medical Pub, Oxford, 1995 44. Blair A, Zahm SH, Pearce NE et al: Clues to cancer etiology from studies of farmers. Scand J Work Environ Health 18:209, 1992 45. davanja MCR, Rush GA, Stewart P, Blair A: Proportionate mortality study of workers in the grain industry. J Natl Cancer Inst 78:247, 1987 46. Pearce NE, Smith AH, Howard JK et al: Case-control study of multiple myeloma and farming. Br J Cancer 54:493, 1986 47. Eriksson M, Karlsson M: Occupational and other environmental factors and multiple myeloma: a population based case-control study. Br J Ind Med 49:95, 1992 48. Brown LM, Burmeister LF, Everett GD, Blair A: Pesticide exposure and multiple myeloma in Iowa men. Cancer Causes Control 4:153, 1993 49. Egedahl RD, Coppock E, Homik R: Mortality experience at a hydrometallurgical nickel refinery in Fort Saskatchewan, Alberta between 1954and 1984.J SOC Occup Med 41:29, 1991 50. Gallagher RP, Threlfall WJ: Cancer mortality in metal workers. Can Med Assoc J 129:1191, 1983 51. McLaughlin JK. Malker HS, Linet MS et al: Multiple myeloma and occupation in Sweden. Arch Environ Health 43:7, 1988 52. Sorahan T, Cooke MA: Cancer mortality in a cohort of United Kingdom steel foundry workers: 1946-85. Br J Ind Med 46:74, 1989 53. Svensson BG, Englander V, Akesson B et al: Death and tumors among workers grinding stainless steel, Am J Ind Med 15:51, 1989 54. Teta MJ, Ott MG: A mortality study of a research, engineering,and metal fabrication facility in westem New York state. Am J Epidemiol 127:540, 1988 55. Pottern LM, Heineman EF, Olsen JH et al: Multiple myeloma among Danish women: employment history and workplace exposures. Cancer Causes Con- trol 3:427, 1992 56. Heineman EF, Olsen JH, Pottern LM et a]: Occupa- tional risk factors for multiple myeloma among Dan- ish men. Cancer Causes Control 3:555, 1992 57. Demers PA, Vaughan TL, Koepsell TD:A case-control study of multiple myeloma and occupation. Am J Ind Med 23:629, 1993 58. Linet MS, Harlow SD, McLaughlin JK: A case-control study of multiple myeloma in whites: chronic antigenic stimulation, occupation, and drug use. Cancer Res 47:2978, 1987 59. Andjelkovich D, Taulbee J, Blum S: Mortality of fe- male workers in a rubber manufacturing plant. J Occup Med 20:409, 1978 60. Monson RR, Nakano EX: Mortalitv among rubber workers. 11. Other emplovees. Am J Epidemiol 103: 297, 1976 61. Gustavsson P, Hogstedt C, Holmberg B: Mortality and incidence of cancer among Swedish rubber workers, 1952-1981. Scand J Work Environ Health 12:538, 1986 62. Delzell E, Monson RR: Mortality among rubber workers: X. Reclaim workers. Am J Ind Med 7:307, 1985 63. Schwartz E: A proportionate mortality ratio analysis of pulp and paper mill workers in New Hampshire. Br J Med 45:234, 1988 64. Kawachi I, Pearce N, Fraser J: A New Zealand Cancer Registry-based study of cancer in wood worken. Cancer 64:2609, 1989 65. Miller B, Blair AE, Raynor HL et al: Cancer and o mortality patterns among United States furni workers. Br J Ind Med 46:508, 1989 66. Nandakumar A, Armstrong BK, de Klerk NH: ple myeloma in Western Australia: a case-c study in relation to occupation, father's occu socioeconomic status and country of birth. Int cer 37:223, 1986 67. Reif J, Pearce N, Kawachi I, Fraser J: Soft-tissue coma, non-Hodgkin's lymphoma and other c in New Zealand forestry workers. Int J Cancer 1989 68. Miller BA, Blair A, Reed, EJ: Extended mo low-up among men and women in a U.S. workers union. Am J Ind Med 25:537, 1994. 