Chapter 68: Essential Monoclonal Gammopathy

• The presence of a serum monoclonal immunoglobulin (Ig) or a serum and urine monoclonal immunoglobulin light chain in the absence of evidence for a B-cell tumor (e.g., B-cell lymphoma, macroglobulinemia, myeloma, plasmacytoma, amyloidosis) over a period of observation.

• The monoclonal immunoglobulin may be of any isotype and may occasionally be of multiple isotypes (see Table 68–1).

• Synonyms for essential monoclonal gammopathy include (a) monoclonal gammopathy, (b) benign monoclonal gammopathy, (c) monoclonal gammopathy of unknown significance, with the acronym MGUS. The latter seems less appropriate now that the significance of this diagnosis is precisely known, and it is one of many examples of nonprogressive, clonal disorders with a predisposition to undergo clonal evolution to a malignant disorder (e.g., adenomatous colonic polyp).

• May occur at any age but very unusual before puberty and increases in frequency with age. Frequency approximately 1 percent in those over 25 years, 3 percent in those over 70 years, and 10 percent in those over 80 years of age based on zonal electropheresis studies.

• Frequency higher with more sensitive immunologic techniques (e.g., isoelectric focusing or immunoblotting).

• Frequency significantly greater among Americans of African descent than those of European descent in comparative age-groups.

• Frequency greater in males than females.

• Familial aggregation of persons with essential monoclonal gammopathy occurs.

• Essential monoclonal gammopathy may harbinger the future development of a B-cell neoplasm, notably myeloma. A large proportion of patients with myeloma evolve from a preceding essential monoclonal gammopathy.

• Result from the growth of single B-lymphocyte into a clone of cells that elaborate a monoclonal immunoglobulin and or monoclonal light chains. Cessation of expansion of the clone occurs and the size of the clone remains stable, at a steady-state of approximately 1 to 5 × 10¹⁰ cells, indefinitely.

• At this clone size, organ pathology such as osteolysis, hypercalcemia, renal disease, or hematopoietic suppression does not occur. Polyclonal immunoglobulin synthesis is usually normal and, thus, increased frequency of infections is not a feature.

• IgA or IgG monoclonal gammopathy arise from a somatically mutated post-switch pre-plasma cell, and IgM monoclonal gammopathy arises from a mutated germinal center B lymphocyte without evidence of isotype switching. This feature influences the result of clonal progression: IgA and IgG monoclonal gammopathy tends to evolve into myeloma or amyloidosis and IgM monoclonal gammopathy tends to progress to lymphoma or macroglobulinemia.

• The monoclonal immunoglobulin may react against self-antigen(s), resulting in symptomatic disease (e.g., neuropathy) that depends on the self-antigen involved and its blood or tissue distribution (see Table 68–2).

• Persons with essential monoclonal gammopathy do not have symptoms or signs of myeloma or another B-cell lymphoproliferative disease (e.g., anemia, marrow plasmacytosis, lymph node enlargement, plasmacytoma, bone lesions, or amyloid deposits).

• Individuals usually are detected by the unexpected identification of a monoclonal protein in plasma or urine by zonal protein electrophoresis or another technique (see "Laboratory Detection," below).

• Patients occasionally have features of diseases that may result from the interaction of the monoclonal protein with antibody specificity for a plasma or cell protein (e.g., acquired von Willebrand disease, neuropathy, others). Table 68–2 lists the diseases that can occur as a result of this effect of the monoclonal protein.

Zonal Electrophoresis and Serum Light Chain Assay

• Serum protein electrophoresis and serum light chain assays to determine κ:λ light chain ratio.

• Molecules of each monoclonal protein have identical size and charge and thus migrate as a narrow band.

• Electrophoresis also can be done on concentrated samples of urine or cerebrospinal fluid (CSF).

• Immunoelectrophoresis and immunofixation electrophoresis are used to identify the heavy-chain class and light-chain type of monoclonal proteins.

• The monoclonal protein is usually IgG, but may be IgM, IgA, IgD, IgE, serum and urine-free light chains, or bi- or triclonal gammopathy (see Table 68–1).

• IgG in 70 percent, IgM in 15 percent and IgA in 10 percent of cases. A few percent have biclonal or triclonal Ig proteins or solely light chains in the urine (Bence Jones proteinuria).

• In IgG monoclonal gammopathy, the concentration of M protein is usually less than 3.0 g/dL and in IgA and IgM, less than 2.5 g/dL, but there are significant exceptions to this rule.

• Features of a B-cell malignancy are absent.

• Patients with monoclonal gammopathy usually have normal polyclonal immunoglobulin levels as opposed to patients with myeloma or macroglobulinemia who do not.

• Blood cell counts and marrow examination are normal. The proportion of plasma cells in marrow is usually <5 percent.

