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ETIOLOGY OF PLASMA CELL NEOPLASM
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Monoclonal Gammopathy
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Although monoclonal gammopathy (Chap. 106) shares the same constellation of risk factors and cytogenetic abnormalities with myeloma, it is an antecedent neoplasm that may undergo clonal evolution to any one of the PCNs or to a B-cell lymphoma.1 Two studies have reported that monoclonal gammopathy is a precursor to myeloma in virtually all cases.23
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Retrospective population-based cohort studies have established that nearly 80 percent of cases of myeloma develop from IGH monoclonal gammopathy. The remaining 20 percent have serum free light chain (FLC) monoclonal gammopathy. The prevalence of FLC monoclonal gammopathy is 0.8 percent in the general population. It progresses to myeloma in a minority of patients at the rate of 0.3 percent per year,3 much lower than the conventional monoclonal gammopathy progression rate of approximately 1 percent.
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Factors such as chronic antigen stimulation and chemical exposure have been suspected in the development of monoclonal gammopathy and other PCNs. Some studies have found a positive association,45 but the results have not been consistent and given our current understanding of the genetic precedents of myeloma, one would have to show a direct effect of such agents on the causal mutations involved.
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A familial history of monoclonal gammopathy and myeloma has been reported to be a risk factor for developing the disease in first-degree relatives, including a population-based study from the Mayo Clinic. A twofold increased relative risk was noted for the development of monoclonal gammopathy among the first-degree relatives of myeloma and monoclonal gammopathy patients. In a large Swedish population study, among first-degree relatives of patients with monoclonal gammopathy, a threefold increased risk for both monoclonal gammopathy and myeloma, a fourfold risk of developing Waldenström macroglobulinemia, and a twofold risk of developing B-cell chronic lymphocytic leukemia was observed.6 These observations support the role of both germline susceptibility genes and possibly immune-related phenomena in the causation.7 Because of the extremely low lifetime-risk of developing myeloma in the general population (0.2 percent), it would be inefficient to screen the first-degree relatives of persons with myeloma or monoclonal gammopathy.
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Hyperphosphorylated paratarg-7, a frequent autoantigenic target of human paraproteins, is linked to both familial and nonfamilial forms of monoclonal gammopathy and myeloma.7 Paratarg-7 is the target of 15 percent of the monoclonal proteins of the IgA and IgG type, and 11 percent of IgM-monoclonal gammopathy or macroglobulinemia patients. All patients with paratarg-7–specific paraproteins were carriers of a hyperphosphorylated protein (pP-7); this hyperphosphorylation is inherited in a dominant fashion. Hyperphosphorylation is a result of inactivation of phosphatase 2A.8 Hyperphosphorylated paratarg-7 carriers are most prevalent among Americans of African wdefined single risk factor for monoclonal gammopathy or myeloma in all ethnic groups9 and is associated with a sixfold increased risk of IgM monoclonal gammopathy or macroglobulinemia.10
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Nearly 50 percent of patients with monoclonal gammopathy have plasma cells with translocations involving the IGH locus on chromosome 14q32 and one of the five partner chromosomes: 11q13 (cyclin D1 gene), 4q16,3 (FGFR-2 and MMSET), 6q21 (CCND3), 16q23 (c-maf), and 20q11 (maf-B).11,12,13,14
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Unfortunately, none of the molecular or chromosomal abnormalities associated with myeloma predict the evolution of monoclonal gammopathy to myeloma. Two clinical risk stratification models propose high-risk features that can predict progression from monoclonal gammopathy and SMM to myeloma.15,16 While one model uses the type of immunoglobulin, quantity of M-protein, and the serum FLC ratio to determine the risk of progression, the other model is based on flow cytometry findings of aberrant plasma cells, marrow plasma cell percentage, DNA aneuploidy, and immune paresis (a decrease in noninvolved immunoglobulins).
