Document daMm3ee4qrrndnqDkELj0GBjR

Volume 1 Neodastic- - - - I - - - - - - - Diseases -- of the Blood Edited b y Peter H. Wiernik, M.D. Gutman Professor and Chairman,Department of Oncology, Montefiore Medical Center; Chief, Division of Medical Oncology, Albert Einstein College of Medicine; Associate Director for Clinical Research, Albert Einstein Cancer Center, New York, New York George P. Canellos, M.D. Professor of Medicine, Harvard Medical School; Chief, Division of Medical Oncology, Dana-Farber Cancer institute; Physician, Brigham and Women's Hospital, Boston, Massachusetts Robert A. Kyle, M.D. William H. Donner Professorof Medicineand of Laboratory Medicine, Mayo Medical School; Consultant, Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Charles A. Schiffer, M.D. Professorof Medicineand Oncology,and Chief, Division of Hematologic Malignancies, University of Maryland Cancer Center; Chief, Division of Hematology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland bRb nnn nnn I ChurchilI Livingstone New York, Edinburgh, London, and Melbourne 1985 :ty of normal Int J Cancer wific marker translocation roc Jpn Acad i S : Specificity ie No. 15 in Cancer Inst 22 Etiology and Epidemiology of Multiple Myeloma and Related Disorders Linda M.Pottern, M,P.H. William A. Blather, M.D. The first case of "mollities ossium" was documented over 135 years ago in a 45-year-old English tradesman. A series of classic reports of this case summarized a number of important clinical, pathologic, and laboratory features of the disease. Particularly relevant was the discovery of Bence Jones protein in the urine which established that multiple myeloma was a disease characterized by abnormalities of protein metabolism.*l Multiple myeloma is the prototype of a group of conditions known as monoclonal gammopathies. A common presenting complaint is bone pain or pathologic fracture associated with radiographic evidence of "punched-out" bony destruction. This clinical characteristic has resulted in myeloma being traditionally classified as a bone tumor for purposes of disease classification. However, since 1950 myeloma has been assigned code number 203 under the category of "neoplasms of lymphatic and hematopoietic tissues" in the sixth, seventh, eighth, and ninth editions of the Manual of the International Statistical Classijication of Diseases, Injuries, and Causes of Death. 140 Benign monoclonal gammopathy (BMG) or monoclonal gammopathy of undetermined significance (MGUS) (Chapter 33) is a laboratory diagnosis when an M-spike is discovered coincidentally on routine medical examination. The benign designation is made when other clinical stigmata of myeloma are absent and the M-spike remains quantitatively static over time.66 Waldenstrom's macroglobulinemia (WM) is a rare lymphomatous malignancy of cells that appear to bridge the gap between lymphocytes and plasma cells.136 These so-called lymphocytoid plasma cells secrete IgM, and many of the bizarre clinical manifestations of this disease arise because of the unusual physiochemical properties of this "macr~globulin."I~n~recent years, with improvements in the diagnosis and reporting of myeloma and related disorders, interesting patterns of disease occurrence have been recognized which suggest opportunities for etiologic study. Demographic Features According to the most recent United States incidence data, 1973 to 1977, from the Surveil- 413 *. 414 Neoplastic Diseases of the Blood U.S. WHITES 1973-1977 us BLACKS 1973-1977 JAPAN JAPANESE 19761978 21 5% Y 6% 194% Fig. 22-1 Rdative proportion of lymphoreticular malignancies in US. whites and blacks14` and Japanese in Japan.'** AGL, acute granulocytic leukemia, ALL, acute lymphoblastic leukemia:CGL, chronic granulocytic leukemia;CLL, chronic lymphocytic leukemia; HD, Hodgkin'sdisease; MM, multiple myeloma: NHL, nomHodgkin's lymphoma. lance, Epidemiology, and End Results (SEER) Program, multiple myeloma accounts for 1.1 percent of all malignancies in whites and 2.1 percent in b 1 a ~ k s .Tl ~he~average annual ageadjusted (1970 U.S. standard) incidence rates for whites are 4.3 per 100,ooO in males and 3.0 in females, while for blacks, the rates are 9.6 in males and 6.7 in fern ale^.'^' Figure 22-1 illustrates that multiple myeloma is the most common form of malignancy of the lymphohematopoietic system in blacks (29.7 percent) while it is the second most common in whites (13.7 percent). Non-Hodgkin's lymphomas account for 24.0 percent in blacks and 35.9 percent in whites. A distinctive feature of myeloma is its late age of onset. The median age at diagnosis IS 68.4 for males and 69.8 for females. The average annual age-specific incidence curves for the United States, 1973 to 1977, are shown by race and sex in Figure 22-2.144The rates increase with increasing age for both sexes and races. Blacks have higher rates of rnyeloma than whites at all ages except for the oldest age group, 85+. A male predominance is seen in both races, although black females have higher rates than white males. The age patterns of mortality for multiple myeloma closely parallel the incidence curves. The median age at death is 69.6years for males and 71.3 years for females.'*Shown in Figure 22-3 are the age-specific mortality rates for multiple myeloma in the United States from 1950 to 1975.'* These patterns demonstrate that multiple myeloma affects primarily persons beyond 55 years of age. Nonwhite rates exceed white rates in all age groups, and peak 316.2k 100 0 - 31 6 100- 321 j 1 ot I I I 03k HBlack M a l e Black Fema c -While m a l e While Fern3 O Il k d l I I I I I I I I I I .I 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 AGE Fig 22- 2 Multiple myeloma, agr-specific in<idence for United States, 1973 to 1977 u4 RdrcS per 1@.ooO -2 `C0 - s 1000 -7 0 ` 1C 30 33 FIg 22-3. M ( A ) Top left. righr. nonwhi 195G1975 C Etiology and Epidemiology of Multiple Myeloma and Related Disorders 415 100 d e m o n s t rate imarily pernwhite rates ps, and peak alack Male Slack Female Whole male While Female L-Lu-L 0 75 80 85 90 specific inci?77.14' Rates B lo1^ 10- 0.1 C 30- 35- 40- 45- 50- 55- 60-6 5 70- 7 1 &+ 3 4 5 3 4 4 4 9 5 4 5 9 4 6 9 7 4 84 10.1 D 1 30-3 5 40- 45- 50. 55 6Q 65 7s 343944495459 646974 75 84 1 85+ Fig. 22-3. Multiple myeloma, age-specific mortality for United States, 1950-1975. Rates per 100,000.12 (A) Top left, white males; (B) top right, white females; (C) bottom left, nonwhite males; (D)bottom right, nonwhite females. (Blattner WA, Blair A, Mason TJ: Multiple myeloma in the United States, 1950-1975. Cancer 48:2547, 1981.) 416 Neoplastic Diseases of the Blood mortality occurs for both between ages 70 and 80. The incidence of multiple myeloma in the United States appears to be increasing. However, it is questionable to what extent this increase is due to improved case ascertainment or diagnostic practice. A comparison between the incidence data from the Second National Cancer Survey, 1947 and the Third National Cancer Survey (TNCS), 1969 to 1971 shows that the percentage increase in reported rates for myeloma was greater than for any other form of cancer.