Contemporary Management of Multiple Myeloma Ravi Vij
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Epidemiology and EtiologyCHAPTER 1

 
INTRODUCTION
Multiple myeloma (MM) is a clonal plasma cell malignancy, characterized by the proliferation of neoplastic plasma cells.1 The first case was documented in the literature in the year 1844.2 Henry Bence Jones evaluated the urine of a patient with multiple myeloma and described its physical properties. He concluded that the protein present in it was the “hydrated deutoxide of albumin” and is essential for the diagnosis of myeloma.3 However, the unique urinary protein that was named after him was not mentioned in any of his works. The term “Bence Jones protein” was first used by Fleischer in 1880.4 von Rustizky in 1873 coined the term multiple myeloma after describing a patient with multiple bone tumor like lesions.
The term “Kahler's disease” was once used to describe multiple myeloma that resulted from a case report of a physician by professor Otto Kahler. The patient had progressive bone pain, proteinuria with the typical heat characteristics of Bence Jones protein, and at autopsy, the presence of large, round cells consistent with multiple myeloma.5 Thereafter, numerous cases described in literature emphasized the presence of pathologic fractures, Bence Jones proteinuria, anemia, and chronic renal disease.
The current therapeutic strategy for multiple myeloma has witnessed a dramatic improvement when compared with the rhubarb pill and infusion of orange peel that were used in 1844.6 It is still an incurable disease but the introduction of novel therapies have altered the natural course of the disease, transforming it into a chronic disease from a terminal illness.7
 
EPIDEMIOLOGY
Globally, approximately 0.8% of all cancer cases diagnosed and 0.9% of cancer deaths in 2002 were attributed to multiple myeloma.8 In the year 2007, approximately 19,900 cases were diagnosed with multiple myeloma and 10,790 patients died of the disease in the United States. The yearly incidence is reported to be 4 per 100,000 and is remarkably similar worldwide.92
The median age of diagnosis is 68 years; the disease being rare prior to 40 years. As per the data from 17 SEER (Surveillance, Epidemiology, and End Results) geographic areas from 2002–2006, the age-adjusted incidence rate was 5.6 per 100,000 men and women per year and the age-adjusted death rate was 3.6 per 100,000 men and women per year.10
Males are more commonly affected than females; the incidence being higher in blacks than in the whites. Multiple myeloma contributes approximately 1% of all the malignancies diagnosed in whites and 2% in blacks, and 13% of all hemato-logic malignancies in whites and 33% in blacks. The reason for this uneven race and sex distribution remains unexplained.
The racial and geographic distribution of multiple myeloma varies widely. African-American and Pacific islanders exhibit the highest incidence rates; followed by Caucasians; the lowest rates being in developing countries, including Asia. Although not fully explained, a higher incidence in developed countries may be explained on the basis of a longer life expectancy and better medical facilities in such countries.9
The age-adjusted incidence rates and death rates by race/ethnicity are presented in figures 1-1A and B.
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Figure 1-1A: SEER incidence rates of multiple myeloma by race (2002–2006). Higher incidence is observed in males than in females. African-American and Pacific islanders exhibit the highest incidence rates; followed by Caucasians; the lowest rates being in developing countries, including Asia.
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Figure 1-1B: SEER death rates of multiple myeloma by race (2002–2006). The mortality pattern closely follows the incidence rates for racial and geographic distribution.
Despite the varied prevalence of multiple myeloma in different geographic areas, the response to therapy and the prognosis remains uniform throughout the world.
 
ETIOLOGY
As multiple myeloma is a relatively uncommon disease entity, etiologic evaluation has proved to be difficult in assessing small number of cases in occupational cohort studies. Few subjects report exposure to specific agents in case-control studies. Several risk factors have been postulated (Table 1-1).11,12
Table 1-1   Difficulties in Identifying Etiology of Multiple Myeloma
• Relatively rare disease
• Multiple risk factors
• Time and dose of exposure, probably critical
• Multiple potential confounding factors
• Difficulty in obtaining detailed statistics regarding
  • – Race
  • – Family history
• ? Inherited susceptibility
• ? Role of tumor cell microenvironment
4
 
