Hypothesis: The African American population has an increased incidence and disease progression of Multiple myeloma because of the interplay between genetic and environmental factors.
Abstract
Hypothesis
The African American population has an increased incidence and disease progression of multiple myeloma because of the interplay between genetic and environmental factors. Methods
Scholarly articles were obtained from PubMed, the New England Journal of Medicine, the American Cancer Society, the American Society of Clinical Oncology, the National Cancer Institute, and the Mayo Clinic. The preliminary search for relevant articles included keywords such as ‘multiple myeloma,’ ‘multiple myeloma risk factors,’ and ‘multiple myeloma in African Americans.’ Literature on disease correlates such as age, gender, race, radiation, medical history, family history, workplace exposures, obesity, and other plasma cell diseases was compared and contrasted for the African American population as compared to Whites.
Results
The etiology of multiple myeloma remains unclear with a range of risk factors contributing to its incidence, prevalence, and progression. Literature reports a higher overall disease incidence in older males and a greater prevalence in African Americans. African Americans with chromosome 13 and 17 abnormalities have a decreased survival time and higher risk of disease progression, respectively. Progression of disease varies by race for each of the disease correlates researched.
Conclusions
African Americans with multiple myeloma have not been well studied in detail, and their epidemiologic and disease characteristics differ from those of Whites.
Abstract word count: 208
Introduction
Multiple myeloma is the third most common blood cancer in the United States and constitutes approximately 1.8% of all cancers (Multiple Myeloma Research Foundation, 2017). Multiple myeloma (MM) is a “neoplastic plasma cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction” (Palumbo et al., 2011). The median age at diagnosis is approximately 69 years (American Cancer Society, 2017). The median time from diagnosis to the progression of symptomatic disease is two to three years.
Multiple myeloma is a cancer involving plasma cells, an important part of the immune system. Plasma cell disorders are characterized by terminally differentiated B-cells with an expanded single clone of immunoglobulin (Ig), secretion of plasma cells, and a resultant increase in serum levels of a single monoclonal immunoglobulin (Jiwani et al., 2015). Genetic and microenvironmental changes can alter these cells to yield a malignant plasma cell or neoplasm. These cells ultimately become widespread in the bone marrow and lead to soft spots in the bone where tissue has been damaged (osteolytic lesions). These lesions are characteristic of multiple myeloma and occur throughout the body (Archer Internal Medicine Board Review, 2011; Kyle et al., 2007). There are several genetic abnormalities that develop in tumor plasma cells that play critical roles in the pathogenesis of multiple myeloma, altering the expression of adhesion molecules on myeloma cells, as well as responses to growth stimuli in the microenvironment (Archer Internal Medicine Board Review, 2011; Kyle et al., 2007).
Generally, the term microenvironment refers to cells or an organ that contains various particles (hormones, growth factors) for a specific function to be carried out. MM cells strongly interact with the bone marrow microenvironment, which is composed of many cells such as endothelial cells, stromal cells, osteoclasts, osteoblasts, immune cells, fat cells and the extracellular matrix. The bone marrow microenvironment actively recruits circulating tumor cells. Their proliferation and persistence is due to the numerous growth factors and cytokines they encounter in the bone marrow. The tumor cells then actively recruit bone marrow cells into their own microenvironment, which contribute to the development of tumor vasculature. Although bone is affected, Multiple myeloma is considered a hematologic (blood) cancer because it is transported through the bloodstream (Kyle et al., 2004; Palumbo et al., 2011). Over time, these bone-marrow-derived cells can transfer and survive in other organs, and the fact that they can attract any other circulating tumor cells, is of major concern when considering the spread of tumor cells.
In the literature, the importance of the bone marrow microenvironment is repeatedly emphasized in understanding the etiology of Multiple myeloma as well as its progression (Kyle et al., 2007). Interactions between myeloma cells and bone marrow cells or extracellular matrix proteins that are mediated through cell-surface receptors increase tumor growth, survival, migration, and drug resistance (American Cancer Society, 2017). Besides molecular alterations of plasma cells, abnormal interactions between plasma cells and bone marrow, as well as abnormal angiogenesis, are hallmarks of disease progression (Otjacques et al., 2011; Palumbo et al., 2011).