*o The upward trend was greater among blacks than whites, especially at older ages. Comparison of the TNCS age- adjusted incidence rates23to more recent 1973 to 1977 calculations144from the SEER program reveals an 18.5 percent increase in the rates of myeloma in black males and appreciably smaller percent increases in black females, white males, and white females (3.1 percent, 7.5 percent, and 11.1 percent, respectively). This suggests that improved case ascertainment or altered diagnostic practices, which were unlikely to have occurred between these two recent time periods, may be responsible for only part of this increase in incidence. During the 25-year period, 1950 to 1975, there has been an increase in myeloma mortality paralleling the rise in multiple myeloma incidence. The bulk of the increase for each race-sex category is seen in the 60-year and older age groups (Fig. 22-3).12 This rise in the rate in older age groups over the past 25 years may reflect improvement in death c e r t i f i c a t i ~ nM. ~o~rtality rates have increased over each time period, with nonwhite males having the highest increase. The proportionate increase in mortality during this 25-year period for nonwhites was 207 percent for males and 210 percent for females, while for whites the increase was not as great, 108 percent for males and 89 percent for females. The rise in multiple myeloma mortality from 1950 to 1975 has been relatively linear for both races and has occurred in all geographic regions of the United States (Fig. 22-4).12 Although the nonwhite rates show some fluctuation due to relatively small numbers in certain regions, the rise in mortality has been more pronounced than among whites. During this time period the male fraction of cases has remained relatively constant at approximately 58 to 60 percent for both races. The contribution of blacks to the total myeloma burden has increased from 54 to 65 percent.12 Time trends in incidence from selected population-based registries from around the world are shown in Figure 22-5.130.131For some registries, slight increases in incidence are observed for the two most recent time periods, while in the majority no significant change over time is seen. A number of studies have attempted to define the source of this rising myeloma incidence and mortality. Linos and colleagues73 reviewed the time trends in incidence of myeloma in Olmsted County, Minnesota, for the past 33 years. The average annual incidence rates for multiple myeloma in Olmsted County between 1945 and 1977 were 2.9, 3.0, and 2.7 per 100,OOO for each of the three decades of the survey. These data suggest that the apparent increases in myeloma reflect the underdiagnosis of this entity in the past rather than a true increased incidence.73 However, Olmsted County has a relatively homogeneous population with regard to race, ethnic background, and occupation, with blacks comprising a negligible proportion of the population. Yet, in the United States, the most marked changes in the incidence of myeloma are occurring among blacks. Valez et aI.lz7examined the national death statistics for England and Wales for the period 1950 to 1979 to determine whether the secular trends in myeloma mortality are due to biases associated with improvements in medical care. Age-adjusted mortality increased more than fivefold during the 30-year time period of the study, with the greatest apparent increase occurring in individuals over 70 years of age. Analysis of mortality by social class and region points toward improved case ascertainment as being responsible for at least part of the apparent increase. The rise in mortality 2 5 t30 I .98 -3 U a" 2 0 - w I<- U >I k 1.5 1 d IU P Fig. 22-4. U tality by geo 100,OOO. (A) males and fc TJ: Multiple 1975. Cancer at younger increase. Li creasing tre loma betwe the reason 1 most studic in the olde majority 01 ments in certificatior age groups increases a! duced etiol posures (se Socioeco with morta on data frc gland and in multiple ist, with th class.105-107 at the cour cates a pos tain regions, more pro- ing this time as remained ely 58 to 60 tribution of den has in- Aected popid the world For some :nce are obme periods, ant change tpted to deeloma inci:olleagues73 :nce of myota, for the I incidence ted County 1.0, and 2.7 decades of the apparthe under)ast rather However, rnogeneous hnic back.s compris)opulation. 1st marked n a are oc- onal death the period the secular e to biases .dical care. nore than -iod of the [crease ocrs of age. ss and reascertain1st part of mortality Etiology and Epidemiology of Multiple Myeloma and Related Disorders 417 I 18 2.5 s9 0 Norrheast 0 South A Central 0 West aaW 2.0 - w c aQ I 1.5 2 a L 0z '1.0 - A O.O wI- 'd I I III K< > k aIQ0 I 1 9 5 0 . ~ 1955-59 1960-65 1965-69 1970-75 YEAR Fig. 2 2 4 . U.S.multiple myeloma age-adjusted mortality by geographic region, 1950 to 1975. Rates per 100,OOO. (A) White males and females; (B) nonwhite males and females. (Blattner WA, Blair A, Mason TJ: Multiple myeloma in the United States, 195G 1975. Cancer 48~2547,1981.) 'B 0.0 1950-54 195558 196064 196649 1970-75 YEAR J at younger ages could, however, reflect a true increase. Ludwig et al.74 also reported an increasing trend in mortality for multiple myeloma between 1969 and 1979 in Austria, but the reason for this increase is unknown. Since most studies document the largest increases in the oldest age groups, it is likely that the majority of the increase represents improvements in medical diagnosis and death c e r t i f i c a t i ~ nH. ~o~wever, the rise in younger age groups could be a harbinger of emerging increases associated with more recently introduced etiologically linked environmental exposures (see below). Socioeconomic status may be associated with mortality from multiple myeloma. Based on data from the Registrar General for England and Wales, a socioeconomic gradient in multiple myeloma mortality appears to exist, with the highest rates in the upper social class.105-107Analysis of U.S. mortality data at the county level for 1950 to 1969 also indicates a positive association with higher socio- economic status, which may be a reflection of patterns in diagnostic practice and as~ertainmentT.~h~is explanation is consistent with the diminution of the social class effect over time in Great Britain, associated with wider dissemination of uniform health care to all classes. However, using incidence data from the TNCS,including census tract information on social class, DeVesa30found a weak inverse association between income level and myeloma incidence. The rates among blacks remained higher than whites after adjustments were made for differences in income. The prognosis for multiple myeloma is poor. The 5-year survival rate for 1973 to 1979 provided by the SEER program is 22 percent for whites and 23 percent for blacks [ R i a L: personal communication (unpublished data)]. These are population-based figures (covering 10percent of U.S. population), whereas earlier statistics showing more favorable survival for blacks than whites used primarily hospitalbased data.6 418 Neoplastic Diseases of the Blood ..s:*n.:*. :.-*s lio*Dc., Fig. 22-5. Multiple myeloma, age-adjusted incidence (world standard population) from selected registries. Rates per 100,000.~50~~3~ Data from a recent comparative hospitalbased record review conducted by Savage et al.Il3 revealed poor survival rates in blacks with myeloma. Several indexes of poverty best explained the lower survival pattern. Even when cases were matched for clinical stage and race, the indexes of poverty were the best correlates of poor survival. The epidemiologic patterns of BMG and WM" resemble those for myeloma. Both BMG and W M share a strong old-age depen- dence. However, accurate incidence data are not available since neither is classified as a malignancy by standard hospital coding practice. However, for WM the rate in hospitalbased surveys is approximately one quarter that of multiple myeloma.11 Racial and Geographic Variation Comparisons between international incidence rates of myeloma based on cancer regis- try data must be made cautiously since the populations served vary in size and age distribution, in the accuracy of case ascertainment (e.g., pathology vs death certificate only), and in the level of medical care and diagnostic p r e c i ~ i o n . ' ~A~cJc~or~ding to the most recent editions of Cancer incidence in Five Continents, black rates in several U.S. registries were among the top for both males and females.13' The excess among blacks in the United States was described by MacMahon and and confirmed by McPhedran et a1.,86 who reported that myeloma was twice as common among blacks in Atlanta, Georgia. The rates also appear to be high in Jamaica, where blacks have a relatively young median age at diagnosis (50 to 55 years) and a low average survival due to the advanced stage at presentation. 