69. Divine BJ, Barron V, Kaplan SD: Texaco mo study: I. Mortality among refinery, petrochemi and research workers. J Occup Med 27:445, 1985 70. Kaplan SD: Update of a mortality study of w in petroleum refineries. J Occup Med 28:514, 71. Marsh GM, Enterline PE, McCraw D: Mortalit terns among petroleum refinery and chemical workers. Am J Ind Med 19:29, 1991 Epidemiology of Multiple Myeloma 451 neoplasms and occupational asbestos exposure. Am J Ind Med 14:661, 1988 eloma. J Natl Cancer Inst 83:1036, 1991 . Dubrow R, Gute DM: Cause-specific mortality among male textile workers in Rhode Island. Am J h d Med 13:439, 1988 a.Goldberg MS, Theriault G: Retrospective cohort study of workers of a synthetic textiles plant in Que- . bec: I. General mortality. Am J Ind Med 25:889, 1994 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 . Lundberg I: Mortality and cancer incidence among Swedish paint industry workers with long-term expo- sure to organic solvents. Scand J Work Environ Health 12:108, 1986 . Decode P, Blattner WA, Blair A: Mortality of work- ers exposed to benzene and other agents. Environ Res 30:16, 1983 1. Goldstein BD: Is exposure to benzene a cause of 97. Heineman EF, Zahm SH,McLaughlin JK et al: A prospective study of tobacco use and multiple myeloma: evidence against an association. Cancer Causes Con- trol 3:31, 1992 98. Mills PK, Newel1 GR, Beeson WL et aI: History of cigarettesmoking and risk of leukemia and myeloma: results from the Adventist Health Study. J Natl Cancer Inst 82:1832, 1990 99. Zahm S, Weisenburger D, Babbitt P et al: Use of hair coloring products and risk of lymphoma, multiple myeloma, and chronic lymphocytic leukemia. Am J Public Health 82:990, 1992 100. Brown LM, Everett GD, Burrneister LF, Blair A: Hair dye use and multiple myeloma in white men. Am J Public Health 82:1673, 1992 101. Herrinton LJ, Weiss NS, Koepsell TD et al: Exposure to hair-coloring products and the risk of multiple myeloma. Am J Public Health 84:1142, 1994 2. Rinsky RA, Smith AB, Hornung R et al: Benzene and leukemia. An epidemiologic risk assessment. N Engl J Med 316:1044, 1987 83. Yin SN, Hayes RB, Linet MS et al: A cohort study of cancer among benzene-exposed workers in China. I. Methods and Resources. Am J Ind Med 26:383, 1994 84. Hagmar L, Bellander T, Englander V et al: Mortality and morbidity among workers in a chemical factory. Scand J Work Environ Health 12:545, 1986 85. Ott MG, Teta MJ, Greenberg HL: Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Am J Ind Med 16:631, 1989 86. Burchfiel CM, Carmill JB, Axe FD, Bond GG: General mortality and respiratory cancer among a cohort of male chemical workers in California. Am J Ind Med 2269, 1992 87. Bond GG, McLaren EA, Carmill JB et al: Cause-specific mortality among male chemical workers. Am J Ind Med 12:353, 1987 88- Spirtas R, Stewart PA, Lee JS et al: Retrospective co- hort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br J Ind Med 48515, 1991 89. Rafm 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 La Vecchia C, Negri E, DAvanzo B, Franceschi S: Occupation and lymphoid neoplasms. Br J Cancer 60:385, 1989 91. Schwartz DA, Vaughan TL, Heyer N J et al: B cell 103. Grodstein F. Hennekens H, Colditz GA et al: A prospective study of permanent hair dye use and hematopoietic cancer. J Natl Cancer Inst 86:1466, 1994 104. Guidotti S, Wright WE, Peters JM: Multiple myeloma in cosmetologists. Am J Ind Med 3:169, 1982 105. Spinelli JJ, Gallagher RP, Band PR, Threlfall WJ: Multiple myeloma, leukemia, and cancer of the ovary in cosmetologists and hairdressers. Am J Ind Med 6: 97, 1984 106. Teta MJ, Walrath J, Meigs WJ, Flannery JT: Cancer incidence among cosmetologists. J Natl Cancer Inst 72:1051, 1984 107. Selby JV,Friedman GD, Fireman BH: Screening prescription drugs for possible carcinogenicity:eleven to fifteen years of follow-up. Cancer Res 49:5736, 1989 108. Kyle RA: Benign monoclonal gammopathy after 20 to 35 years of follow-up. Mayo Clin Proc 68:26, 1993 109. Potter M, Morrison S, Wiener F et al: Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J Natl Cancer Inst 86:1058, 1994 110. Osserman RF, Takatsuki K Considerations regarding the pathogenesis of the plasmacytic dyscrasias. Series Haematol 4:28, 1965 111. Penny R, Hughes S: Repeated stimulation of the reticuloendothelial system and the develpment of plasma-cell dyscrasias. Lancet 1:77, 1970 112. Isobe