Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites

Abstract

There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes.

Introduction

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant plasma cell disorders. It is a precursor for multiple myeloma and other related malignancies. Patients diagnosed with MGUS have a serum monoclonal protein of <3 g/dl, <10% of clonal plasma cells in their bone marrow and none of the clinical characteristics that would be attributable to a proliferative plasma cell disorder (including hypercalcemia, renal insufficiency, anemia and/or bone lesions).¹ MGUS is detected by screening for monoclonal protein via serum protein electrophoresis, serum immunofixation and serum-free light chain assay.² Electrophoresis using agarose gel is standard; any localized band, spike or suspicion of either is confirmed using immunofixation, which also aids in the determination of free light chain type.

MGUS is found in approximately 3% of the general population aged 50 years and older.³ Prevalence of MGUS increases with age, from 1.7% in those in their 50s to greater than 5% in those older than 70.^3,4 Rate of progression of MGUS to malignancy is approximately 1% per year.⁴ MGUS is more prevalent in men (4.0%) than in women (2.7%).³ Furthermore, there is approximately a 2.6 fold higher rate of MGUS in blood-related first-degree relatives of individuals with either MGUS or multiple myeloma, supporting the idea that there are underlying genetic risk factors at play.⁵

In addition to these trends, there are striking differences in the prevalence of MGUS and multiple myeloma across races. Individuals of Asian descent have been reported to have a lower prevalence of MGUS as compared with whites.^6,7 Persons of African and African-American descent, however, have been reported to have a two to threefold increased prevalence compared with whites.⁸ This review aims to critically examine the existing literature on racial disparities in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites, and to discuss future directions for research in this area.

Prevalence of MGUS in Africans and African Americans

Several studies have assessed the prevalence of MGUS in Africans and African Americans, consistently demonstrating increased rates compared with white populations. Singh et al.⁹ assessed potential racial disparities in the prevalence of MGUS in a study of 398 primarily males seen at the Houston Veterans Affairs hospital. Of these, 270 were white and 128 were black; only one was female. Serum samples were tested by serum electrophoresis and immunofixation. The prevalence of MGUS was twice as high in black patients compared with whites (14.8% versus 7.8%). A trend of increasing prevalence with increasing age was noted in both races. While this study identified a great disparity in the prevalence of MGUS between black and white patients, these individuals were part of a diagnostic population rather than a screening population, and therefore may not be representative of the general population. Despite this issue in study design, Singh and colleagues were among the first to identify this racial disparity in the prevalence of MGUS.

Cohen et al.¹⁰ conducted a community-based study to investigate whether the difference in prevalence and incidence of multiple myeloma in blacks versus whites was due to differences in the prevalence of the precursor lesion, MGUS. They studied 1732 individuals aged 70 and older from the Duke Established Populations for the Epidemiologic Study of the Elderly. In this study, researchers oversampled black individuals to increase statistical precision. Serum samples taken from individuals were analyzed using serum electrophoresis and immunofixation. The prevalence of MGUS was significantly higher in blacks compared with whites, 8.4% versus 3.8%, which represented an approximately twofold increase in prevalence of MGUS in blacks. This difference in risk persisted after adjusting for socioeconomic status and education level. Notably, this study used immunofixation only to confirm suspicious bands on electrophoresis, thereby eliminating the problem of overestimation of cases due to the high specificity of immunofixation.