123 While high rates occur in American black populations, blacks in Africa generally have low rates (Fig. 22-5).130**3T1he difference may be explained by the small percentage of older blacks, limited diagnostic facilities, and incomplete ascertainment. However, in a recent survey of myeloma cases seen between 1973 and 1975 at hematology clinics in Johannesburg, South Africa, the age-adjusted (world standard) rates for black males (7.47/100,000) and females (5. I 1/1OO,OOO) closely resembled the incidence rates reported in U S . blacks for a comparable period.13 Case series from French West Africa,97 Rhodesia,IZ9 Zambia,Iz6Nigeria,S3 Kenya,gG and South Africa31 suggest a younger median age at diagnosis and a sizable male excess (in some series by as much as 4 to 1). In Nigeria34.35and Uganda,139 a striking proportion of the myeloma cases have been reported in young people. Since Burkitt's lymphoma is endemic in these areas, there may be common etiologic factors (e.g., malarial infestation) for these B-cell tumors. In Latin America, the incidence data for multiple myeloma are lacking, mainly as a result of underdiagnosis and incomplete reporting. An interesting observation comes from El Salvador, where a peculiar form of plasmac! cate long tients, cf rhinoscle cytic infi t ransforn Amon; Scandina America! are slight lower in 1 5). In No tiple my< lymphore with high 60 years, et aL6*in also suggc although Ludwig dence of commen t dient in , ences, altl tributing 1 by an ana also show: tically sigi sons of Sc The inc era1 Asiar Republic Japan.10.12 tions closc countries.' mortality white and for a corn1 firms that in Japan, in older ag A5 shou whites and various lyr a relative lymphoid I percent of i kin's lymr chronic lyr ly since the Id age distri-certainment e only), and 1 diagnostic most recent Five ContiS. registries males and the United Mahon and dran et a1.,86 wice as comieorgia. The naica, where edian age at low average tage at pre- erican black nerally have fference may age of older ies, and in-,in a recent ?tween 1973 n Johannesisted (world 47/ 100,OOO) ly resembled S. blacks for series from ia,lz9 Zamuth Africa3' iagnosis and series by as a striking s have been urkitt's lymi, there may malarial in- ice data for mainly as a :omplete reition comes liar form of Etiology and Epidemiology of Multiple Myeloma and Related Disorders 419 plasmacytoma has been reported to compli- percent for US. whites and 63.1 percent for cate long-standing rhinoscleroma. In these pa- U.S. blacks, the percentage in Japan is 43 per- tients, chronic nasal infection with Klebsiella cent. This shift results almost entirely from rhinoscleromatis predisposes to local plasma- the extreme deficit of CLL in Orientals'32 and cytic infiltration with potential for malignant a low occurrence of multiple myeloma. This transformation as plasma cell l e ~ k e m i a . ~ low rate of differentiated B-cell malignancies Among Western countries, the rates in probably reflects genetic factors'32 as well as. Scandinavia are similar to those in the North the excess of T-cell malignancies in Japan,lZ2 American white population, while the rates which appears to be related to the newly rec- are slightly lower in England and substantially ognized human T-cell leukemia virus lower in Eastern European countries (Fig. 22- (HTLV).61.109.11A0 role for genetic facto= 5 ) . In Norway, Stalsberg'21 reported that mul- is also suggested by the higher percentage of tiple myeloma is the most frequent form of immunoglobulin D (IgD) myeloma in Lymphoreticular malignancy (32 percent), oriental^.^^*^^ Since IgD involves a Less-differ- with higher rates in the rural population over entiated plasma cell, this increase may be con- 60 years, a finding that parallels that of Kyle sistent with the tendency of Orientals to de- et in the United States. High rates were velop undifferentiated, as opposed to dif- also suggested for Ireland36and S c ~ t l a n d , ~ f~er~en' t~ia~ted, forms of B-cell neoplasms." although based on small numbers of cases. Ludwig et al.74report a relatively low inci- dence of multiple myeloma in Austria and comment that the apparent north-south gradient in Europe could reflect ethnic differ- ENVlRONMENTAL AND OCCUPATIONAL EXPOSURES ences, although quality of reporting is a con- Environmental determinants of multiple tributing factor. This conclusion is supported myeloma have not been well documented in by an analysis of U.S. mortality data which the epidemiologic literature. Case-control also shows a north-south gradient and a statis- studies of myeloma patients have only recently tically significant ethnic association with per- been undertaken in several centers and the sons of Scandinavian ancestry.12 findings have not yet been reported. The scar- The incidence of myeloma is low in sev- city of studies is primarily due to the inherent eral Asian countries, including the People's methodologic problems associated with inves- Republic of China,89 South Korea,64 and tigating a rare disease of older individuals who Japan.10.122J3R2 ates in U.S. Oriental popula- have a poor prognosis. The majority of.the tions closely resemble those of their native etiologic information has been provided by countries.132 A comparison of age-specific county mortality data, cancer surveys, mortal- mortality rates for Japan (1969 to 1973) to ity studies of specific occupational groups, and white and nonwhite rates in the United States clinical case reports.'' for a comparable period (1970 to 1975) con- Several large studies that have reported as- firms that multiple myeloma is less common sociations between specific occupations or in- in Japan, with the differences most marked dustries and multiple myeloma are presented in older age groups.ll in Table 22-l.1.2.12.aJ35These data must be As shown in Figure 22-1 comparing U.S. interpreted with caution since some of the as- whites and blacks to Japanese in Japan for sociations may have occurred by chance alone various lymphoreticular neoplasms, there is as a consequence of multiple comparisons. a relative deficit of malignancies of mature Farming has been suggested as a possible lymphoid cells in Japan.lzZ While the total risk factor for myeloma although the evidence percent of all cancers attributed to non-Hodg- is weak. Bross et a1.l' reported a nonsignificant kin's lymphoma, multiple myeloma, and excess of dairy farmers among patients who chronic lymphocytic leukemia (CLL) is 60.5 developed myeloma. In Texas, mortality rates 420 Neoplastic Diseases of the Blood Table 22-1. Reported Associations Between Industry or Occupation and Multiple Myeloma: General Studies Study Blattner et aLL2 Year 1981 Industry or Occupation U.S. county mortality data, 1950-1969 Petroleum manufacturing (WM)* Paper manufacturing (WM)? Furniture manufacturing (WM)$ Study Design Correlated age-adjusted mortality rates in state economic areas with selected manufactunng industnes Agu et aL2 I980 State of Texas, 1969-1971 Agriculture; Beauty shops* Carpentry* Mining' Milham" Adelstein' 1976 1972 Washington State, 1950-1971 Foresters and conservationistsf Paper and pulp mill workers. Plywood workersf Construction and building contractors$ Plasterers and latherem$ British census, 1961 Administrators/managers* Professional/technicl workers and artistst Painters and decorators1 Food, drink, and tobacco worken$ Williams et al.135 1977 Third National Cancer Survey, 1969-1971 Sales personnel (M, F)* Manufacturing (M, F)$ Correlated age-adjusted mortality rates in Texas state economic areas with selected occupations, controlled for percentage of blacks in population, problem data not presented separately for males and females Proportionate mortality analysis of death certificate occupational statement and cause of death for men aged 20 and older Proportionate mortality analysis of census occupational data and cause of death for males aged 1574;problems: (1)denominator includes only 10% sample of census,(2) length ofemployment not designated Interview data on main lifetime occupation, and so forth, from a 10% sample of individuals identified in the Survey; problems: ( I ) poor response rate (57%), (2) based on relatively small numbers in many occupational Abbreviurionc F, female; M, male; WM. white male. P <0.05. t P<O.Ol. $ Not statistically significant. of myeloma have been positively correlated with areas that employ a high percentage of the population in agricultural industriesz This is in contrast to the total United States, where significantly lower rates have been noted among rural residents living on farms." A death certificate analysis of 26 1 myeloma cases and matched controls conducted in Washington State revealed a significant association between farming occupations and death from myeloma.88Similar studies using Nebraska15 and WisconsinZo death certificates also showed an association with farming. In the Nebraska study, decedents who had resided in counties with high levels of pesticide use had elevated, but nonsignificant risks of multiple myeloma, while significant