Chapter 67: Essential Monoclonal Gammopathy

• Essential monoclonal gammopathy is 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 (eg, 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 67–1).

• Synonyms for essential monoclonal gammopathy include (1) monoclonal gammopathy; (2) benign monoclonal gammopathy; and (3) 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 (eg, adenomatous colonic polyp), making its significance apparent.

• Essential monoclonal gammopathy may occur at any age, but it is very unusual before puberty and increases in frequency with age. Frequency approximately is 1% in those over 25 years, 3% in those over 70 years, and 10% in those over 80 years of age based on zonal electrophoresis studies.

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

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

• Frequency is 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 (eg, myeloma). Most, and perhaps, all patients with myeloma evolve from a preceding essential monoclonal gammopathy.

• The gammopathy results from the growth of a single mutated 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 and IgG monoclonal gammopathy arise from a somatically mutated postswitch preplasma 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 tend 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 (eg, neuropathy) that depends on the self-antigen involved and its blood or tissue distribution (see Table 67–2).

• Persons with essential monoclonal gammopathy do not have symptoms or signs of myeloma or another B-cell lymphoproliferative disease (eg, 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 (eg, acquired von Willebrand disease, neuropathy, others).

• Patients may also have symptomatic disease because of the physicochemical features of the monoclonal immunoglobulin, such as predisposition to form crystals (eg, corneal keratopathy, Fanconi renal disease) or exaggerated copper binding (pseudo–Kayser-Fleischer corneal rings) resulting in visual impairment.

• Table 67–2 lists the clinical abnormalities or 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 are used 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.

• Serum and urine light chain assays may be useful.

• 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 67–1).

• IgG occurs in 70% of people, IgM in 15%, and IgA in 10%. A few percent have biclonal or triclonal Ig proteins or solely monoclonal light chains in the plasma and 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 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 less than 5%.

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

• 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.

• Oligoclonal immunoglobulins are detected by high-resolution electrophoresis in patients with acute-phase reactants or polyclonal hyperglobulinemia.

• These immunoglobulins are frequent in the CSF of patients with neurologic conditions (eg, multiple sclerosis).

• Serum oligoclonal or monoclonal immunoglobulins occur in patients with the acquired immunodeficiency syndrome (AIDS).

Occurrence, Clinical, Laboratory, and Pathologic Findings

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

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

• Approximately 10% 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, 9th ed, Chap. 107, 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 (1) mild with minor motor and/or sensory signs with or without mild functional impairment; (2) moderately disabling but with full range of activities; or (3) severely disabling, interfering with walking, dressing, and 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; and 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: (1) intravenous IgG; (2) glucocorticoids; (3) immunoabsorption of perfused blood with staphylococcal protein A; (4) plasma exchange or plasmapheresis; (5) immunosuppressive cytotoxic chemotherapy with cyclophosphamide, fludarabine, or chlorambucil with or without glucocorticoids; (6) rituximab; and (7) high-dose cytotoxic therapy with autologous hematopoietic stem cell rescue.

• Plasma exchange (acute benefit) followed by immunosuppressive chemotherapy (chronic benefit) is a sequence sometimes 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 67–3).

• Because the incidence of essential monoclonal gammopathy increases with age, other disorders that increase with age may be expected to coassociate 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 exists.

• Obesity has been associated with an increased incidence of essential monoclonal gammopathy (and myeloma).

• 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 do not have progression (clonal evolution) during their lifetime.

  — Although studies have shown some variables at diagnosis that may predict for earlier progression in groups of patients (eg, higher marrow plasma cell concentrations, higher monoclonal Ig levels, lower levels of polyclonal Ig, abnormal serum light chain ratio), they are not sufficiently predictive in a single patient. In addition, there is no evidence, as yet, that early treatment for an incipient B lymphocyte neoplasm 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 (eg, acquired antithrombin) or tissue constituent (eg, neuropathy) (see Table 67–2).