Progress in Myeloma: Biology of Myeloma 1980 Edition

U.S.A.

Epidemiology of Multiple Myeloma and Related Plasma Cell Disorders: An Analytic Review

William A. Blattner, M.D.,     Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Publisher Summary

This chapter presents an analytical review of epidemiology of multiple myeloma and related plasma cell disorders. A variety of etiologic factors may contribute to the development of multiple myeloma and related dyscrasias. The major risk indicator is age, with myeloma being especially common at older ages. Similarly, BMG also manifests a parallel old-age pattern, which may be etiologically related. In the postulated two hit mutation model, BMG may be one manifestation of the first hit, representing the controlled proliferation of a clone of plasma cell synthesizing the M-spike. The second hit occurs when another mutation leads to uncontrolled malignant proliferation. An age-dependent loss of regulatory cell function may be involved in the first hit by increasing the pool of terminally differentiated, immunoglobulin-secreting cells potentially available for malignant transformation. This old-age determinant may also help explain why an excess has not been found in some occupational and high-risk cohort studies which are limited in extent of long-term follow-up. Race is another important determinant. The higher rate and earlier age of onset of myeloma in Blacks suggests an inborn susceptibility, although environmental factors cannot be excluded. This may correlate with racial differences in baseline immunoglobulin levels 40 and with altered patterns of in vitro cellular response to mitogens in Blacks.

Introduction

Epidemiologists have given limited attention to multiple myeloma and related disorders, whereas basic and clinical scientists have shown a long-standing and abiding interest. To the laboratory scientist, multiple myeloma is an experiment of nature that opens a biological window to normal and pathologic immune function; to the clinician, its protean manifestations are a continual challenge. In recent years, improvements in the diagnosis and reporting of myeloma have enabled the recognition of epidemiologic patterns that suggest opportunities for etiologic study.

Multiple Myeloma

From the first report of Mr. McBean’s illness in 1845,⁴⁵ through the development of more precise clinical, pathologic, and laboratory methods, multiple myeloma has presented problems in classification and diagnosis. Myeloma was traditionally classified as a bone tumor until the sixth edition of the Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-6), published in 1949, when it was assigned rubric No. 203 under the category of neoplasms of lymphatic and hematopoietic tissues. The accuracy and ease of diagnosis was improved by the introduction of paper electrophoresis in the early 1950′s. Thus, early epidemiologic studies were limited not only by imprecise nomenclature, but also by case underascertainment.

Multiple myeloma, as shown in Table I, is the prototype of a group of conditions known as monoclonal gammopathies. The most frequent form, secretory myeloma, is a malignant proliferation of plasma cells that secrete an essentially normal immunoglobulin product,²⁹⁶ usually IgG or IgA, but sometimes IgD and, rarely, IgE. In some cases, free light chains or Bence-Jones protein are produced alone or along with the complete immunoglobulin.

Table I

Classification of Monoclonal Gammopathies

In modern immunopathologic terms, multiple myeloma is classified as a malignancy of B-cell lineage (Figure 1).²²,³⁴ Recent studies from a number of laboratories, however, suggest that the malignant clone may not be confined solely to the bone marrow plasma cell compartment since populations of circulating peripheral blood as well as bone marrow lymphocytes have surface markers that cross react with the serum M-globulin. The finding of these so-called idiotype-bearing lymphocytes in peripheral blood may explain the early and wide dissemination of malignant cells in most cases of myeloma.¹,¹⁰⁴,¹¹⁰,¹¹²,¹⁶⁰,¹⁹⁴,²³¹,²⁵¹,²⁹⁸

Figure 1 Schema of B-cell differentiation.

Background Studies

Although the first case of mollities ossium was documented over 135 years ago,¹⁴⁷ prehistoric cases are suggested in skeletal remains from archaeological digs.²⁰⁴ Some of these cases may be suspect because of the young age of the skeletons; but others, especially from so-called senile skeletons, probably represent genuine examples.

Geschickter and Copeland⁸⁸ reviewed the demographic and clinical features of multiple myeloma based on 425 cases, including 13 of their own, derived from the literature traced from 1845.

Gilliam,⁹⁰ using mortality data for 1949, was the first to report population-based crude death rates of 0.86 and 0.68 per 100,000 per year in white males and females and 0.89 and 0.54 per 100,000 per year in nonwhite males and females. MacMahon and Clark¹⁶⁴ undertook the first population-based incidence survey, involving 279 new cases of multiple myeloma in Brooklyn, New York, from 1943 to 1952. Myeloma was more than twice as common in Blacks than Whites, with an earlier median age of diagnosis.

The Second National Cancer Survey,⁶¹ conducted between 1947 and 1948 in ten metropolitan centers in the U.S., reported crude incidence rates of 1.0 ier 100,000 for white males, 0.8 for white females, 1.9 for nonwhite males, and 0.8 for nonwhite females.

Reports by Waldenström²⁹² and Martin¹⁷⁵ provided risk estimates for myeloma in western Europe. In Sweden, there were 3.0 cases per 100,000 per year among the 200,000 inhabitants of Malmo over a 10-year period. This rate was high compared to the Brooklyn experience and probably reflected the special interest of the Scandinavian investigators in myeloma and the older age of the population under study. Although the rates for England and Sweden were similar, there was an unexplained discrepancy in median age (70-80 years in Sweden versus 50-60 years in England). An international comparison from 18 countries³⁰¹ reported death rates of approximately 1.0 per 100,000 per year in most western countries, but substantially lower rates in France, Italy, Australia, and Japan.