excesses were noted among residents of Wisconsin counties with high insecticide use. Similar findings were also reported for non-Hodgkin's lymphoma in Wisconsin, suggesting shared etiologic relationships for these types of B-cell malignancy.n Due to possible misclassifications of occupation and cause of death on death certificates, such results should be viewed with caution. Exposure to metals has been reported as a potential risk factor. Greene et al. found a relative excess of myeloma deaths in male employees of the Government Printing Office. Cases were confined to compositors, whose major exposure was to molten lead and lead vapor.44The presence of trace levels of lead and cadmium in U.S. water supplies has also been positive multiple myc Males resit facture syntl 'appear to hz The findings in the rubber One mort found an ex workers alth ated with t h were not at of female pro ufacturing pl from myelor Employmi such as pap paper, pulp, try has beer from myelon ery and petrc tologists anc leather work risk of myell the benzene plant cohort in the pathc cell lineage a case of CL was also sugi by Nakayan where both years of expc lated to agric reports have phoprolifera eloma,4z.56-5 been seen in workers.116 The role case reports nytoin (DII. Exposure documented but the mec nerd Studies aign ~~ isted mortality iomic areas with tunng indus- rstrd mortality iie economic :d occupations. rcentage of ion; problem: d separately for s ality analysis of xcupational use of death for older ality analysis of nal data and males aged 15denominator b sample of cen:mployment not lain lifetime ocforth, from a idividuals ideny; problems: (1) e (57%). (2) y small numu pat ional with high {ere also reiphoma in iologic rela-cell maligassifications h on death be viewed :ported as a al. found a in male emiting Office. tors, whose ad and lead vels of lead lies has also Etiology and Epidemiology of Multiple Myeloma and Related Disorders 421 been positively correlated with mortality from induces the cancer has not yet been multiple m y e l ~ m a . ~ established. The strongest evidence linking Males residing in U.S.counties that manu- radiation to myeloma has been provided by facture synthetic rubber and synthetic fibers a recent report on the mortality experience appear to have elevated rates of myeloma.80 of 109,000 atomic bomb survivors. Twenty- The findings of an increased risk of myeloma nine multiple myeloma deaths were identified in the rubber industry have been inconsistent. over the years 1950 to 1976.22 of which were One mortality study of rubber workers exposed to the bomb. Those survivors who found an excess of myeloma among female received 50 or more rad in marrow total doSe workers although no specific job was associ- had significantly increased risks of myeloma. ated with the risk.s1 White male employees These individuals were 20 to 59 years of age were not at increased risk.w A similar study at time of exposure and their excess risk be- of female production workers in a rubber man- came apparent only after a latent period of ufacturing plant also revealed no excess deaths 20 years or greater.4s Atomic bomb survivors from myeloma.3 have had elevated serum immunoglobulin Employment in wood-related industries levels46and chromosome aberrations in B lym- such as paper and furniture manufacturing, phocytes.62 which may represent subclinical paper, pulp, plywood and lumber, and carpen- markers of multiple myeloma risk. try has been associated with excess deaths Studies on the mortality experience of ra- from myeloma (Table 22-1). Petroleum refin- diologists and nuclear processing plant em- ery and petrochemical workers,16.28.125cosme- ployees have provided information on the risk tologists and beauty shop employee^,^.^^ and of occupational exposures to radiation. Le- leather worker^^^.^^ may also be at increased w i P observed five multiple myeloma deaths risk of myeloma. Decoufle et noted that among 425 American radiologists who died the benzene exposure in their petrochemical between 1948 and 1961 (P= 0.004). Whether plant cohort may have played an etiologic role this excess was solely attributable to radiation in the pathogenesis of several tumors of B- exposure is uncertain since other factors may cell lineage since two cases of myeloma and have contributed to the risk.6s Matanoski et a case of CLL were observed. A benzene link al. also found excess deaths of myeloma was also suggested by a case report from Japan among approximately 6,500 radiologists who by Nakayama et aLS3 of a conjugal cluster were followed from 1920 to 1969and hypothe- where both husband and wife experienced 30 sized that long-term, low-dose exposure may years of exposure to benzene hexachloride re- have had an etiologically related immunosup- lated to agricultural employment. Several case pressive effect.82To examine the relationship reports have linked asbestos exposure to lym- between dose levels and risk of myeloma, she phoproliferative neoplasms, including my- evaluated the mortality experience of the ra- eloma,42*56-58.b7u1t this association has not diologists from early periods of practice, when been seen in the follow-up studies of asbestos radiation exposures were high, and those workers.116 whose entry period was more recent, when The role of drugs has been suggested by exposures should have been lower. No in- case reports of myeloma following use of phe- creased myeloma risk was seen for radiologists nytoin ( D i l a r ~ t i n )a~n~d sulphinpyrazone.138 who entered practice in the early time period; however, leukemia risk was high for this group. In contrast there was a two-fold excess Radiation Exposures of myeloma among those who entered practice more recently, supporting the conclusion that Exposure to ionizing radiation is the best long-term exposure to low levels of external documented risk factor of multiple myeloma radiation is a risk factor for myeloma.81 but the mechanism by which the radiation Excess multiple myeloma mortality has 422 Neoplastic Diseases of the Blood been reported among male employees engaged in plutonium manufacturing at the Hanford Works. Mancuso et al. observed 1 1 myeloma deaths when 7.6 were expected. However, only eight of these workers were exposed to radiation.77Reanalysis of these data by Darby and Reissland revealed that there was an excess of myeloma by two to three deaths for those workers whose total dose was 5 rem or greater 10 years previous to death.26 Four cases of myeloma occurred among workers at the Windscale Nuclear Processing Plant in Great Britain over the years 1950 to 1974. Only three of these workers were exposed to radiation, two of whom had accumulated doses of 4 and 3.3 rem, respectively, and one of whom had worked with plutonium. Retired and ex-workers were not included in the study; thus an underestimate of the occurrence of myeloma in this population may have taken place.32 Familial and Genetic Factors Genetic factors, as discussed above, appear to contribute to racial and ethnic variation in myeloma occurrence. Familial Occurrence is well documented and a recent review documents that the median age and sex ratio of the 75 reported familial cases resemble those of nonfamilial cases.l0 Siblings are affected 70 percent of the time, suggesting recessively inherited s~sceptibility,a~lt~hough underascertainment of cases in earlier generations is likely. Among cases in the same family, the heavychain types were usually different, while in 80 percent of cases the light-chain type was the same. This pattern of concordance for light chains may be genetically determined.l0 In addition, although based on small numbers, there was an imbalance of the K to h ratio for IgG myeloma in familial cases compared to the general population, which may reflect an altered antibody repertoire in familial cases. Benign monoclonal gammopathy has been reported occasionally in the relatives of mye- loma cases.66.14N3 evert heless, some myelomaprone families have had clinically normal relatives with benign M-spikes, suggesting that a variant of familial myeloma is associated with parapr~teinemia.'~.~~.'A~x~elsson and Hallen,' in a population-based survey of 6,994 sera from rural Sweden, uncovered three families with benign monoclonal gammopathy in close relatives, including sibs in two families. Williams et al.134 also reported that probands with BMG have an increased number of relatives with BMG, as compared to control families. Several studies have also suggested that polyclonal immunoglobulin levels are increased among the close relatives of myeloma case^.