Normal blood cell production becomes compromised as myeloma cells outnumber normal cells in the bone marrow (Otjacques et al., 2011; Palumbo et al., 2011). Reduction in the number of white blood cells may increase the risk of infection and decreases in red blood cells may result in anemia (Palumbo et al., 2011). Excess M-protein and light chain protein produced by the myeloma cells can thicken the blood, potentially damaging and impairing the function of the kidneys (Kyle et al., 2004; Kyle et al., 2007; Palumbo et al., 2011). When myeloma cells thicken the blood, circulatory problems in the kidneys arise. Hypercalcemia, a condition caused by an increase in levels of calcium in the bloodstream, is a result of bone destruction and also overworks the kidneys. Potential problems arise when this overworking of the kidneys results in reduced calcium excretion, increased urine production, and possible dehydration (Palumbo et al., 2011).
The diagnosis of Multiple myeloma is based on the presence of “at least 10% clonal bone marrow plasma cells and monoclonal protein in serum or urine” (Kyle et al., 2004, Palumbo et al., 2011). In patients with non-secretory Multiple myeloma, diagnosis is based on the presence of 30% monoclonal bone marrow plasma cells or a biopsy-proven plasmacytoma (Otjacques et al., 2011; Palumbo et al., 2011). Myeloma is classified as asymptomatic or symptomatic, depending on the absence or presence of myeloma-related organ or tissue dysfunction, including hypercalcemia, renal insufficiency, anemia, and bone disease (Kyle et al., 2004; Palumbo et al., 2011). Anemia is present in approximately 73% of patients at diagnosis and bone lesions develop in about 80% of patients (Palumbo et al., 2011). The risk of infection is increased with active disease but decreases with response to therapy (Kyle et al., 2004; Palumbo et al., 2011).
Diagnosis of Multiple myeloma includes recording a detailed medical history and physical examination, laboratory testing, and bone marrow examination (Palumbo et al., 2011). Laboratory testing includes a complete blood count, protein electrophoresis, and measuring monoclonal protein levels. Conventional radiography remains the standard to identify myeloma-related bone lesions, although MRIs are used as well. Staging of MM is done according to the International Staging System, which defines three risk groups on the basis of serum 2-microglobulin and albumin levels (Otjacques et al., 2011; Palumbo et al., 2011; Anderson et al., 2012).
Any chromosomal abnormality that is discovered on standard cytogenetic analysis is usually associated with worse outcomes than that associated with a normal karyotype (Palumbo et al., 2011). Specific translocations such as those on chromosome 14, deletions on chromosomes 13 and 17, and chromosome 1 abnormalities are associated with a poor prognosis (Palumbo et al., 2011; Anderson et al., 2012). High-risk disease and poor prognosis are defined by the presence of one of the following in each category: hypodiploidy, chromosome 14 translocation or chromosome 17 deletion, high levels of serum 2-microglobulin or lactate dehydrogenase (LDH), and International Staging System stage III (Palumbo et al., 2011).
Multiple myeloma is thought to progress most commonly from a monoclonal gammopathy of undetermined significance (MGUS) (Kyle et al., 2004; Otjacques et al., 2011; Palumbo et al., 2011). Given a range of risk factors, MGUS can then progress to smoldering myeloma and, finally, to symptomatic myeloma (American Cancer Society, 2017). The appearance of a limited number of these clonal plasma cells is the first step or precursor in the progress of Multiple myeloma (Kyle et al., 2004; American Cancer Society, 2017). MGUS is characterized by a serum monoclonal protein level of less than 3 g/dL, less than 10% plasma cells, and an absence of related organ or tissue impairment (Palumbo et al., 2011).