Since then, Landgren et al.⁸ conducted a prevalence study of clinical diagnoses of MGUS among patients seen at 142 the United States Veterans Affairs Hospitals over a period of approximately 15 years. This involved over 4 million veterans who had been clinically diagnosed, of whom 3 248 795 were white and 749 020 were black. They found that the age-adjusted prevalence rate was threefold higher for African-American patients than for white patients. Furthermore, this trend was relatively constant across the age groups examined. A continuation of this study using the same cohort found that risk of MGUS was of similar magnitude for individuals of both races with a history of specific prior autoimmune diseases, pernicious anemia and those with chronic active hepatitis infections, which may be attributable to similarities of testing.¹¹

Additional research into validating this phenomenon has been conducted in the past few years using African populations. A sample of 917 Ghanian men were studied to determine if the increased risk of MGUS in African Americans was also seen in blacks from West Africa.¹² An age-adjusted prevalence of 5.8% was found in the sample of Ghanian men. This rate was significantly higher when compared with the Olmsted County, MN white population, with a twofold greater prevalence of MGUS in the Ghanian population. A commentary by Munshi¹³ on the article hypothesized a race-related predisposition to MGUS. As an increased risk in Ghana and in African Americans could still be due to similar socioeconomic disparities compared with whites, a separate study was done on a large cohort of women of similar socioeconomic status, 50% of whom were black and 50% white. This was also perhaps the only notable MGUS study to focus on females.¹⁴ The study found that there was a twofold increased prevalence of MGUS in black women compared with white women of similar socioeconomic status, suggesting that the racial disparity is likely related to a genetic predisposition or other unmeasured risk factors that differ between these two populations. In addition to this important finding, the study also found a link between obesity and MGUS independent of race, and that increasing age, race and obesity were all independent risk factors for MGUS. Given that there is a higher prevalence of obesity in black women than white, this could help to explain the disparity in MGUS prevalence between races.¹⁵

Ethnic differences in clinical characteristics of MGUS

Immunoglobulins

One means of characterizing MGUS subtypes and risk of progression to malignancy is through the identification of the type of immunoglobulin present (IgA, IgG, IgM). While IgA and IgG isotypes are frequently grouped together under the umbrella of ‘non-IgM MGUS’, individuals with an IgA monoclonal-protein do have a higher risk of progression to malignancy as compared with those with IgG MGUS.^4,16,17 Furthermore, those with small IgG MGUS are considered to be ‘low’ risk, whereas those with IgA or IgM are at higher risk of progression.¹⁸ Additionally, each type of immunoglobulin is associated with different progression patterns; non-IgM MGUS tends to progress to a more advanced premalignant stage known as smoldering multiple myeloma¹⁹ or to multiple myeloma. In contrast, IgM MGUS tends to evolve into Waldenström’s macroglobulinemia much more frequently than to IgM myeloma.

The distribution of immunoglobulin isotypes varies by race. The most striking difference is seen between whites and blacks. In a study of the primarily white population of Olmsted County, MN, Kyle et al.³ found the rate of IgG MGUS to be 68.9%; IgA, 10.8%; IgM, 17.2%; and biclonal, 3.0%. In contrast, the distribution of immunoglobulin isotypes was markedly different in clinical diagnoses of the population of black men from the Walter Reed Army Medical Center and the Washington Veterans Affairs Medical Center, with a rate of 81% for IgG, 13% for IgA and 2% for IgM (Table 1).²⁰ In the screening study in Ghana mentioned earlier, a similar distribution was found (Table 1).¹² However, Cohen et al.¹⁰ found a very different distribution in screening their elderly population from the Duke Established Populations for the Epidemiologic Study of the Elderly, in which only 65% were IgG and 5% were IgA (Table 1). Taken together, these studies suggest that the prevalence of the various immunoglobulin subtypes may differ considerably across races, and this may affect prognosis and counseling.²¹

Table 1.

Prevalence of Ig isotypes across studies of Africans and African Americans, compared with a white reference population

Reference	Population	Prevalence (%)
		IgG	IgA	IgM	Biclonal
Cohen et al.10	Duke Established Populations for the Epidemiologic Study of the Elderly	65	5	10	17
Landgren et al.12	Ghana Screening Study	74	19	6	2
Weiss et al.20	Walter Reed Army Medical Center and the Washington Veterans Affairs Medical Center	81	13	2	4
Kyle et al.4	Olmsted Co., MN (white)	69	11	17	3

Abbreviation: Ig, immunoglobulin.