^'.^' In some myeloma-prone families, other lymphoproliferative neoplasms have been described, including giant follicular lymphoma, with an immunoglobulin M (IgM) paraprotein, CLL, and mycosis fungoides.43.120.137 In contrast to myeloma, the relatives of patients with WM seem to have a plethora of immunologic abnormalities, including an excess of polyclonal IgM, benign IgM-spikes in close relatives, various autoantibodies, and subclinical immune defects.9~39~4T1h~e59vast majority of serum M-spikes (12 of 15) in normal family members are IgM, concordant with the heavy-chain type of the proband. Longterm follow-up of one family documented the malignant transformation in two relatives of one family.38 The predominant light-chain type, as in familial myeloma, is K (only 5 of 25 were A).1o Kalff and HijmansS9studied 353 relatives of 23 WM patients and reported seven benign M-spikes-five were IgMwhich clearly exceeded expectation. In contrast to myeloma, where all classes of immunoglobulins seem elevated in first-degree relat i v e ~t,h~e ~polyclonal increases in WM were confined to the IgM class.41.59J1i Seligmann et al.l17 reported a high frequency of rheumatoid factor (an IgM autoantibody) in patients with WM and in their relatives compared to healthy control subjects, especially for the group under 60 years of age. No difference antinuclear, a bodies. Genetic ma unrevealing B quency of hu of the "4C" in myeloma.8 gested an ass myeloma anc (IgA) myelon A three- to fl and B27 in T a n a n ~ v . l *I ~ ported an exc tion from AI BMG are als to certain HL dominance 01 For WM li 8, DRW3 wi of macroglc abnormalities positive react Ia 172 and 35 with the lym The constella autoimmune sult from a f munoregulati age of this ab that a defect predispose to munity. The cytoge ologic releva 14q+ abnorn Hill et al.142 this abnorma mia and mui quently confi globulin G ( I Drivsholmlol cases and Liz this abnorm; disease and 1 though the found in ever me rnyelornanormal relaggesting that is associated .xelsson and rvey of 6,994 :d three faminmopathy in two families. hat probands rnber of relacontrol fami- ggested that ?els are inives of myeloma-prone 'e neoplasms $ant follicu>globulin M nycosis fun- latives of paplethora of iding an exgM-spikes in ibodies, and s9 The vast I f 15) in norcordant with band. Longumented the relatives of light-chain K (only 5 of studied 353 nd reported /ere IgMion. In conof immunodegree relan WM were a high fre:gM autoanIn their rela-01 subjects, years of age. Etiology and Epidemiology of Multiple Myeloma and Related Disorders 423 No differences were seen in the frequency of pattern suggests that a common cytogenetic antinuclear, antithyroid, and antigastric anti- abnormality may play a role in the pathogen- bodies. esis of various B-cell neoplasms, and this may Genetic marker studies have been generally have a biological basis since human immuno- unrevealing for the gammopathies. The fre- globulin genes have recently been assigned to quency of human leukocyte antigens (HLA) this chromosome.22 Dalla-Favera et al.25de- of the "4C" group seems slightly increased fined a translocation in Burkitt's lymphoma in Smith et al.ll9 also sug- involving the transfer of the human onc gene, gested an association of W-22 with u-chain c-myc, to a position juxtaposed to the heavy- myeloma and A-9 with immunoglobulin A or light-chain genes of chromosomes 14 (IgA) myeloma, but the numbers were small. (heavy chain), 2 (K-light chain), or 22 (A-light A three- to four-fold excess of antigens A28 chain). Cytogenetic studies of WM have in and B27 in myeloma was reported by general been ~ n r e v e a l i n g . ~ ~ T a n a n ~ v . 'L~u~dwig and M a ~ rrece~nt~ly re- ported an excess of HLA-B5 in their popula- tion from Austria. Genetic determinants of Role of Chronic Antigenic BMG are also suggested by the relationship Stimulation to certain HLA types108.128J4a2nd by the pre- dominance of the IgG-1 subclass.1o2 Clinical reports have suggested that my- For WM linkage to the HLA type A-2, B- eloma or macroglobulinemia may occur 8, DRW3 was reported in a familial cluster more often among persons with diseases as- of macroglobulinemia and immunologic sociated with chronic antigenic stimulation. abn0rma1ities.l~ These individuals also had but epidemiologic confirmation is generally positive reactions for the B-cell allo-antigens lacking.ll These primarily anecdotal reports Ia 172 and 350,previously reported in patients have described myeloma in allergic pa- with the lymphoma-prone sicca syndr0rne.~2 tients repeatedly h y p o s e n s i t i ~ e d " . ~ ~ . ~ . ~ ~ ~ . ~ ~ The constellation of lymphoproliferative and and in patients with chronic biliary tract autoimmune disorders in this family may re- di~ease.51.5~.65.~1~A."m5ong patients with he- sult from a heritable abnormality in the im- reditary spherocytosis, which predisposes to munoregulation of B lymphocytes. The link- chronic biliary tract disease, a high prevalence age of this abnormality to Ia antigens suggests of IgA myeloma was In a follow-up that a defective immune response gene may study of 136 women with sic- syndrome, 7 predispose to lymphoproliferation or autoim- developed non-Hodgkin's lymphoma, and 3 munity. WM.63 The cytogenetic abnormality of greatest eti- In family studies, autoimmune disorders ologic relevance to multiple myeloma is the have been reported to occur in the close rela- 14q+ abnormality (see Chapter 26). Wurster- tives of patients with WM.14.117Hamaker et Hill et al.142reported the first examples of aL4' described a 48-year-old man who devel- this abnormality in cases of plasma cell leuke- oped plasmacytoma in the cutaneous pocket mia and multiple myeloma, a finding subse- where a silastic-covered pacemaker w-a~im- quently confirmed by PhiliplOO in an immuno- planted, a possible counterpart to the plastic- globulin G (1gG)-A-myeloma case. Philip and induced plasmacytoma in the BALB/c mouse. Drivsholmlol described three additional 14qf Seligmann et al.118 reported a patient with cases and Liang et al.'O described 6 of 18 with myeloma that reacted specifically with the this abnormality associated with accelerated a- 2 macroglobulin of the horse. The 30-year disease and high serum paraprotein level. Al- latent period between sensitization to antiteta- though the 14q-t abnormality has not been nus horse serum and myeloma argues for a found in every case of multiple myeloma, the two-hit mutation model, the first hit leading 424 Neoplastic Diseases of the Blood to a premalignant monoclonal B-cell proliferation, and the second causing neoplastic growth of a susceptible subclone.Il2 In a populationbased study from Finland, the incidence of lymphoproliferative neoplasms, including myeloma, was higher in patients with rheumatoid arthritis than in the general population.52 If chronic stimulation by a specific antigen predisposes to malignancy in the responding clone, then malignant M-spikes with definable antigenic activity should be identified, especially against common types of bacterial or other antigens. Single cases suggesting such a mechanism have been reported infrequently.w.118 These findings suggest that chronic antigenic stimulation may act as a promoting factor to enhance clonal expansion of cell populations susceptible to malignant transformation to myeloma. cupational chemicals. It is possible that some agents may act through antigenic stimulation or suppression of immunoregulatory function. Genetic factors are likely to account for racial and ethnic patterns. Family studies have been of interest, particularly in uncovering subclinical immunopathy in relatives. The overlap between immunodeficiency and autoimmunity in plasma cell dyscrasias, particularly WM, suggests that a widespread defect in immunoregulation may be involved. The role of chronic antigenic stimulation, perhaps by increasing the size of the clone at risk of plasma cell neoplasia, is suggested by several clinical observations. Clarification of causes of myeloma and related disorders is likely to emerge as analytic epidemiologic studies provide etiologic clues and molecular studies