Demographic Features

Multiple myeloma was once thought to be extremely rare, with an estimated frequency in the 1928 report of Geschickter and Copeland⁸⁸ of less than 0.1% of all malignancies. With the widespread application of bone marrow aspiration and serum protein electrophoresis, multiple myeloma is more common than previously realized. Tables II and III give the incidence and percentage of total cancers for 29 forms of malignancy among Whites and Blacks in the Third National Cancer Survey, 1969-1971.⁴⁸ In Whites, multiple myeloma ranked 20th, accounting for 1.1%, while for Blacks it ranked 11th, accounting for 7.2%. The age-adjusted incidence (1970 standard) in Whites was 4.0 in males and 2.7 per 100,000 in females, while for Blacks the rate was 8.1 in males and 6.5 in females. The most recent U.S. incidence rates, based on 1973-1976 data from the Surveillance, Epidemiology and End Results (SEER) Program, showed no change in Whites, but an increase in Blacks.³¹⁵ Multiple myeloma is the most common form of malignancy in the lymphohematopoetic system in Blacks (33%), while it is the third most common in Whites (14.1%) (Figure 2).

Table II

Incidence of Multiple Myeloma in U.S. Whites and Percentage of Total Cancers, Ranked in Descending Order

aCases per 100,000 per year.

(Source: Cutler and Young, 1975.)⁴⁸

Table III

Incidence of Multiple Myeloma in U.S. Blacks and Percentage of Total Cancers, Ranked in Descending Order

aCases per 100,000 per year.

(Source: Cutler and Young, 1975.)⁴⁸

Figure 2 Relative proportion of lymphoreticular malignancy in Whites and Blacks.

A distinctive feature of multiple myeloma is the late age of onset. Except for chronic lymphocytic leukemia, multiple myeloma shows the strongest age dependence of any neoplasm.¹⁶⁴ The age-specific incidence curves for the United States, 1969-1971, in males and females, Whites and Blacks, are shown in Figure 3. Peak incidence in Whites and Blacks occurs between 75 and 80; however, Blacks have higher rates for all age groups throughout life, except for black females 44 years and under.

Figure 3 Multiple myeloma, age-specific incidence for U.S., 1969-1971. SOURCE: Cutler and Young, 1975.⁴⁸

Multiple myeloma predominates in males, with the excess apparent for all groups after age 40 (Figure 3). The biologic basis of this excess is not known, although experimental animal studies suggest a role for male hormones in the induction of mouse plasmacytoma.¹⁰⁹ Perhaps the higher baseline immunoglobulin levels for most classes in males also correlate with this observation.⁴⁰ Martin¹⁷⁵ emphasized that there has been an apparent shift in sex ratio from an overwhelming male excess (70 to 80 percent),⁸⁸ to a slight excess or equality now. Recent population-based studies, however, have shown that the male-to-female ratio is remaining stable. Shown in Table IV are the sex ratios for selected registries for the three volumes of Cancer Incidence in Five Continents⁵⁷,⁵⁸,³⁰⁰ calculated from world-standardized rates. For each registry, the percentage of male cases has remained relatively constant for the time periods covered, while comparison between most shows a 5 to 10% male predominance. The lower sex ratio in Israel results from a deficit of male cases in north African, Asian, and native-born Jews. A follow-up study of this ethnic variation would be of interest. Mortality data for the U.S. from 1950 through 1967⁴¹ confirms that the male to female ratio in Whites and non-Whites has remained constant.

Table IV

Sex Ratio: Percentage of Male Cases Calculated Using Age Standardized Rates

(Source: Doll et al., 1966;⁵⁷ Doll et al., 1970;⁵⁸ Waterhous et al., 1976.)³⁰⁰

MacMahon¹⁶³ was the first to emphasize a socioeconomic gradient in multiple myeloma mortalits. Based on data from the Registrar General²⁴⁰ for England and Wales from the 1949-1953 report, a higher mortality rate was noted in the highest social class, a trend paralleled in recent Registrar General’s reports.²¹¹,²⁴¹ Mortality data analyzed at the county level for 1950-1969¹¹¹ supports a similar positive association with higher socioeconomic status. This positive gradient may result in part from better diagnostic practice in higher socioeconomic groups and the diminution of the social class effect over time in the English studies may reflect the wider dissemination of uniform health care to all classes. A recent study employing incidence data from the Third National Cancer Survey linked to demographic data obtained by census tract is at odds with the findings summarized above.⁵⁴ A weak negative association with income level was suggested for myeloma. Income adjustment reduced the observed differences between black and white rates, although Blacks continue to have significantly higher rates than Whites.

Racial and Ethnic Determinants

The study of cancer incidence around the world has been enhanced by the serial publications entitled Cancer Incidence in Five Continents (1966, 1970, 1976),⁵⁷,⁵⁸,³⁰⁰ Comparisons are hazardous since the populations served by the registries vary in size and age distribution, in the accuracy of case ascertainment (e.g., pathology review versus death certificate only), and in the level of medical care and diagnostic precision.

As shown in Figure 4, Black populations comprise 4 of the top 10 rates. This black excess, first emphasized by Mac Manon and Clark¹⁶⁴ was confirmed by McPhedren et al.,¹⁹² who reported that myeloma was twice as common among Blacks in Atlanta, Georgia. This Black predominance was seen in all age groups except the very youngest and oldest. A Black excess in mortality was also reported by Stober and Asal²⁷⁴ for the state of