Free light chain ratios (FLC-R)

An additional known biological factor in MGUS that may indicate progression towards malignancy is an abnormal FLC-R, which measures excessive expression of either kappa (κ) or lambda (λ) free light chains.^22,23 FLC-Rs that are considered ‘normal’ range from 0.26–1.65; anything outside of that range is considered ‘abnormal’.²⁴ Most MGUS cases are characterized by the expression of immunoglobulin heavy chain (IgH). Approximately 20% of MGUS cases do not, however, present with IgH expression.³ These individuals have what is known as light chain MGUS, a precursor to light-chain multiple myeloma. ²² An abnormal FLC-R, however, even if not indicative of light chain MGUS, has previously been shown to be an independent risk factor in those with MGUS for progression to malignancy.²⁵

In an examination of the mostly white Olmsted County, MN population, abnormal FLC-Rs were observed in 33% of individuals who underwent testing (Table 2).³ In a smaller study of clinical diagnoses of 125 black patients at the Walter Reed Army Medical Center and the Washington Veterans Affairs Medical Center, investigators found abnormal FLC-Rs in a striking 45% of patients.²⁰ This finding is striking, given that many of the population κ:λ ratios from other studies fall within the ‘normal’ range; however, the small sample size calls for validation (Table 2).^10,12,21 Collectively, these studies suggest that there is a higher rate of abnormal FLC-Rs in Africans and African Americans; however, there is a need for additional studies examining the number of individuals with abnormal FLC-Rs. Additionally, as a result of the findings in the studies above and an understanding of renal diseases prevalent in blacks that can affect FLC-Rs, it has been suggested that an alternative range of ‘normal’ ratios be applied for these individuals.^20,26

Table 2.

Prevalence of kappa, lambda and abnormal FLC-Rs across studies of Africans and African Americans, compared with a white reference population

Reference	Population	Prevalence (%)
		Kappa	Lambda	Abnormal FLC-R	Ratio
Cohen et al.10	Duke Established Populations for the Epidemiologic Study of the Elderly	—	—	—	1.2
Landgren et al.12	Ghana Screening Study	48	50	—	0.96
Weiss et al.20	Walter Reed Army Medical Center and the Washington Veterans Affairs Medical Center	—	—	45	—
Kyle et al.4	Olmsted Co., MN (white)	62	37	33	1.67

Abbreviation: FLC-R, free light chain ratio.

Progression to multiple myeloma

Depending on the clinical characteristics presented, MGUS may have one of many different paths of progression. One study, conducted on a referral sample of 241 patients seen at the Mayo Clinic, found an overall rate of progression of 1.5% per year; progression was defined as the development of multiple myeloma or any related disease.²⁷ An additional population-based study conducted in order to try and eliminate referral bias found an overall rate of progression of 1% per year.⁴

As these results are clinically informative, both of these studies focused on primarily white populations. Few studies have been published that focus on the rate of progression of MGUS to multiple myeloma in Africans and African Americans. In a study conducted across 142 Veterans Affairs hospitals in the United States in black and white males, Landgren et al.⁸ estimated that the cumulative risk of developing multiple myeloma within 10 years post-MGUS diagnosis was not significantly different between blacks and whites (17% in African Americans versus 15% in whites). Based on these results, the authors suggest that the increased prevalence and risk of multiple myeloma in Africans and African Americans is due to the increased prevalence of the premalignant MGUS stage, rather than an increased rate of progression of MGUS to malignancy. But, due to the scarcity of studies on this topic, more research in needed.