clarify mechanisms of transformation. CONCLUSIONS The cause@) of multiple myeloma and related dyscrasias are unknown. The major risk indicator is old age. An age-dependent loss of regulatory cell function may be involved, thereby increasing the pool of terminally differentiated, immunoglobulin-secreting cells potentially available for malignant transformation.lo3 The striking predisposition of blacks to myeloma suggests genetic susceptibility, although environmental factors probably also contribute to risk. The elevated risk in blacks may be correlated with their higher baseline immunoglobulin levels.le In addition, differences in regulatory cell function may alter the balance of precursor and terminally differentiated B-lymphocytes. In Japan, there is an unusual predominance of T-cell malignancies with a relative deficit of mature B-cell forms. The upward trend in myeloma among blacks suggests that environmental exposures may be involved, in addition to improvements in diagnosis. Further studies are needed to evaluate leads to immunogenetic factors and environmental exposures, including radiation and oc- REFERENCES 1. Adelstein AM: Occupational mortality: cancer. Ann & c u p Hyg 15:53, 1972 2. Agu VU, Christensen BL, Buffler PA: Geographic patterns of multiple myeloma: racial and industrial correlates, state of Texas, 19691971. J Natl Cancer Inst 65735, 1980 3. Andjelkovich D, Taulbee J, BIum S: Monality of female workers in a rubber manufacturing plant. J Occup Med 20409, 1978 4. Axelsson U. Hallen J: Familial Occurrence of pathological serum-proteinsof different gammaglobulin groups. Lancet 2:369, 1965 5. Astacio JN, Poubleau V, Alfaro DA, et al: Plasmocitomas extramedulares de 10s tractos respiratorio superiorY gastro-intestinal. Relacion escleroma-plasmocitoma.Arch Coll Med El Salvador 18:213, 1965 6. Axtell LM, Myers MH: Contrasts in survival of black and white cancer patients. J Natl Cancer Inst 60:1209, 1978 7. Berg JW. Burbank F: Correlations between carcinogenic trace metals in water supplies & cancer mortality. Ann NY Acad Sci 199:249, 1972 8. Bertrams J, Kuwert E, Bohme U. et al: HL-A antigens in Hodgkin's disease and rnultiple myeloma-increased frequency of W 18 in both c 9. Bjornsso et al: M family. P 10. Blattner eloma ar analytic res in M ier Nortl 11. Blattner globulint meni JF Preventi t 12. Blattner myelomi cer 4 8 ~ 2 ' 13. Blattner tiple my1 1:928, 1' 14. Blattner denstror mune d 93:830, 15. Blattner myelorn for pub1 16. Blot W. with pc 1977 17. Bross I tional c: environ 33:300, 18. Buckle! globulii healthy 19. Cantor Hodgki Int J C 20. Cantor from m with th cer Ins 21. Clamp case o 1967 22. Croce Chrom immun Acad ! 23. Cutler de that some c stimulation ory function. c o u n t for rastudies have uncovering latives. The :y a n d autoias, particupread defect volved. T h e ion, perhaps le a t risk o f d by several n of causa , is likely t o studies pro- studies clar- irtality: can2 f r PA: Geo:loma: racial rexas, 1969- 1980 n S: Mortalmanufactur1978 zcurrence of fferent gam, 1965 DA, et al: : 10s tractos itinal. Rela:h Coil Med . in survival nts. J Natl ns between er supplies Acad Sci U. et al: .e and mulcy of W18 Etiology and Epidemiology of Multiple Myeloma and Related Disorders 425 in both diseases. Tissue Antigens 2:41, 1972 9. Bjornsson OG,Arnason A, Gudmundsson S, et al: Macroglobulinaemia in an Icelandic family. Acta Med Scand 203:283, 1978 10. Blattner WA: Epidemiology of multiple myeloma and related plasma cell disorders: an analytic review. p. 1. In Potter M (ed): Progress in Myeloma: Biology of Myeloma. Elsevier North-Holland, New York, 1980 1 1. Blattner WA: Multiple myeloma and macroglobulinemia. p. 795. In Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention, WB Saunders, Philadelphia, 1982 12. Blattner WA, Blair A, Mason TJ: Multiple myeloma in the United States, 1950-75. Cancer 48:2547, 1981 13. Blattner WA, Jacobson RJ,Shulman G: Mul- tiple myeloma in South African blacks. Lancet 1:928, 1979 14. Blattner WA, Garber J, Mann DL, et al: Waldenstrom's macroglobulinemia and autoimmune disease in a family. Ann Intern Med 93:830, 1980 15. Blattner WA, Wilkins Y, Blair A: Multiple myeloma risk in Nebraska farmers (submitted for publication) 16. Blot WJ: Cancer mortality in U.S. counties with petroleum industries. Science 198:5 1. 1977 17. Bross IDJ, Viadana E, Houten L: Occupational cancer in men exposed to dust and other environmental hazards. Arch Environ Health 33:300, 1978 18. Buckley C E 111, Dorsey FC: Serum immuneglobulin levels throughout the life-span Of healthy man. Ann Intern Med 75:673, 1971 19. Cantor KP: Farming and mortality from nonHodgkin's lymphoma: a c S e control study. Int J Cancer 29:239, 1982 20. Cantor KP, Blair A: Farming and mortality from multiple myeloma: A case-control study with the use of death certificates. J Natl Cancer Inst 72:251. 1984 21. Clamp JR:Some aspects of the first recorded case of multiple myeloma. Lancet 2:1354, 1967 22. Croce CM, Shander M, Martinis J, et al: Chromosomal location of the genes for human immunoglobulin heavy chains. Proc Natl Acad Sci USA 76:3416, 1979 23. Cutler SJ, Young JL: The Third National Cancer Survey: Incidence data. Natl Cancer Inst Monogr 41, 1975 24. Cuzick J: Radiation-induced myelomatosis. New Engl J Med 304:204, 1981 25. Dalla-Favera R, Bregni M,Erikson J, et al: Human C-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 79:7824, 1982 26. Darby SC, Reissland JA: Low levels of ionizing radiation and cancer: are we underestimat-. ing the risk? J R Statist Soc A 3:298, 198127. Dawson AA, Ogston D: High incidence of myelomatosis in north-east Scotland. Scott Med J 18:75, 1973 28. Decoufle P, Blattner WA, Blair A: Mortality among workers exposed to benzene and other agents. Environ Res 30:16. 1983 29. Decoufle P, Stanislawczyk K, Houten L, et al: A retrospective survey of cancer in relation to occupation. Department of Health, Education and Welfare (National Institute for Occupational Safety and Health) Publication 77, Washington D.C., 1977 30. DeVesa ss: A study of the association of can- cer incidence with income and education among whites and blacks. Ph.D. dissertation, Johns Hopkins University, 1979 31. DeVilliers LS: Dysgammaglobulinemia in the Bantu. S Afr Tydskrifuir Geneeskunde 43536, 1969 32. Dolphin GW: A comparison of the observed and the expected cancers of the haematopoietic and lymphatic systems among workers at Windscale: a first report. National Radiation Protection Board NRPB-RS4, Hawell; England, 1976 ne33, Darken H, vollmer 1: epidemiology of multiple myeloma. Investigation of 149 cases. Arch Geschwulstforsch 31:18, 1968 34. Edington GM: Tumorsof lymphoreticular tissue including the Burkitt lymphoma but excluding leukaemia in Nigeria with special reference to the northern savanna. Niger Med J 8:75, 1978 35. Edington GM, Hendrickse M: Incidence and frequency of lymphoreticular tumors in Ibadan and the western state of Nigeria. J Natl Cancer Inst 50:1623, 1973 36. Egan EL, Grimes H, O'Beirn Dp: Multiple myeloma in the west of Ireland, presentation and frequency. Ir Med J 71:23, 1978 426 9 Neoplastic Diseases of the Blood 37. Festen JM, Mamnk J, de Waard-Kuiper EH, et al: Immunoglobulins in families of myeloma patients. Scand J Immunol 6:887, 1977 38. Fine JM, Lambin P, Massari M. et al: Malignant evolution of asymptomatic monoclonal IgM after seven and fifteen years in two siblings of a patient with Waldenstrom's macroglobulinemia. Acta Med Scand 211:237, 1982 39. Fine JM, Lambin P, Valentin L. et al: IgG monoclonal gammopathy in the sister of a patient with Waldenstrom's macroglobulinemia. Biomedicine 19:117, 1973 40. Fraumeni JF Jr: Environmental and genetic determinants of cancer. J Envir Pathol Toxicol 1:19, 1977 41. Fraumeni JF Jr, Wertelecki W, Blattner WA, et al: Vaned manifestations of a familial lymphoproliferative disorder. Am J Med 59:145, 1975 42. Gerber MA: Asbestosis and neoplastic disorders of the hematopoietic system. A m J Clin Pathol 53:204, 1970 43. Greene MH, Dalager NA, Lamberg SI, et al: Mycosis fungoides: epidemiologic observa- tions. Cancer Treat Rep 63597, 1979 44. Greene MH. Hoover RN, Eck RL, et al: Can- cer mortality among printing plant workers. Environ Res 2066, 1979 45. Guidotti S, Wright WE, Peters JM: Multiple myeloma in cosmetologists. Am J Indust Med 3:169, 1982 46. Hall CB. Hall WJ, Ashley FW, et al: Serum immunoglobulin levels in atomic bomb survivors in Hiroshima, Japan. Am J Epidemiol 98:423. 