T, Osserman E F Pathologic conditions associated with plasma cell dyscrasias: a study of 806cases. Ann NY Acad Sci 90:507, 1971 P- 452 Neoplastic Diseases of the Blood 113. Lewis DR, Pottern LM, Brown LM et al: Multiple myeloma among blacks and whites in the United States: the role of chronic antigenic stimulation. Cancer Causes Control 5:529, 1994 114. Doody MM, Linet MS, Glass AG et al: Leukemia, lymphoma, and multiple myeloma following selected medical conditions. Cancer Causes Control 3:449, 1992 115 . Katusic S, Beard CM, Kurland LT et al: Occurrence of malignant neoplasms in the Rochester, Minnesota, Rheumatoid Arthritis Cohort. Am J Med, suppl. 1A. 7850, 1985 116. Isomaki HA, Hakulinen T, Joutsenlaht U: Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chron Dis 31:691, 1978. 117. Gridley G, McLaughlin JK, Ekbom A et al: Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 85:307, 1993 118. Linet MS: Is chronic antigenic stimulation etiologically related to multiple myeloma? p. 99. In Obrams GI, Potter M (eds):Epidemiology and Biology of Multiple Myeloma. Springer-Verlag, Berlin, 199l 119. Mueller N: The etiology of multiple myeloma: a role for viruses? p. 103. In Obrams GI, Potter M (eds): Epidemiology and Biology of Multiple Myeloma. Springer-Verlag, Berlin, 1991 120. 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 92:222, 1989 121. von Keyserlingk H, Baur R, Stein H et al: Multiple myeloma in a patient at risk for AIDS. Cancer Detect Prey 14:403, 1990 122. 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 123. Olshan AF: Familial and genetic associations. p. 31. In Obrams GI, Potter M (eds):Epidemiology and Biology of Multiple Myeloma. Springer-Verlag, Berlin, 1991 124. Bourguet CC, Grufferman S, Delzell E et al: Multiple myeloma and family history of cancer. A case-control study. Cancer 56:2133, 1985 125. Eriksson M, Hallberg B: Familial occurrence of hematologic malignancies and other diseases in multi- ple myeloma: a case-control study. Cancer Causes Control 3:63, 1992 126. Linet MS, McLaughlin JK, Harlow SD, Fraumeni JF Jr: Family history of autoimmune disorders and cancer in multiple myeloma. Int J Epidemiol 17:512, 1988 127. Blattner WA: Epidemiology of multiple myeloma and related plasma cell disorders: an analytic review. In Potter M (ed): Progress in Myeloma: Biology of My- eloma. Elsevier/North-Holland, New York, 1980 128. Grufferman S, Cohen HJ, Delzell ES et a]: Familial aggregation of multiple myeloma and central nervous system diseases. J Am Geriatr SOC37:303, 1989 129. Brugiatelli M, Comis M, Iacopino P et a]: Multiple myeloma in husband and wife. Acta Haematol 64: 227, 1980 130. Kanoh T: Multiple myeloma in spouses, letter. Eur J Haematol 41:397, 1988 131. Kardinal CG: Multiple myeloma in a husband and wife. JAMA 239:22, 1978 132. Kyle RA,Greipp PR: Multiple myeloma. Houses and spouses. Cancer 51:735, 1983 133. Linet MS: Chronic lymphocytic leukemia and multiple myeloma in husband and wife. Am J Med Sci 288: 21, 1984 134. Leech SH, Bryan CF, Elston RC et al: Genetic studies in multiple myeloma. I. Association with HLA-Cw5. Cancer 5 1:1408, 1983 135. Pottern LM, Gart JJ, Nam JN et al: HLA and multiple myeloma among black and white men: evidence of a genetic association. Cancer Epidemiol Biomarkers Prev 1:177, 1992 136. Durie BGM: Cytogenetic abnormalities in multiple myeloma. p. 137. In Obrams GI, Potter M (eds):Epidemiology and Biology of Multiple Myeloma. Springer-Verlag, Berlin, 1991 137. Dewald GW, Jenkins RB: Cytogenetic and molecular genetic studies of patients with monoclonal gammo- pathies. p. 427. In Wiernik PH, Canellos GP, Kyle a, Schiffer CA (eds): Neoplastic Diseases of the Blood. 2nd Ed. Churchill Livingstone, New York, 1991 138. Durie BGM: Cellular and molecular genetic features of myeloma and related disorders. Hematol Oncol Clin North Am 6:463, 1992 139. 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