Patients diagnosed with MGUS have an annual risk of one percent of progression to myeloma or another related malignant disease, although they may not show signs of end-organ damage (Multiple Myeloma Research Foundation, 2017; Kyle et al., 2004; Goldin et al., 2011). As MGUS develops into myeloma, the plasma cell undergoes intricate genetic events (Otjacques et al., 2011). The bone marrow functions as the site where macrophages destroy old cells and recycle their components, where hemoglobin is broken down, and where iron is recycled and stored. In the bone marrow microenvironment, the initiation of angiogenesis, suppression of cell-mediated immunity, and paracrine signaling contribute to persistence of the tumor and its resistance to drugs (Multiple Myeloma Research Foundation, 2017; Otjacques et al., 2011). Paracrine signaling involves the activation of cells adjacent to each other to multiply. Recognizing the importance of the cellular microenvironment has facilitated the development of drugs such as thalidomide and bortezomib. Thalidomide is used because of its anti-angiogenic activity (Kyle et al., 2004). Bortezomib disrupts the normal action of enzyme complexes in all cells that degrade proteins in both normal and cancer cells. Bortezomib thereby inhibits tumor progression. The lifetime risk of progressing to multiple myeloma among those with MGUS is 1 in 161 (0.62%) and the 5-year relative survival rate is approximately 48.5% (National Cancer Institute, 2017). The most important predictor of progression is the size of the M-protein at the time of recognition of MGUS (American Cancer Society, 2017; Palumbo et al., 2011; Goldin et al., 2011). The type of M-protein is also important since IgM and IgA monoclonal proteins have a greater risk of progression than an IgG M-protein (Palumbo et al., 2011; Anderson et al., 2012).
Although no cause for Multiple myeloma has been identified and disease etiology remains unclear, multiple myeloma is evidently caused by the interplay of numerous factors. Risk factors for incidence of MM include age, gender, race, radiation, family history, workplace exposures, obesity, and other plasma cell diseases (Multiple Myeloma Research Foundation, 2017; Kyle et al., 2004; Palumbo et al., 2011; Kaya et al., 2012). As explained earlier, risk factors for progression of the disease include the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins (Kyle et al., 2004; Kyle et al., 2007; Palumbo et al., 2011). Research also suggests possible associations with a decline in the immune system, genetic factors, as well as occupational exposures and hazards. (Multiple Myeloma Research Foundation, 2017; Kaya et al., 2012). This paper will explore the literature’s suggestion that the African American population has an increased incidence and disease progression of Multiple myeloma because of the interplay between genetic and environmental factors. Comparing and contrasting the available literature will seek to prove that African Americans have a differing relationship between disease correlates and disease prognosis when compared to Whites.
Methods
The principal database that was used for scholarly articles to be found was PubMed, belonging to the United States National Library of Medicine at the National Institutes of Health. Other scholarly articles were found through the American Cancer Society, American Society of Clinical Oncology, National Cancer Institute, and the Mayo Clinic websites. Additional literature was found in The New England Journal of Medicine, Medscape, and Google Scholar. Overall, inclusion criteria for article selection included selecting articles that have been published by prominent journals or recognized and valued by medical organizations.
The search strategy to narrow down relevant articles included keywords such as: multiple myeloma, multiple myeloma risk factors, multiple myeloma epidemiology, multiple myeloma in African Americans, and correlates of multiple myeloma. The articles and journals referenced were inclusive of specific criteria such as: published in the last 10 years, treatment of patients with multiple myeloma, risk factors, incidence and progression of multiple myeloma, and multiple myeloma and racial/ethnic groups. Articles were excluded if they included study populations outside of the United States and if they were strictly preclinical studies. Articles obtained from database searches were subsequently reviewed by reading the abstracts and scanning each individual section of the article such as the results, discussion, and conclusion, to ensure the article’s relevance to the topic of interest.
Articles that met all previously stated criteria were compiled into an Evidence Table, as seen in the Appendix. Information corresponding to First Author, Date of Publication, Study Design, Level of Evidence, Study Population, Therapy or Exposure and Outcomes/Results were obtained from each article.
Using the methods section of each individual article, the Study Design and Level of Evidence listed in the Evidence Table were determined according to the following widely used article-classification system:
- Level 0: Preclinical studies- including experimental studies and animal models
- Level 1: Randomized controlled trials
- Level 2: Non-randomized controlled trials- a prospective (pre-planned) study with a predetermined eligibility criteria and outcome measures
- Level 3: Observational studies with controls- includes retrospective, case-control studies, and cohort studies
- Level 4: Observational studies without controls- includes cohort studies without controls, case series without controls, case studies without controls (RLRA Syllabus for Fall 2015, Medical University of the Americas).