1973 47. Hamaker WR, Lindell ME, Gomez AC: Plasmacytoma arising in a pacemaker pocket. Ann Thorac Surg 21:354, 1976 48. Hoover RN, Mason TJ, McKay FW, et al: Geographic patterns of cancer mortality in the United States. p. 343. In Fraumeni JF Jr (ed): Persons at High Risk of Cancer, an Approach to Cancer Etiology and Control. Academic Press, New York, 1975 49. Ichimaru M. Ishimaru T, Mikami M, et al: Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950-76: relationship to radiation dose absorbed by marrow. J Natl Cancer Inst 69:323, 1982 50. Imahori S , Moore GE: Multiple myeloma and prolonged stimulation of reticuloendothelial system. NY State J Med 72:1625, 1972 51. Isobe T, Osserman EF: Pathologic conditions associated with plasma cell dyscrasias: a study of 806 cases. Ann NY Acad Sci 190507, 1971 52. Isomaki HA, Hakulinen T, Joutsenlahti V: Excess risk of l~ym.phoma, leukemia, and myeloma in patients with rheumatoid arthritis. J Chronic Dis 31:691, 1978 53. Iyun A, Isaacs-Sodeye A: Multiple myelomatosis in Ibadan: a comparative study. East Afr Med J 53581, 1976 54. Jancelewicz Z. Takatsuki K, Sugai S , et al: IgD multiple myeloma. Review of 133 cases. Arch Intern Med 13587, 1975 55. Jeannet M. Magnin C: HL-A antigens in haematological malignant diseases. Eur J Clin Invest 2:39, 1971 56. Kagan E, Jacobson RJ, Yeung K, et al: Asbestos-associated neoplasms of B e l l lineage. Am J Med 67:325, 1979 57. Kagan E, Solomon A, Cochrane JC, et al: Immunological studies of patients with asbestosis. I. Studies of cell-mediated immunity. Clin Exp Immunol 28:261, 1977 58. Kagan E. Solomon A. Cochrane JC, et al: Immunological studies of patients with asbestosis. 11. Studies of circulating lymphoid cell numbers and humoral immunity. Clin Exp Immunol 28:268, 1977 59. Kalff MW, Hijmans W: Immunoglobulin analysis in families of macroglobulinemia patients. Clin Exp Immunol 5479, 1969 60. Kalliomaki JL, Gransfors K, Toivanen A: An immunoglobulin G myeloma with antistreptolysin activity and a lifelong history of cutaiieous streptococcal infection. Clin Immunol Immunopathol 9:22, 1978 61. Kalyanaraman VS. Sarngadharan MG, Na- kao Y,et al: Natural antibodies to the struc- tural protein (p24) of the human T-cell leukemia (lymphoma) retrovirus found in sera of leukemic patients in Japan. Proc Natl Acad Sci USA 79:1653. 1982 62. Kamada N, Kuramoto A, Katsuki T, et al: Chromosome aberrations in B lymphocytes of atomic bomb survivors. Blood 53:1140, 1979 63. Kassan S S , Thomas TL, Moutsopoulos HM, et al: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89:888, 1978 64. Kim SI, Lee CK: Leukemia among Koreans. A statistical and hematological study of 601 cases of leukemia and allied conditions. G A N N Monogr Cancer Res 18:229, 1976 65. Krause RM: Factors controlling the occur- rence of a . Fed Proc 66. Kyle RA: termined cases.Am 67. Kyle RA Gammopz lated Plas Charles C 68. Kyle RA. myeloma 1945-196 69. Lewis EB aplastic ai ence 142: 70. Liang W, abnormal: with mull teinemic ( 71. Lieben J: Arch En\ 72. Lin KT: patients. 73. Linos A, dence anc in Olmst, Natl Can 74. Ludwigt and age-d in Austn 75. Ludwig I to multil 45:225, 1 76. MacMah multiple 77. Mancusc exposure cancer ar 1977 78. Maldona Report o proteins 1974 79. Mason I: cies in IT 80. Mason 1 with pla Health I 81. Matano! with occ other rat JH, Oett xasias: a study i 190:507. 1971 outsenlahti V: emia, and myatoid arthritis. iple myeloma.tudy. East Afr Sugai S, et al: of 133 cases. ntigens in haeEur J Clin In- <, et ai: Asbes- &cell lineage. m e JC. et ai: its with asbesed immunity. 7 me JC, et al: its with asbeslymphoid cell ity. Clin Exp munoglobulin bulinemia pa), 1969 livanen A: An h antistrepto)ry of cutaneImmunol Im- an MG, Nato the strucT-cell leukend in sera of c Natl Acad .uki T, et al: lymphocytes md 53:1140, )poulos HM, ima in sicca 238, 1978 mg Koreans. itudy of 601 conditions. 229, 1976 ; the occur- Etiology and Epidemiology of Multiple Myeloma and Related Disorders 427 rence of antibodies with uniform properties. Fed Proc 2959, 1970 66. Kyle RA: Monoclonal gammopathy of undetermined significance: natural history in 241 cases. Am J Med 64:814, 1978 67. Kyle RA, Bayrd ED: The Monoclonal Gammopathies: Multiple Myeloma and Related Plasma-cell Disorders. Springfield, IL, Charles C Thomas, 1976 68. Kyle RA, Nobrega FT,Kurland LT: Multiple myeloma in Olmsted County, Minnesota, 1945-1964. Blood 33~739,1969 69. Lewis EB: Leukemia. multiple myeloma, and aplastic anemia in American radiologists. Science 142:1492, 1963 70. Liang W, Nopper JE, Rowley JD: Karyotypic abnormalities and clinical aspects of patients with multiple myeloma and related paraproteinemic disorders. Cancer 44:630, 1979 71. Lieben J: Malignancies in asbestos workers. Arch Environ Health 13:619, 1966 72. Lin KT: Myeloma proteins in adult Chinese patients. Chin J Microbiol 10:28, 1977 73. Linos A, Kyle RA, OFallon MW, et al: Incidence and secular trend of multiple myeloma in Olmsted County, Minnesota: 1965-77. J Natl Cancer Inst 66:17, 1981 74. Ludwig H, Fritz E, Fried1 HP: Epidemiologic and age-dependent data on multiple myeloma in Austria. J Natl Cancer Inst 68:729, 1982 75. Ludwig H, Mayr WR: Genetic susceptibility to multiple myeloma (meeting abstr). Blut 45:225, 1982 76. MacMahon B, Clark DW: The incidence of multiple myeloma. J Chron Dis 4508, 1965 77. Mancuso TE, Stewart A, Kneale G: Radiation exposures of Hanford workers dying from cancer and other causes. Health Phys 33:369, 1977 78. Maldonado JE, Kyle RA: Familial myeloma. Report of eight families and a study of serum proteins in their relatives. Am J Med 57:875, 1974 79. Mason DY. Cullen P:HL-A antigen frequen- cies in myeloma. Tissue Antigens 5238, 1975 80. Mason TJ: Cancer mortality in U.S.counties with plastics and related industries. Environ Health Perspect 11:79, 1975 81. Matanoski GM: Risk of cancer associated with occupational exposure in radiologists and other radiation workers. p. 241. In Burchenal JH, Oettgen H F (eds): Cancer, Achievements, Challenges, and Prospects for the 1980's. Grune and Stratton, New York, 1982 82. Matanoski GM, Seltser R, Santwell RE, et ai: The current mortality rates of radiologists and other physician specialists: specific causes of death. Am J Epidemiol 101:199, 1975 83. Matzner Y, Polliack A: Lymphoproliferative . disorders in four patients receiving chronic diphenylhydantoin therapy: etiologic correlation or chance association? Isr J Med Sci 14:865, 1978 84. McDevitt HO, Bodner W F Histocompatibil-ity antigens, immune responsiveness and susceptibility to disease. Am J Med 5 2 1 , 1972 85. McKusick VA: Mendelian inheritance in man. In: Catalog of Autosomal Dominant, Autosomal Recessive and X-linked Pheno- types. p. 605. Johns Hopkins University Press, Baltimore, 1978 86. McPhedran P, Heath CW Jr, Garcia J: Multi- ple myeloma incidence in metropolitan Atlanta, Georgia: racial and seasonal variations. Blood 39:866, 1972 87. Meijers KAE, Leeuw B, Voormolen-Kalova M: The multiple Occurrence of myeloma and asymptomatic paraproteinaemia within one family. Clin Exp Immunol 12:185. 1972 88. Milham S Jr: Occupational mortality in Washington State, 1950-1971. p 76. Department of Health, Education and Welfare (National Institute of Occupational Safety and Health) Publication 76175, Government Printing Ofice, Washington, DC,1976 89. Miller RW: Cancer epidemics in the People's Republic of China. J Natl Cancer Inst 60:1195, 1978 90. Monson RR, Nakano KK: Mortality among rubber workers. I. White male union employees in Akron, Ohio. Am J Epidemiol 103:284, 1976 91. Monson RR, Nakano KK: Mortality among rubber workers. 11. Other employees. Am J Epidemiol 103:297, 1976 92. Moutsopoulos HM, Chused TM, Knudsen B, et al: B-Lymphocyte antigens in sic& syndrome. Science 199:1441, 1978 93. Nakayama S, Kitajima K. Veno K. et al: Multiple myeloma in spouses with special reference to BHC as a mssible cause. Rinsho Ketsueki 21:73, 1980 94. Odeberg H. Johansson BG, Berlin SO: Immunoglobulin analysis in families of myeloma patients. Acta Med Scand 96:361. 