ENVIRONMENTAL AND OCCUPATIONAL FACTORS
 
Ionizing Radiation
It is the single most important risk factor associated with an increased risk of multiple myeloma. An excess risk of multiple myeloma was witnessed among survivors of the atomic explosions in Hiroshima and Nagasaki.13 Unlike atomic bomb survivors who received acute exposures to the high doses of radiation, workers in the nuclear industry or other radiation-exposed occupational cohorts, such as radiologists, receive chronic exposures at presumably lower doses over aworking lifetime. An increased risk of multiple myeloma with increasing numbers of diagnostic radiographs was demonstrated without an increased risk of leukemia or lymphoma, which suggests that even a low level of radiation may be a risk factor.5
 
Agriculture and Farming
A systemic review of case-control studies of multiple myeloma published from 1970 to 2007 showed a pooled OR for working as a farmer of 1.39; 95% CI 1.18 to 1.65.14 For working on a farm for more than ten years OR was 1.87; 95% CI 1.15 to 3.16. A meta-analysis using 32 studies published between 1981 and 1996 demonstrated a significant association between multiple myeloma and farming.15 The studies evaluating the association of multiple myeloma with farming are limited by the broad classification of farming as an occupational group. Farmers are exposed to multiple chemicals and microorganisms, including solvents, fuels and oils, lubricants, wood preservatives, engine exhausts, dusts, zoonotic viruses, and other microbes. There is also substantial published data on exposures to pesticides.15
 
Organic Solvents
Several authors have reported a nonsignificant relative risk estimate for multiple myeloma mortality of workers exposed to a general category of organic solvents (meta-RR = 1.14, 95% CI: 0.83–1.56).16–18 Evidence in the form of case reports have suggested an association between multiple myeloma and benzene exposure. However, case reports alone are insufficient for the determination of causation. Studies among petroleum workers, painters and paint-exposed subgroups have provided inconsistent results. Trichloroethylene and formaldehyde have not been identified as a risk factor for multiple myeloma.11
 
Others
Although several other chemicals including rubber, asbestos, lumbar or wood dust, leather dust, diesel exhaust and/or engine exhaust, etc. have been associated with an increased risk of multiple myeloma, no causal relationship has been 5proved.11 In a case series described by Moline and colleagues, an unusual number of multiple myeloma cases in World Trade Center (WTC) responders under 45 years were observed.18 Among 28,252 responders of known sex and age, between September 11, 2001 and September 10, 2007, eight cases of multiple myeloma were observed (6.8 expected). Four of these cases were observed in responders younger than 45 years at the time of diagnosis (1.2 expected). A slight deficit of multiple myeloma cases was observed in responders older than 45 years (4 observed, 5.6 expected).18,19
 
DIET AND LIFESTYLE FACTORS
 
Diet and Obesity
There is a body of literature to support a correlation of baseline body mass index (BMI) with multiple myeloma. The higher frequency of obesity among blacks may partly explain the higher incidence of multiple myeloma among blacks compared to whites in the United States.20 Although physical activity is not significantly related to multiple myeloma risk, an inverse association has been suggested in women.21 There is limited evidence on the contribution of diet to multiple myeloma. There is suggestion of an inverse correlation with the consumption of fish, cruciferous vegetables and green vegetables, and a positive association for some dairy products.22 Alcohol and tobacco consumption has not been clearly linked to multiple myeloma.19
 
Cosmetics and Hair Dyes
An increased incidence of multiple myeloma has been reported in females working as cosmetologists, hairdressers, and manicurists.23 People in these occupation have potential exposure to a number of chemical mutagens.24,25 There is a conflicting data on the use of hair coloring products and the risk for multiple myeloma.26 A recent population-based case-control study found no association between hair coloring product use and myeloma risk among all users (OR 0.8; 95% CI 0.5 to 1.1), semi-permanent dye users (OR 0.7; 95% CI 0.4 to 1.2), permanent dye users (OR 0.8; 95% CI 0.5 to 1.1), or dark permanent dye users (OR 0.8; 95% CI 0.5 to 1.3).27
 
CHRONIC ANTIGENIC STIMULATION
The association between repeated or chronic antigenic stimulation and multiple myeloma has been extensively investigated. Epidemiologic studies have yielded inconsistent results and most of them do not support a causal relationship. The few factors that have been associated with multiple myeloma include a history of 6rheumatic fever and urinary tract infection. Less significant association was found with the number of past viral/bacterial illnesses and desensitization for allergies. Myeloma risk was found to be inversely related to the number of diseases against which a subject reported having been immunized, perhaps because of differences in socioeconomic status between cases and controls.28 Case studies evaluating specific autoimmune diseases like rheumatoid arthritis have also reported no significant associations.11
 