The articles were then compared and contrasted to derive conclusions regarding the relationship between multiple myeloma in African Americans and genetic and environmental factors. The results and conclusion derived were used to support or refute the hypothesis.
Results
Age
Plasma cell disorders are generally more prevalent in older age groups. Less than 1% of cases are diagnosed in people younger than 35, 96% in people older than 45 years, and more than 75% are diagnosed in people older than 70 years (American Cancer Society, 2017; Kaya et al., 2012; Ludwig et al., 2008). Research studies report the median age at diagnosis to be 71 years for both MM and MGUS (Palumbo et al., 2011; Kaya et al., 2012). As seen in Table 1 of the Appendix, a population-based study showed the mean age at diagnosis was 65.8 years for African Americans and 69.8 years for whites; incidence among African Americans being twice that among whites (Waxman et al., 2010). Rates of Multiple myeloma are known to rise exponentially with age in both African Americans and whites.
Gender
Multiple myeloma appears more often in men than in women (Kaya et al., 2012; Landgren et al., 2008). In 2016, the American Cancer Society estimated about 30,280 new cases of Multiple myeloma- 17,490 were diagnosed in men and 12,790 in women (American Cancer Society, 2017). MGUS is also more common in men compared with women (Ludwig et al., 2008; Goldin et al., 2011). The SEER incidence data from 2009-2013 reported a rate of 6.5 per 100,000 men and women per year (American Cancer Society Cancer Statistics Center, 2017). The age-adjusted annual incidence of MM is 7.7 cases per 100,000 white men, 4.5 cases per 100,000 white women, 15.7 cases per 100,000 black men, and 11.5 cases per 100,000 black women (National Cancer Institute SEER program, 2017). Overall, incidence of multiple myeloma is almost twice as high among African Americans than among whites.
Race
African Americans reportedly have the highest rates of multiple myeloma and Asian Americans have the lowest rates. (Saraf et al., 2012; Landgren et al., 2009). Yet despite the higher incidence among African Americans, post-diagnosis survival is markedly higher among African and Asian Americans compared to non-Hispanic Whites (Kaya et al., 2012). The non-Hispanic black (African American) population has been found to have the highest incidence of multiple myeloma, with some studies showing the incidence to be nearly twice the incidence of the white population (American Cancer Society, 2017).
Medical comorbidities and history of infection
A personal history of all infections combined is associated with a significantly increased risk of MM (Kyle et al., 2007). Significantly increased risk of MGUS was associated with any personal history including infections, inflammatory illnesses, and autoimmune diseases. (Ludwig et al., 2008; Kyle et al., 2007). Elevated risk of Multiple myeloma was observed similarly for white and African American men with autoimmune diseases such as polymyositis/dermatomyositis, systemic sclerosis, autoimmune hemolytic anemia, pernicious anemia, and ankylosing spondylitis (Brown et al., 2008). In addition, osteoarthritis is associated with an increased risk of inflammatory disorders and, subsequently, MGUS and Multiple myeloma among African Americans.
Family History
A significant correlation exists between risk of multiple myeloma and close relatives having the disease (Goldin et al., 2011; Multiple Myeloma Research Foundation, 2017). Although most MM patients rarely have affected relatives, those who have a sibling or parent with the disease are four times more likely to get it (Archer Internal Medicine Board Review, 2012; American Cancer Society, 2017). Studies have shown that a family history of autoimmune diseases increase the risk of MGUS, indicating a relationship between susceptibility and precursor conditions (Goldin et al., 2011; Brown et al., 2008).
Other Exposures
Other studies have proposed that workplace exposures affect the incidence of MM. Workers in petroleum-related industries are at considerably higher risk of developing multiple myeloma (Archer Internal Medicine Board Review, 2012). Research has suggested a substantial risk of developing MM in individuals with significant exposures in the agriculture, food, and petrochemical industries, the greatest risk being among farmers who use herbicides and insecticides (Medscape, 2016).