Multiple myeloma in Africans and African Americans

Ethnic differences in prevalence, incidence and survival

Previously, differences in prevalence of multiple myeloma have been found between African Americans/Africans and other races. Reports vary slightly, but mostly attribute a twofold increased prevalence of multiple myeloma in these populations. ^21,28 In a 2001 study conducted in Martinique, French West Indies, 34% of the hematological malignancies reported in the predominantly black sample were myeloma, a statistic similar to that reported in African Americans.²⁹ Gebregziabher et al.³⁰ investigated risk patterns of myeloma (Los Angeles County, CA, USA), from 1972 to 1999. Results indicated that African Americans in the area had the highest age-adjusted incidence rates, followed by those with Spanish surnames, then non-hispanic whites and Asians. In a population-based study, Waxman et al.³¹ employed nine different Surveillance, Epidemiology and End Results (SEER) databases in order to examine differences in incidence rates between blacks and whites between 1973 and 2005. Analysis of data from 5798 black and 28 939 white myeloma patients validated prior studies’ findings of a twofold increase in prevalence of multiple myeloma among blacks. Furthermore, the study found that the mean age at diagnosis was significantly lower for blacks than whites (65.8 years versus 69.8 years, respectively).

Reports of disease-specific survival among Africans and African Americans have been mixed. In a SEER-based population study conducted by Waxman et al.,³¹ however, both disease-specific and relative survival rates were significantly higher in blacks than in whites (P<0.001). Additionally, over the time period examined (1973–2005), significant improvements in survival were noted for whites, but not for blacks; the authors hypothesize that this may have to do with disparate healthcare access or differences in treatment response. A smaller study conducted as part of the Southwest Oncology Group Study analyzed survival of black patients versus whites in a large randomized clinical trial; results indicated that there was no significant difference in survival between the two races, even after adjusting for clinical characteristics, such as stage.^32,33 More recently, a study by the Eastern Cooperative Oncology Group found that when treated with immunomodulatory drugs, blacks had a significantly better overall survival compared with whites. These studies indicate that there may be significant differences in the cytogenetic subtypes of myeloma in blacks compared with whites, which coincide with differential survival, and this needs further study.³⁴

Familial multiple myeloma

As family history of hematological malignancies is thought to be a risk factor for multiple myeloma, few studies of familial myeloma have been conducted in Africans and African Americans. In 1999, Brown et al.³⁵ published a population-based case–control study of both black and white patients with multiple myeloma and matched controls in three regions of the United States to assess whether family history of cancer contributes to the increased risk of multiple myeloma in blacks. Analyses of the two ethnicities combined revealed that those with a first-degree blood-related relative with myeloma had a significantly increased risk of myeloma, compared with those who did not have a family history of the disease. When stratified by race, the risk was found to be higher for blacks than for whites. The difference in odds ratios for the two subpopulations was not statistically significant, however, indicating that family history may not be the primary key to explaining the racial disparity in risk.

A more recent case study of one African American family with five myeloma cases and three MGUS cases was released in 2008.³⁶ These diagnoses were spread across two generations, and were assessed using serum and urine protein electrophoresis and immunofixation. One family member had offspring with two different partners that, in both cases, went on to develop MGUS and multiple myeloma, indicating that there may be an underlying genetic component.

Although provocative, further investigation needs to be conducted to see whether there is a difference in familial multiple myeloma between ethnicities that could elucidate risk differences.

Lifestyle- and socioeconomic-related risk factors

Many putative risk factors for a variety of cancers have been investigated in multiple myeloma. Obesity, diet and nutrition are among the most common lifestyle-related risk factors examined in with myeloma in both whites and African Americans. One early clinic-based study found that higher body mass index was associated with the development of multiple myeloma in African American men and women; the association was found only in men in whites. The frequency of obesity was reported to be greater in African Americans than in whites, which the authors put forth as a possible explanation for the elevated prevalence of multiple myeloma in blacks. A cohort study of male veterans in the United States, which included 3 668 486 whites and 832 214 blacks, were followed for all major types of cancer.³⁷ All individuals in the study had been hospitalized with a diagnosis of obesity in their medical records. Multiple myeloma was found to be significantly associated with obesity in both black and white patients, suggesting that obesity may be a risk factor of similar magnitude for both ethnicities. More recently, Landgren et al.¹⁴ found that obesity and race were independently associated with MGUS, and that the increased risk of MGUS in blacks is not explained by differences in socioeconomic factors or obesity.