VIRUSES
Patients infected with human immunodeficiency virus and hepatitis C viruses have been associated with an increased likelihood of developing multiple myeloma.5 A causal association between Kaposi's sarcoma-associated herpes virus (KSHV) and multiple myeloma has been a topic of controversy.12
 
FAMILIAL MULTIPLE MYELOMA
The literature clearly indicates a risk of developing multiple myeloma in individuals with a positive family history. The overall risk of multiple myeloma in first-degree relatives of persons with multiple myeloma is reported to be increased by a factor of two to four.29 Lynch et al. described a family with five cases of multiple myeloma, three cases of monoclonal gammopathy of undetermined significance (MGUS), and five cases of prostate cancer in twogenerations.30 In a study evaluating 39 families with the multiple cases of multiplemyeloma or related disorders, 17 families had affected members in two or more generations, and eight families had two or more affected members in asingle generation. Four families had two or more members with plasma celldyscrasias, with or without a single case of multiple myeloma. In the remaining10 families, a single multiple myeloma case occurred with a family history ofother cancers. In families with multiple myeloma in multiple generations, there was a decrease in the age of multiple myeloma diagnosis in successive generations.
Vachon et al. further emphasized on the shared environment and/or genetics of multiple myeloma by demonstrating an increased risk of MGUS in first-degree relatives of MGUS or myeloma compared with a reference population.31 The age-and sex-adjusted prevalence of MGUS was 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age.
The risk of plasma cell and lymphoproliferative disorders among first-degree relatives of individuals with MGUS and patterns of familial disease was charac-terized in a population-based data from Sweden.32 Compared with the relatives of controls, relatives of individuals with MGUS had an increased risk of MGUS 7[relative risk (RR) = 2.8; 1.4–5.6], multiple myeloma (RR = 2.9; 1.9–4.3), lympho-plasmacytic lymphoma/Waldenström macroglobulinemia (RR = 4.0; 1.5–11), and chronic lymphocytic leukemia (RR = 2.0; 1.2–2.3).
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Figure 1-2: Multiple myeloma-disease progression. An initiation genetic event causes immortalization of either a long-lived plasma cell or a memory B cell and formation of a malignant plasma cell clone. Further genetic events result in stepwise progression of karyotypic complexity and clinical progression from monoclonal gammopathy of undetermined significance to multiple myeloma.
8
 
PRENEOPLASTIC LESIONS
Monoclonal gammopathy of undetermined significance is a premalignant plasma cell proliferative disorder associated with a life-long risk of progression to multiple myeloma. In a classic multistep development model, MGUS progresses to smoldering multiple myeloma (SMM), and ultimately to symptomatic intramedullary and extramedullary multiple myeloma, or plasma cell leukemia (Figure 1-2). The progression to multiple myeloma occurs at an average rate of 1% per year for MGUS and initially 10% per year for SMM.33 The cumulative risk of multiple myeloma during the first 10 years of follow-up among 2,406 MGUS cases were similar for African-Americans (17%) and white (15%) in a cohort of US veterans.34
Recent publications suggest that multiple myeloma is probably always preceded by a MGUS stage.33 Among 77,469 healthy adults enrolled in the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, 71 subjects developed multiple myeloma during the course of the study. Evaluation of serum samples obtained 2 to 9.8 years prior to the diagnosis of myeloma demonstrated an asymptomatic MGUS stage to consistently precede the development of overt multiple myeloma. In a separate retrospective analysis, newly diagnosed myeloma were found to have evolved from a pre-existing plasma cell disorder (PPCD).35 The events that trigger progression of MGUS are of prime interest. It should also be remembered that vast majority of MGUS cases never progress to multiple myeloma.34,36,37
 
CONCLUSION
Most of the work on the etiology of multiple myeloma focuses on understanding potential risks associated with long-term environmental and occupational exposures and lifestyle factors. However, with a known familial clustering more research is needed on inherited genetic factors predisposing to the development of the disease. With the recent confirmation that MGUS probably always precedes the development of multiple myeloma, future research efforts should seek the causes of MGUS and the genetic events that lead to its progression to multiple myeloma.
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