• Plasma cell labeling index is low (<1 percent).

• Blood T-lymphocyte subsets are normal.

• Serum β₂-microglobulin level is not elevated.

• Marrow microvessel density is three times that of normal individuals but less than that of marrow vasculature in patients with myeloma (although some overlap occurs).

• Interphase fluorescence in situ hybridization frequently uncovers numerical abnormalities (monosomy or trisomy) of chromosomes but progression to a symptomatic B-cell disease is not correlated with presence or absence of hyperdiploidy or hypodiploidy.

• Detected by high-resolution electrophoresis in patients with acute-phase reactants or polyclonal hyperglobulinemia.

• Oligoclonal immunoglobulins are frequent in the CSF of patients with neurologic conditions, e.g., multiple sclerosis.

• Serum oligoclonal or monoclonal immunoglobulins occur in patients with AIDS.

Occurrence, Clinical, Laboratory, and Pathologic Findings

• Approximately 4 percent of patients with monoclonal gammopathy have neuropathy.

• IgM monoclonal gammopathy more strongly associated with neuropathy than patients with IgG or IgA.

• Approximately 10 percent of patients with idiopathic neuropathy have a monoclonal protein, a frequency about eight times that of age-matched comparison groups.

• Pathogenesis unclear (see Williams Hematology, 8th ed, Chap. 108, p. 1637 for discussion).

• Dysesthesias of hands and feet, loss of vibration and position sense, ataxia, intention tremor, and atrophy of distal muscle groups can occur, especially in association with IgM gammopathy.

• Patients with IgG or IgA gammopathy usually have chronic inflammatory demyelinating neuropathy. A minority have sensory axonal or mixed neuropathy.

• Severity of neuropathy can range from (a) mild with minor motor and/or sensory signs with or without mild functional impairment, (b) moderately disabling but with full range of activities, or (c) severely disabling interfering with walking, dressing, eating.

• The course may be remitting or progressive.

• IgA gammopathy may be associated with dysautonomia.

• Decreased nerve conduction velocity indicates demyelinization; decreased sensory potentials indicates axonal loss; electromyography may indicate denervation of muscles.

• Nerve biopsies may detect demyelinization of nerve fibers or axonal degeneration.

Management

• At least seven approaches have been used to improve the neuropathic findings: (a) intravenous IgG; (b) glucocorticoids; (c) immunoabsorption of perfused blood with staphylococcal protein A; (d) plasma exchange or plasmapheresis; (e) immunosuppressive cytotoxic chemotherapy with cyclophosphamide, fludarabine or chlorambucil with or without glucocorticoids; (f) rituximab; (g) high-dose cytotoxic therapy with autologous hematopoietic stem cell rescue.

• Plasma exchange (acute benefit) followed by immunosuppressive chemotherapy (chronic benefit) is a sequence sometime used.

• In patients with IgM and neuropathy, therapists may start with intravenous IgG as a less toxic initial approach.

• Response rates to each type of therapy are low and the duration of response unpredictable.

• Mild symptoms may not be an indication for therapy because of the low response rate and the noxious effects of therapy.

• Essential monoclonal gammopathy has been reported coincidental to a large number of conditions (see Table 68–3).

• Since the incidence of essential monoclonal gammopathy increases with age, other disorders that increase with age may be expected to co-associate without having any pathogenetic relationship and few studies have examined formally whether a causal relationship exists.

• Gaucher disease is one disorder in which a pathogenetic relationship may exist.

• Patterns of outcome in patients with essential monoclonal gammopathy:

  — Twenty-five percent of patients progress to develop myeloma, amyloidosis, macroglobulinemia, lymphoma, chronic lymphocytic leukemia over a 25-year period of observation. (Approximately 1% per year progress to some form of B-cell malignancy.)

  — Twenty-five percent of patients have a modest increase in Ig protein levels over time but do not progress to a B-cell malignancy.

  — Fifty percent of patients die of unrelated causes.

  — Although studies have shown some variables at diagnosis that may predict for earlier progression in groups of patients (e.g., higher marrow plasma cell concentrations, higher monoclonal Ig levels, lower levels of polyclonal Ig, abnormal serum light chin ratio), they are not sufficiently predictive in a single patient. In addition, there is no evidence, as yet, that early treatment is worthwhile.

  — Currently, neither gene expression analysis nor cytogenetic findings are sufficient to predict time of progression.

  — Rarely, the monoclonal protein disappears spontaneously.

  — Periodic reevaluation is required to determine the stability of the clinical course after diagnosis and to identify evidence of progression during long periods of observation.

• Therapy is generally not required for essential monoclonal gammopathy unless the monoclonal protein impairs the function of a normal plasma (e.g., acquired antithrombin) or tissue constituent (e.g., neuropathy) (see Table 68–2).