Genetic Factors
Evidence for the role of genetic factors includes increased risk amongst first-degree relatives of patients with either MM or MGUS, as well as racial disparities in the incidence patterns of MM and MGUS (Goldin et al., 2011; Kyle et al., 2007). There are a number of chromosomal abnormalities detected upon cytogenetic analysis that indicate poor prognosis of MM. Specific translocations occurring on chromosome 14, deletions on chromosomes 13 and 17, and chromosome 1 abnormalities are the most common chromosomal abnormalities that are associated with a poor prognosis (Palumbo et al., 2011). In African Americans, the most common chromosomal abnormalities include hyperdiploidy, translocations of the immunoglobulin heavy chain, chromosome 13 monosomy, and deletions on chromosome 17 (Saraf et al., 2012). Furthermore, African Americans are at higher risk of multiple myeloma progression if they specifically have deletions on chromosome 17, and resistance to chemotherapy leading to decreased survival time if they have monosomy of chromosome 13. In a multi-center study, African Americans with a lower frequency of chromosome 14 translocations and a higher prevalence of trisomy had a better prognosis and a better response to lenalidomide therapy (Greenberg et al., 2014).
Factors associated with disease progression and survival
Benefits of survival have been determined to vary across distinct groups by age, gender, race, and comorbidity (Kyle et al. 2004). Younger age (<65 years) has been associated with improved overall survival when compared with patients greater than 75 years of age (Kaya et al., 2012). A study analyzing Multiple myeloma patient characteristics and decade of treatment, demonstrated improved overall survival for patients of a younger age and patients who were treated in more recent decades (Anderson et al., 2012). There is a significant increase in survival among patients who have chemotherapy during the course of the disease.
In a study of multiple myeloma patients referred for autologous hematopoietic transplantation, it took longer for African Americans (median of 1.3 years) to be referred for transplant compared to their white counterparts (median of 0.9 years) (Bhatnagar et al., 2015). Although there wasn’t a substantial difference in the time of transplant contributing to survival time between African American and white patients, African Americans lived longer than whites after being diagnosed with Multiple myeloma.
Discussion
Findings suggest that the clinical presentation and progression of multiple myeloma in African Americans differs from whites. Comparison of disease correlates and disease-related factors by gender revealed few differences, however, disease-specific survival is greater among African Americans (Greenberg et al., 2014). Overall, African Americans have a less evident survival improvement. Through the contrast of the numerous genetic and environmental factors researched, a distinct difference of these correlates was proven to exist between the African American population as compared to Whites.
There are many limitations worth noting when it comes to multiple myeloma studies and existing literature. The most notable limitation in this review was the scarcity of literature that includes data stratified by race/ethnicity. There are many purely descriptive studies of a series of cases. The limited number of longitudinal cohort studies to date, makes it rather difficult to assess factors related to disease incidence as well as assess relative differences in the prevalence of potential correlates of disease. Subsequently, due to the limited number of studies, age at disease presentation and differences in gender distributions of disease, may be chance findings. Insufficient clinical and laboratory data available when medical chart reviews are conducted also hinders the verification of a multiple myeloma diagnosis, leading to a potential underestimate of multiple myeloma cases.
Planned future analyses should include (1) an analysis of disease indicators and correlates by disease stage at diagnosis and cytogenetic factors, and (2) a survival analysis assessing trajectories of disease progression (disease-free survival, overall survival duration, and response to treatment) by demographic and cytogenetic factors. In addition, future studies should also focus on the impact of therapies on survival, as well as gradual advancement of supportive care for the elderly. Ideally, larger studies are needed to assess Multiple myeloma by race. Ongoing and prospective efforts in treatment strategies include the development of immune approaches, development of new agents targeting the MM cell in the bone marrow microenvironment, and development of multi-agent combination therapies. Advances in genomics will also improve both patient classification and allow for tailored treatments (Anderson et al., 2012).
In terms of health policy, there are numerous implications to be taken into consideration. A more complete characterization of potential environmental exposures in this population is especially important. As an incurable disease, Multiple myeloma is an expensive cancer to cope with when considering costs related to hospital stays, visiting specialists, and potential stem cell transplants. Programs that could help patients cover out-of-pocket costs would especially be successful in having patients follow-up with their care and may result in better survival rates in some cases.