Page 1733 - Williams Hematology ( PDFDrive )

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

and reexpress surface Ig. The centrocytes with high-affinity antibodies A familial history of monoclonal gammopathy and myeloma has
differentiate into either memory B cells or plasmablasts, which then been reported to be a risk factor for developing the disease in first-degree
move to the marrow and terminally differentiate to plasma cells. Mar- relatives, including a population-based study from the Mayo Clinic. A
row plasma cells produce most of the plasma immunoglobulins and twofold increased relative risk was noted for the development of mono-
have a life span of approximately 3 weeks. clonal gammopathy among the first-degree relatives of myeloma and
Three distinct gene segments, the variable (V ), diversity (D), and monoclonal gammopathy patients. In a large Swedish population study,
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joining region (J ) genes, encode the variable region of the heavy chain, among first-degree relatives of patients with monoclonal gammopathy,
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whereas two segments, variable (Vκ or V ) and joining (Jκ or J ) region a threefold increased risk for both monoclonal gammopathy and mye-
genes, encode the variable fraction of the light chain. The IGH locus loma, a fourfold risk of developing Waldenström macroglobulinemia,
on chromosome 14q32 contains an estimated 100 to 150 V genes, 30 and a twofold risk of developing B-cell chronic lymphocytic leukemia
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D, and six J gene segments. Because some of the V genes are nearly was observed. These observations support the role of both germline
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identical, it is likely that 60 to 70 V genes are available for rearrange- susceptibility genes and possibly immune-related phenomena in the
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ment. These 60 to 70 genes belong to seven families (V 1 to 7) whose causation. Because of the extremely low lifetime-risk of developing
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members have more than 80 percent sequence homology. Of the 75 myeloma in the general population (0.2 percent), it would be inefficient
known Vκ sequences, only 36 are potentially functional and of the 36 to screen the first-degree relatives of persons with myeloma or mono-
known V sequences, only 24 are functional. Rearrangement of the V clonal gammopathy.
gene segments is dependent on the protein products of the recom- Hyperphosphorylated paratarg-7, a frequent autoantigenic target
binase-activating genes RAG-1 and RAG-2. Recombination of V genes of human paraproteins, is linked to both familial and nonfamilial forms
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starts in lymphoid progenitors within the IGH locus of either the mater- of monoclonal gammopathy and myeloma. Paratarg-7 is the target of
nal or paternal chromosome 14. If the initial V -D-J rearrangement 15 percent of the monoclonal proteins of the IgA and IgG type, and
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yields a sequence that cannot be translated, then rearrangement of the 11 percent of IgM-monoclonal gammopathy or macroglobulinemia
IGH locus proceeds on the other allele. The presence on the B-cell sur- patients. All patients with paratarg-7–specific paraproteins were carri-
face of a fully assembled μ heavy chain rearrangement begins when ers of a hyperphosphorylated protein (pP-7); this hyperphosphorylation
one of the Vκ genes rearranges to one of the Jκ genes. If κ light-chain is inherited in a dominant fashion. Hyperphosphorylation is a result
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rearrangement is unsuccessful on both alleles, by default light chains of inactivation of phosphatase 2A. Hyperphosphorylated paratarg-7
will subsequently rearrange. The Ig heavy and light chains each contain carriers are most prevalent among Americans of African wdefined sin-
three hypervariable complementarity determining regions segments, gle risk factor for monoclonal gammopathy or myeloma in all ethnic
which are the areas of the immunoglobulin in direct contact with the groups and is associated with a sixfold increased risk of IgM monoclo-
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antigen. In a process of trial and error, immunoglobulins increase their nal gammopathy or macroglobulinemia. 10
affinity for an antigen by a series of somatic mutations. The complemen- Nearly 50 percent of patients with monoclonal gammopathy have
tarity determining regions of the IGH (CDR) 3 is the most variable por- plasma cells with translocations involving the IGH locus on chromo-
tion of the Ig molecule, because it not only contains somatic mutations some 14q32 and one of the five partner chromosomes: 11q13 (cyclin D1
as is the case for CDR 1 and CDR 2, but it also encompasses the 3′ end gene), 4q16,3 (FGFR-2 and MMSET), 6q21 (CCND3), 16q23 (c-maf),
of V , all of D, and the 5′ end of J . It is, therefore, an ideal marker to and 20q11 (maf-B). 11–14
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detect a very small population of the malignant myeloma clone within a Unfortunately, none of the molecular or chromosomal abnor-
larger population of normal cells. malities associated with myeloma predict the evolution of monoclonal
gammopathy to myeloma. Two clinical risk stratification models pro-
pose high-risk features that can predict progression from monoclonal
ETIOLOGY AND PATHOGENESIS gammopathy and SMM to myeloma. 15,16 While one model uses the
type of immunoglobulin, quantity of M-protein, and the serum FLC
ETIOLOGY OF PLASMA CELL NEOPLASM ratio to determine the risk of progression, the other model is based on
Monoclonal Gammopathy flow cytometry findings of aberrant plasma cells, marrow plasma cell
Although monoclonal gammopathy (Chap. 106) shares the same con- percentage, DNA aneuploidy, and immune paresis (a decrease in
stellation of risk factors and cytogenetic abnormalities with myeloma, non i nvolved immunoglobulins).
it is an antecedent neoplasm that may undergo clonal evolution to any
one of the PCNs or to a B-cell lymphoma. Two studies have reported Smoldering Myeloma
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that monoclonal gammopathy is a precursor to myeloma in virtually SMM is discussed in Chap. 107. In addition to the marrow plasma cell
all cases. 23 burden and quantitative M-protein (>3 g/dL), presence of light-chain
Retrospective population-based cohort studies have established proteinuria and IgA M-heavy chain were identified as separate risk fac-
that nearly 80 percent of cases of myeloma develop from IGH monoclo- tors predicting progression to active myeloma. 17–20 The median time of
nal gammopathy. The remaining 20 percent have serum free light chain progression to myeloma has been reported to range between 3 and 8 years
(FLC) monoclonal gammopathy. The prevalence of FLC monoclonal in low-risk groups, and between 1 and 2 years in high-risk groups. 17–22
gammopathy is 0.8 percent in the general population. It progresses to Some studies have also investigated the use of magnetic resonance imag-
myeloma in a minority of patients at the rate of 0.3 percent per year, ing (MRI) in detecting skeletal abnormalities not seen on a skeletal sur-
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much lower than the conventional monoclonal gammopathy progres- vey; time to progression to myeloma was much shorter in patients with
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sion rate of approximately 1 percent. focal lesions on the MRI and these patients should be treated.
Factors such as chronic antigen stimulation and chemical exposure A number of models estimating the risk of progression to myeloma
have been suspected in the development of monoclonal gammopathy have been proposed. The presence of serum M-protein of greater
and other PCNs. Some studies have found a positive association, but than 3 g/dL, an FLC ratio outside the reference range of 0.125 to 8,
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the results have not been consistent and given our current understand- and greater than 10 percent plasma cells in the marrow represents SMM
ing of the genetic precedents of myeloma, one would have to show a with a high-risk of progression. Patients with these three risk factors
direct effect of such agents on the causal mutations involved. had a cumulative risk of 76 percent of progression to myeloma within

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