There are suggestions of associations between cigarette and alcohol use with hematologic malignancy; however, few studies have examined differences in risk associated with their use in different races and ethnicities.^38,39 The one study that directly addressed these potential risk factors in both black and white multiple myeloma patients was a population-based case–control study of myeloma among individuals living in Georgia, Michigan and New Jersey.⁴⁰ Of the 571 cases, 365 were white and 206 were black; 1155 of the 2122 controls were white, whereas 967 were black. For individuals of both ethnicities and genders, no significant elevated risk of multiple myeloma was found with use of alcohol and cigarettes, both in analyses considering ever/never use or duration/intensity of use.

Socioeconomic status has been implicated as a potential risk factor for risk in many cancers. Population-based case–control study using individuals from three different geographic areas in the United States similarly found risk of multiple myeloma was significantly elevated in individuals with the lowest occupation-based socioeconomic status; furthermore, the authors reported that socioeconomic status accounted for 37% of multiple myeloma in blacks versus 17% in whites.⁴¹ Low education and income were also cited as accountable for the excess incidence in blacks. However, this was not seen in the Multiple Risk Factor Intervention Trial (MRFIT) in which 361 662 men were screened at 22 sites between 1972–1975 for physiological and lifestyle risk factors.⁴² These individuals were followed for 16 years; cause of death, including myeloma, was documented. While this study identified a higher prevalence of multiple myeloma in black men, researchers found no association between socioeconomic status and multiple myeloma risk. Further investigation needs to be conducted to assess whether socioeconomic status and related factors are associated with elevated risk in African Americans; additionally, examination of the factors discussed here should be conducted in individuals with MGUS.

Polymorphisms, biomarkers and other molecular risk factors

The search for ethnicity-specific polymorphisms and genetic markers for multiple myeloma has been the focus of a number of previous investigations. A study of human leukocyte antigens typing on 46 black and 85 white cases (and 88 black and 122 white controls)⁴³ revealed higher frequencies of a specific human leukocyte antigen (Cw2) in both black and white cases; however, these frequencies were similar, leading the authors to conclude that, while elevated Cw2 may be a risk factor for multiple myeloma, it does not explain the difference in racial risk of disease development. Another study, conducted by Patel et al.⁴⁴, found a significant association between human leukocyte antigens B18 subtypes and multiple myeloma in blacks from South Africa. Additionally, investigators found a significant protective effect associated with human leukocyte antigens Cw7.

In another study, Cao et al.⁴⁵ examined a rare deletion in a pseudogene on chromosome 13 that occurs more frequently in blacks than in whites and is associated with both Burkitt’s and follicular lymphomas. An investigation involving 41 black and 56 white multiple myeloma cases and 13 black and 17 white patients with MGUS revealed that the frequency of the deletion is higher in patients than in the general public (37% versus 23%), suggesting that expression of this version of the allele may predispose individuals to developing multiple myeloma or MGUS. However, the sample sizes for these genetic studies are very small, indicating the need for well, powered genetic association studies in both black and white populations.

Future directions

There is a critical need for additional studies examining prevalence, risk and progression of MGUS and myeloma in blacks. These findings could translate into different prognostic and diagnostic approaches in the clinic for African American and African patients. One area of importance is investigating whether MGUS clusters in African American and African families as it does in whites.⁵ Only one such study has been conducted to date that examined eight African American families and found elevated frequencies of MGUS and multiple myeloma in first-degree blood family members.⁴⁶ We are also completing a formal study on the prevalence of light chain MGUS in blacks, as has been done in the white population of Olmsted County.²² Further investigation is needed to determine the specific cytogenetic types of MGUS and multiple myeloma that account for the bulk of the racial disparity in prevalence. Finally, we need to fully understand the genetic mechanisms involved, so that we can better assess patient risk in blacks, and this knowledge can then feed into better management strategies and outcomes for all races and ethnicities.