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SMM is discussed in Chap. 107. In addition to the marrow plasma cell burden and quantitative M-protein (>3 g/dL), presence of light-chain proteinuria and IgA M-heavy chain were identified as separate risk factors predicting progression to active myeloma.17,18,19,20 The median time of progression to myeloma has been reported to range between 3 and 8 years in low-risk groups, and between 1 and 2 years in high-risk groups.17,18,19,20,21,22 Some studies have also investigated the use of magnetic resonance imaging (MRI) in detecting skeletal abnormalities not seen on a skeletal survey; time to progression to myeloma was much shorter in patients with focal lesions on the MRI23 and these patients should be treated.
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A number of models estimating the risk of progression to myeloma have been proposed. The presence of serum M-protein of greater than 3 g/dL, an FLC ratio outside the reference range of 0.125 to 8, and greater than 10 percent plasma cells in the marrow represents SMM with a high-risk of progression. Patients with these three risk factors had a cumulative risk of 76 percent of progression to myeloma within 5 years.15,24 The risk of progression decreased to 51 percent in patients with two of the risk factors and to 25 percent in patients with a single risk factor.24,25 Another clinical risk stratification model uses flow-cytometry of marrow aspirates. Using as risk factors (1) greater than 95 percent of all plasma cells being aberrant at diagnosis, (2) DNA aneuploidy, and (3) immune paresis, the presence of one, two, or three risk factors translated to 4, 46, and 72 percent risk of progression to myeloma with 5 years of observation, respectively.16 Other researchers have found that in addition to the intrinsic, molecular, and cytogenetic abnormalities of the plasma cells, an angiogenic switch and immunologic factors play a key role in the transformation of SMM to established myeloma.26
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The development of myeloma is a complex multistep process involving karyotypic instability, Ig translocations, cell-cycle abnormalities (cyclin Ds), and multiple other mutations27 (Chap. 107). No molecular or chromosomal abnormalities can distinguish among monoclonal gammopathy, SMM, or myeloma at the time of diagnosis. Certain mutations occur in much higher frequencies in myeloma, such as p53 deletions, especially in refractory and extramedullary presentations,12,28 N-RAS and K-RAS mutations, chromosome 1p deletion and gain of 1q21, and translocations involving MYC (8q24).29,30,31,32,33 In whole-exome sequencing studies, intraclonal heterogeneity has been shown to be present at all stages of development—from monoclonal gammopathy to SMM to progressive myeloma.39 Genetic complexity increases as the disease progresses to myeloma.
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Effect of Endogenous Factors There is an increased relative risk of monoclonal gammopathy and myeloma in overweight and obese patients based on their body mass index (BMI). With the exception of elite athletes, a BMI of 25.0 to 29.9 kg/m2 and 30 kg/m2 or greater define overweight and obese individuals, respectively.35,36,37,38,39,40,41 Fat tissue is a dynamic endocrine organ, secreting adipokines, hormones that play an important role in energy homeostasis and inflammation. Several adipokines, such as leptin and adiponectin, have been implicated in the development of cancer.40 Adiponectin levels are inversely correlated with obesity. Adiponectin serum concentrations were lower in monoclonal gammopathy patients who subsequently developed myeloma. In the KaLwRij strain of C57 black mice, which is permissive to the growth of 5T myeloma, compared to the parental strain of C57B16, which is not, adiponectin gene expression is significantly lower than in the parental strain. An increased myeloma burden was found in adiponectin-deficient mice, while pharmacologic enhancement of circulating adiponectin resulted in apoptosis of myeloma cells and also prevented bone disease. Fat tissue is a principal source of interleukin (IL)-6, one of the principal growth and antiapoptotic cytokines acting on myeloma cells. Obese individuals have been shown to have shorter telomeres than nonobese individuals. Because telomeres protect chromosomes from injury, including undesirable translocations, this effect may also contribute the relationship of body mass with PCN.