1974 I L i 428 Neoplastic Diseases of the Blood 95. Ohtani H: Myeloma and immunoglobins. Jpn J Clin Pathol 24:287, 1976 96. Otieno Ls, Ogada T: Multiple myeloma at Kenyatta National Hospital 1973-1976. East Afr Med J 54574, 1977 97. Payet M, Sankale M, Pene P, et al: La maladie de Kahle chez l'Africain, a propos de 38 cas. Bull Soc Med Afr Noire Lang Fr 8:338, 1963 98. Penny R, Hughes S: Repeated stimulation of the reticuloendothelial system and the development of plasma-cell dyscrasias. Lancet 1:77, 1970 9 9 Percy C. Stanek E, Gloeckler L: Accuracy of cancer death certificates and its effect on cancer mortality statistics. Am J Public Health 71:242, 1981 100. Philip P: Marker chromosome 14q+ in multiple myeloma. Hereditas 80:155, 1975 101. Philip P, Drivsholm A: G-banding analysis of complex aneuploidy in multiple myeloma bone marrow cell. Blood 47:69, 1976 102. Pick AI, Shoenfeld Y. Skvaril F, et al: Asymptomatic (benign) monoclonal gammopathya study of 100 patients. Ann Clin Lab Sci 74:335, 1977 103. Rad1 J, Sepers JM, Skvaril F, et al: Immunoglobulin patterns in humans over 95 years of age. Clin Exp Immunol 22:84, 1975 104. Ramsey DM: A five-year cumulative survey of cases of leukemia and myelomatosis in the southcast of Scotland. Health Bull (Edinb) 33:158. 1975 105. Registrar General of England and Wales: Registrar General's Decennial Supplement. England and Wales, 1951: Occupational Mortality Tables. Her Majesty's Statistics Office, London, 1958 106. Registrar General of England and Wales: Registrar General's Decennial Supplement. England and Wales. 1961: Occupational Mortality Tables. Her Majesty's Statistics Office, London. 1971 107. Registrar General of England and Wales: Registrar General's Decennial Supplement. England and Wales, 1970-1972: Occupational Mortality Tables. Series DS No. 1. Her Majesty's Statistics Office. London, 1978 108. Ritzman SE, Loukas D, Sakai H, et al: Idiopathic (asymptomatic) monoclonal gammopathies. Arch Intern Med 135:95, 1975 109. Robert-Guroff M, Kalyanaraman VS, Blatt- ner WA, et al: Evidence for human T-cell lymphoma-leukemia virus infection of family members of human T-cell lymphoma-leukemia virus positive T-cell leukemia-lymphoma patients. J Exp Med 157:248, 1983 110. Robert-Guroff M, Nakao Y,Notake K, et al: Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T-cell leukemia. Science 215:975, 1982 111. Rosenblatt J, Hall CA: Plasma-cell dyscrasia following prolonged stimulation of reticuloendothelial system. Lancet 1:301, 1970 112. Salmon SE, Seligmann M: B-cell neoplasia in man. Lancet 2:1230, 1974 113. Savage D, Lindenbaum J, VanRyzin J et al: Race, poverty and survival in multiple myeloma (meeting abstr). Clin Res 31:365A. 1983 114. Schafer AI, Miller JB: Association of IgA multiple myeloma with preexisting disease. Br J Haematol 41:19. 1979 115. Schafer AI, Miller JB, Lester EP, et al: Monoclonal gammopathy in hereditary spherocytosis: a possible pathogenetic relation. Ann Intern Med 88:45, 1978 116. Selikoff IJ, Hammond EC. Seidman H: Cancer risk of insulation workers in the United States. p. 209. In Bogoski P, Gilson JC, Timbrell V, Wagner JC (eds): Biological Effects of Asbestos. International Agency for Research on Cancer Publication 8.Lyon. France, 1973 117. Seligmann M, Danon F, Mihaesco C, et al: Immunoglobulin abnormalities in families of patients with Waldenstrom's macroglobulinemia. Am J Med 43:66, 1967 118. Seligmann M,Sassy C, Chevalier A: A human IgG myeloma protein with anti-alpha 2 macroglobulin antibody activity. J Immunol 110:85, 1973 119. Smith G , Waldorf RL, Fishkin B, et al: HL-A phenotypes, immunoglobulins and K and L chains in multiple myeloma. Tissue Antigens 4:374, 1974 120. Spengler GA, Butler R, Fischer C, et al: On the question of familial occurrence of paraproteinemia. Helv Med Acta 33:208, 1966 121. Stalsberg H: Lymphoreticular tumors in Norway and in other European countries. J Natl Cancer Inst 50:1685, 1973 122. Takatsuki K, Uchiyama T, Veshima Y,et al: Adult T-cell leukemia: proposals as a new disease and cytogenetic phenotypic, and func- tional stu( ogr Cance 123. Talerman tiple myell 1969 J24. Tananov I gens and c 23:45, 19; 125. Thomas ' Mortality leum refin cup Med 126. Traub N: Teaching study. Mc 127. Valez R, of multipl Wales; 19 Cancer Ir 128. VanCam antigens s Clin Imrr 129. Waldbaui the Rhoc 26:26, 19 130. Waterhoi cer Incidl ternation; Publicatic 131. Waterhoi K, et al: ( Vol. 4. In Cancer F 132. Weiss N! dence of Cancer 1. 133. Wiederm al: Multil noglobuli plasma 2 134. Williams al: Studi (M-comr tern Mec :tion of family Iphoma-leukenia-lymphoma 1983 Notake K, et nan retrovirus : patients with 215:975,1982 .-cell dyscrasia 1 of reticuloen- 1970 cell neoplasia Ryzin J et al: multiple myRes 31:365A, iation of IgA isting disease. P, et al: Monory spherocytoition. Ann In- iman H: Canin the United ikon JC. Tim- logical Effects .ency for ReLyon, France, esco C, et al: in families of icroglobuline- r A: A human -alpha 2 mac- J Immunol <in B, et al: bulins and K la. Tissue An- r C, et al: On ce of paraprob8. 1966 ]mors in Normtries. J Natl .hima Y, et al: as a new disIC, and func- Etiology and Epidemiology of Multiple Myeloma and Related Disorders 9 429 tional studies of leukemic cells. G A N N Monogr Cancer Res 28:15, 1982 123. Talerman A: Clinico-pathologic study of multiple myeloma in Jamaica. Br J Cancer 23:285, 1969 124. Tananov AT: Histocompatibility (HLA) antigens and disease. Probl Gematol Pereliv Krovi 23:45,1978 125. Thomas TL, Decoufle P, Moure-Eraso R: Mortality among workers employed in petroleum refining and petrochemical plants. J Occup Med 22:97, 1980 126. Traub N:Multiple myeloma at the University Teaching Hospital, Lusaka: a retrospective study. Med J Zambia 11:148,1977 127. Valez R, Beral V, Cuzick J: Increasing trends of multiple myeloma mortality in England and Wales; 1950-79:are the changes real? J Natl Cancer Inst 69:387,1982 128. Van Camp BG, Cole J, Peetermans ME: HLA antigens and homogeneous immunoglobulins. Clin Immunol Immunopathol 7:315, 1977 129. Waldbaum B, Gelfand M: Myelomatosis in the Rhodesian African. Trop Geogr Med 26:26, 1974 130.Waterhouse JA, Muir C, Correa P, et al: Cancer Incidence in Five Continents. Vol. 3. International Agency for Research on Cancer Publication 15, Lyon, France, 1976 131. Waterhouse JA. Muir C, Shanmugaratnam K, et al: Cancer Incidence in Five Continents. Vol. 4. International Agency for Research on Cancer Publication 42, Lyon, France, 1982 132. Weiss NS: Geographic variation in the incidence of the leukemias and lymphomas. Natl Cancer Inst Monogr 53:139, 1979 133. Wiedermann D, Urban P, Wiedermann B, et al: Multiple myeloma in two brothers. Immunoglobulin levels among their relatives. Neoplasma 23:197, 1976 134. Williams RC, Erickson JL. Polesky HF, et al: Studies of monoclonal immunoglobulins (M-components) in various kindreds. Ann Intern Med 67:309,1967 135. Williams RR,Stegens NL, Goldsmith JR: Associations of cancer site and type with occupation and industry from the Third National Cancer Survey interview. J Natl Cancer Inst 59:1147, 1977 136. Wintrobe MM, Lee GR, Boggs DR, et al: Macroglobulinemia, heavy chain diseases and other lymphocyte plasma cell dyscrasias. p. 1624. In Clinical Hematology. 6th Ed. Lea & Febiger, Philadelphia, 1975 -137. Wirtschafter SK,Rappaport SI:The familial occurrence of chronic lymphocytic leukemia and multiple myeloma. Calif Med 92:165, I960 138. Witwer MW, Schmid FR, Tesar JT: Acute myelomonocytic leukaemia and multiple myeloma after sulphinpyrazone and colchicine treatment of gout. Br Med J 239, 1976 139. Woodroffe AJ: Multiple myeloma associated with long history of hyposensitisation with allergen vaccines. Lancet 1:99,1972 140. World Health Organization: Manual of the International Statistical Classification of Diseases, Inquiries, and Causes of Death. Geneva, 1949, 1959, 1969, 1979 141. Wright DH: Lymphoreticular neoplasms. p. 270. In Stempleton AC (ed): Recent Results in Cancer Research. Tumors in a Tropical Country. Springer-Verlag. New York, 1973 142. Wurster-Hill DH, McIntyre OR, Cornwell GG, et al: Marker-chromosome 14 in multiple myeloma and plasma-cell leukemia. Lancet 2:1031, 1973 143. Youinou P: Genetic propensity to benignity in monoclonal-gammopathy. Acta Haematol (Basel) 62:173,1979 144.Young JL, Percy CL, Asire AJ: Surveillance, epidemiology, and end results: incidence and mortality data, 1973-1977.National Cancer Institute Monograph 57, Department of Health and Human Services Publication (National Institutes of Health) 81-2330, 1981