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1708 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1709

5 years. 15,24 The risk of progression decreased to 51 percent in patients BCL-2 and BAX and suppression of vascular endothelial growth fac-
with two of the risk factors and to 25 percent in patients with a single risk tor (VEGF). In addition, in vivo studies in mice showed that aspirin
factor. 24,25 Another clinical risk stratification model uses flow-cytometry administration resulted in retardation of tumor growth and in increased
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of marrow aspirates. Using as risk factors (1) greater than 95 percent of survival. A number of case-control and cohort studies have established
all plasma cells being aberrant at diagnosis, (2) DNA aneuploidy, and that smoking has no association with the incidence of myeloma. Con-
(3) immune paresis, the presence of one, two, or three risk factors vincing evidence has not been found linking alcohol consumption to
translated to 4, 46, and 72 percent risk of progression to myeloma with myeloma development. 45
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5 years of observation, respectively. Other researchers have found that Occupation Many studies evaluated the potential role of exposure
in addition to the intrinsic, molecular, and cytogenetic abnormalities of to certain occupations and/or toxin and the subsequent risk of mye-
the plasma cells, an angiogenic switch and immunologic factors play a loma development. Agricultural workers and farmers were studied in
key role in the transformation of SMM to established myeloma. 26 the United States and Europe. The majority of studies report an increase
frequency of myeloma in agricultural workers, whereas other reports
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Myeloma fail to find such a correlation. Exposure to toxins such as organic sol-
The development of myeloma is a complex multistep process involving vents (e.g., toluene, benzene), pesticides, paints, and others products
karyotypic instability, Ig translocations, cell-cycle abnormalities (cyclin with trace benzene content have been investigated for an association
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Ds), and multiple other mutations (Chap. 107). No molecular or chro- with the incidence of myeloma, but the findings are inconsistent. 47
mosomal abnormalities can distinguish among monoclonal gammo- Radiation Studies on the survivors of the atomic bombing in
pathy, SMM, or myeloma at the time of diagnosis. Certain mutations Japan have failed to establish a cause-and-effect relationship between
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occur in much higher frequencies in myeloma, such as p53 deletions, high-dose radiation exposure and an increased incidence of myeloma.
especially in refractory and extramedullary presentations, 12,28 N-RAS Studies from the United Kingdom have reported no increased frequency
and K-RAS mutations, chromosome 1p deletion and gain of 1q21, and of myeloma in workers exposed to ionizing radiation, nuclear plants,
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translocations involving MYC (8q24). 29–33 In whole-exome sequencing and/or plutonium. In a large study in China of x-ray technicians, there
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studies, intraclonal heterogeneity has been shown to be present at all were no reported cases of myeloma or plasma cells disorders. Thus,
stages of development—from monoclonal gammopathy to SMM to radiation exposure is not linked to the risk of myeloma.
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progressive myeloma. Genetic complexity increases as the disease pro- Chronic immune stimulation has not been shown to play a caus-
gresses to myeloma. ative role in the etiology of myeloma. No link between infections, aller-
Effect of Endogenous Factors There is an increased relative risk gic conditions, or immunizations and the development of myeloma has
of monoclonal gammopathy and myeloma in overweight and obese been established. Patients with autoimmune disorders, in general, have
patients based on their body mass index (BMI). With the exception not been found to have an excess risk of myeloma. Some studies report
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2
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of elite athletes, a BMI of 25.0 to 29.9 kg/m and 30 kg/m or greater an increased risk of myeloma in HIV 50,51 and hepatitis C patients,
define overweight and obese individuals, respectively. 35–41 Fat tissue is a although more convincing data are needed to establish a cause-and-effect
dynamic endocrine organ, secreting adipokines, hormones that play an relationship.
important role in energy homeostasis and inflammation. Several adi-
pokines, such as leptin and adiponectin, have been implicated in the Waldenström Macroglobulinemia
development of cancer. Adiponectin levels are inversely correlated Etiology In a small study of 65 patients and 213 controls, a pre-
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with obesity. Adiponectin serum concentrations were lower in mono- ceding autoimmune condition did not predict the development of
clonal gammopathy patients who subsequently developed myeloma. In Waldenström macroglobulinemia. In contrast, many other studies
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the KaLwRij strain of C57 black mice, which is permissive to the growth have found such a link. In a large population-based study, that included
of 5T myeloma, compared to the parental strain of C57B16, which is 146,394 hepatitis C patients and 572,293 controls, a threefold increased
not, adiponectin gene expression is significantly lower than in the risk of macroglobulinemia was observed along with a 20 to 30 percent
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parental strain. An increased myeloma burden was found in adiponect- increased risk of lymphoma. In a study of 361 U.S. veterans with Wal-
in-deficient mice, while pharmacologic enhancement of circulating denström macroglobulinemia after a 27-year followup, a two- to three-
adiponectin resulted in apoptosis of myeloma cells and also prevented fold increased risk of developing the disease was found in patients with
bone disease. Fat tissue is a principal source of interleukin (IL)-6, one autoimmune-related conditions, hepatitis, HIV infection, and rickettsi-
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of the principal growth and antiapoptotic cytokines acting on myeloma osis. In two Swedish population-based studies, a personal history of
cells. Obese individuals have been shown to have shorter telomeres than autoimmune conditions and infections was associated with an increased
nonobese individuals. Because telomeres protect chromosomes from risk of macroglobulinemia. 56
injury, including undesirable translocations, this effect may also con- Case-control studies and a large population-based study in Sweden
tribute the relationship of body mass with PCN. have established the role of familial clustering of macroglobulinemia,
Effect of Exogenous Factors Aspirin has been shown not only thereby raising the concept of common susceptibility genes that
to reduce cancer incidence, but to also dramatically decrease cancer could predispose to the disease. 53,57–61 In study of macroglobuline-
mortality, especially in colorectal cancer, esophageal, gastric cancer, mia, 19 percent of patients had at least one identified first-degree rel-
breast cancer, prostate cancer, and lung cancer. Aspirin inhibits several ative with macroglobulinemia or a B-cell disorder. In genome-wide
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pathways that are important in myeloma, including nuclear factor κB linkage analyses of high-risk families with macroglobulinemia and
(NF-κB), AKT activation, and the BCL-2 family of proteins. Aspirin is IgM monoclonal gammopathy, the strongest linkage was found to be
used frequently as thromboprophylaxis in myeloma patients receiving chromosomes 1q, 3q, 4q, and 6q. 58,60,62–64 In a gene-sequencing study
immunomodulatory therapy. In a prospective study designed to exam- performed on marrow cells of macroglobulinemia patients, a recurrent
ine whether regular aspirin use influences the risk of myeloma, partic- somatic mutation of the gene MYD88L265P on chromosome 3 that
ipants taking 5 or more tablets of 325 mg per week had a 39 percent encodes signal transduction and innate immunity was found to be in
lower myeloma incidence than nonusers. The association appeared approximately 91 percent of the patients tested. 60
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stronger in men than in women. Aspirin inhibits proliferation and In a novel study using expression cloning, several common
induces apoptosis of myeloma cell lines in vitro through regulation of self-antigens designated Paratarg-7 were discovered. When carriers of
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