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Effect of Exogenous Factors Aspirin has been shown not only to reduce cancer incidence, but to also dramatically decrease cancer mortality, especially in colorectal cancer, esophageal, gastric cancer, breast cancer, prostate cancer, and lung cancer. Aspirin inhibits several pathways that are important in myeloma, including nuclear factor κB (NF-κB), AKT activation, and the BCL-2 family of proteins. Aspirin is used frequently as thromboprophylaxis in myeloma patients receiving immunomodulatory therapy. In a prospective study designed to examine whether regular aspirin use influences the risk of myeloma, participants taking 5 or more tablets of 325 mg per week had a 39 percent lower myeloma incidence than nonusers. The association appeared stronger in men than in women.43 Aspirin inhibits proliferation and induces apoptosis of myeloma cell lines in vitro through regulation of BCL-2 and BAX and suppression of vascular endothelial growth factor (VEGF). In addition, in vivo studies in mice showed that aspirin administration resulted in retardation of tumor growth and in increased survival.44 A number of case-control and cohort studies have established that smoking has no association with the incidence of myeloma. Convincing evidence has not been found linking alcohol consumption to myeloma development.45
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Occupation Many studies evaluated the potential role of exposure to certain occupations and/or toxin and the subsequent risk of myeloma development. Agricultural workers and farmers were studied in the United States and Europe. The majority of studies report an increase frequency of myeloma in agricultural workers, whereas other reports fail to find such a correlation.46 Exposure to toxins such as organic solvents (e.g., toluene, benzene), pesticides, paints, and others products with trace benzene content have been investigated for an association with the incidence of myeloma, but the findings are inconsistent.47
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Radiation Studies on the survivors of the atomic bombing in Japan have failed to establish a cause-and-effect relationship between high-dose radiation exposure and an increased incidence of myeloma.48 Studies from the United Kingdom have reported no increased frequency of myeloma in workers exposed to ionizing radiation, nuclear plants, and/or plutonium.45 In a large study in China of x-ray technicians, there were no reported cases of myeloma or plasma cells disorders.49 Thus, radiation exposure is not linked to the risk of myeloma.
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Chronic immune stimulation has not been shown to play a causative role in the etiology of myeloma. No link between infections, allergic conditions, or immunizations and the development of myeloma has been established. Patients with autoimmune disorders, in general, have not been found to have an excess risk of myeloma. Some studies report an increased risk of myeloma in HIV50,51 and hepatitis C patients,52 although more convincing data are needed to establish a cause-and-effect relationship.
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Waldenström Macroglobulinemia
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Etiology In a small study of 65 patients and 213 controls, a preceding autoimmune condition did not predict the development of Waldenström macroglobulinemia.53 In contrast, many other studies have found such a link. In a large population-based study, that included 146,394 hepatitis C patients and 572,293 controls, a threefold increased risk of macroglobulinemia was observed along with a 20 to 30 percent increased risk of lymphoma.54 In a study of 361 U.S. veterans with Waldenström macroglobulinemia after a 27-year followup, a two- to threefold increased risk of developing the disease was found in patients with autoimmune-related conditions, hepatitis, HIV infection, and rickettsiosis.55 In two Swedish population-based studies, a personal history of autoimmune conditions and infections was associated with an increased risk of macroglobulinemia.56
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Case-control studies and a large population-based study in Sweden have established the role of familial clustering of macroglobulinemia, thereby raising the concept of common susceptibility genes that could predispose to the disease.53,57,58,59,60,61 In study of macroglobulinemia, 19 percent of patients had at least one identified first-degree relative with macroglobulinemia or a B-cell disorder.60 In genome-wide linkage analyses of high-risk families with macroglobulinemia and IgM monoclonal gammopathy, the strongest linkage was found to be chromosomes 1q, 3q, 4q, and 6q.58,60,62,63,64 In a gene-sequencing study performed on marrow cells of macroglobulinemia patients, a recurrent somatic mutation of the gene MYD88L265P on chromosome 3 that encodes signal transduction and innate immunity was found to be in approximately 91 percent of the patients tested.60
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In a novel study using expression cloning, several common self-antigens designated Paratarg-7 were discovered.10 When carriers of the phosphorylated forms of Paratarg-7 were studied, they were found to have a 6.5-fold higher risk of developing IgM monoclonal gammopathy or macroglobulinemia. The antigen causes continuous autostimulation of cognate T-helper cells, which, in turn, specifically activate B cells with high affinity to Paratarg-7.