Chapter 106: Essential Monoclonal Gammopathy

Marshall A. Lichtman

INTRODUCTION

SUMMARY

Essential monoclonal gammopathy is defined by two key features: (1) the presence of a monoclonal immunoglobulin or a monoclonal immunoglobulin light chain in the serum and (2) the absence of evidence for an overt malignancy of B lymphocytes or plasma cells (e.g., lymphoma, myeloma, or amyloidosis). The prevalence of essential monoclonal gammopathy depends on the demographic features in the population under study. In Americans of European descent, the prevalence increases from approximately 2 percent in individuals 50 years of age to approximately 7 percent in octogenarians. It is two to three times as prevalent in persons of African descent. The condition has been reported in association with a large variety of disorders, especially nonlymphocytic cancers. These coincidences are thought, in most cases, to be the chance concurrence of conditions that have a high prevalence in older persons. Some cases of essential monoclonal gammopathy are symptomatic because in those cases the immunoglobulin can interact with plasma proteins, blood cells, kidney, ocular structures, or neural tissue and cause serious dysfunction, for example, an acquired bleeding disorder, renal insufficiency, or an incapacitating neuropathy. In such cases, disability may be so great that attempts to remove the immunoglobulin by plasmapheresis and to suppress its production using immune or cytotoxic therapy can be warranted. Because myeloma or lymphoma may emerge at the time the monoclonal immunoglobulin is first detected, periodic evaluation of the patient is required to ascertain if essential monoclonal gammopathy is the appropriate diagnosis. Long-term followup at appropriate intervals is prudent to detect conversion from a stable, asymptomatic condition to a progressive lymphoma or myeloma, which occurs in approximately 0.5 to 1.0 percent of cases per year. In the absence of a symptomatic gammopathy or evolution to a progressive clonal gammopathy, periodic followup is all that is required.

Acronyms and Abbreviations

CD, cluster of differentiation; HLA, human leukocyte antigen; Ig, immunoglobulin; IL, interleukin.

DEFINITION AND HISTORY

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The syndrome of essential monoclonal gammopathy has two important characteristics. The first feature is a plasma immunoglobulin (Ig) or Ig light chain that has the molecular features of the product of a single clone of B lymphocytes or plasma cells: homogeneous electrophoretic migration and a single light-chain type. The second feature is the absence of evidence of an overt neoplastic disorder of B lymphocytes or plasma cells, such as lymphoma, myeloma, macroglobulinemia, or amyloidosis.

The observations that Bence Jones proteinuria could precede the clinical signs of multiple myeloma by many years¹ and that hyperglobulinemia without evidence of multiple myeloma could occur in some patients² antedated the concept of monoclonal gammopathy as a syndrome. With the more frequent clinical application of zonal electrophoresis of plasma proteins during the 1950s and 1960s, patients were discovered who had a monoclonal Ig, either without an associated disease or with diseases such as nonlymphoid cancers, infections, and inflammatory disorders, which typically are not associated with a monoclonal proliferation of B lymphocytes.^{3,4,5,6,7,8,9,10} The presence of a monoclonal Ig or monoclonal free light chain in serum, if it is not associated with an overt neoplastic disease of lymphocytes, is referred to as essential monoclonal gammopathy. Several synonyms for the syndrome have been used, particularly monoclonal gammopathy and benign monoclonal gammopathy.⁶ Monoclonal gammopathy of unknown significance (MGUS) has become fashionable as a designation preferable to benign monoclonal gammopathy because approximately one quarter of patients eventually progress to myeloma, macroglobulinemia, amyloidosis, or a B-cell lymphoma over decades of observation.^10,11,12 The suffix “of unknown significance” was justified, it was argued, because one did not know in whom or when the progression might occur. Now the term “monoclonal gammopathy of renal significance” has been coined, arguing that in this case the monoclonal gammopathy is of significance. However, other organs (e.g., nerves, eyes, bones), plasma proteins, and blood cells, as well as kidneys, may be injured or inactivated by a monoclonal protein (see “Functional Impairment from a Monoclonal Protein” below) and we will have to have (an unnecessary) proliferation of such designations. The term essential monoclonal gammopathy seems best, because it neither highlights a benign process nor indicates that the risks of subsequent lymphoma or myeloma are unknown; that risk is universally appreciated. It is unnecessary to assign the postscript “of unknown significance” to the numerous well-defined benign neoplasms at risk of clonal evolution and progression, such as colonic adenomatous polyps, other adenomas, uterine leiomyomas, monoclonal B-cell lymphocytosis, and clonal sideroblastic anemia. Biologically, essential monoclonal gammopathy is one of many such well-defined examples of a stable (“benign”) neoplasm with the potential to evolve through the acquisition of additional somatic mutations to a progressive neoplasm. More is known about its significance and pathobiology than perhaps any other benign neoplasm with a risk of clonal evolution to a malignant state.¹² As in all diseases, the physician should understand its pathobiology and act accordingly.

Table 106–1 presents an immunologic classification of essential monoclonal gammopathy.

Table 106–1.Types of Monoclonal Immunoglobulin Synthesized By B-Cell Clone in Essential Monoclonal Gammopathy

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Table 106–1. Types of Monoclonal Immunoglobulin Synthesized By B-Cell Clone in Essential Monoclonal Gammopathy

Serum IgG, IgA, IgM,^{6,7,8,9,10,11,12} IgE,⁶³ IgD^64,65,66

Serum IgG + IgA, IgG + IgM, IgG + IgA + IgM^67,68,69,70

Serum Monoclonal κ or λ light chain^*^71,97

^*Urinary monoclonal immunoglobulin light chain excretion (Bence Jones proteinuria) may accompany serum monoclonal light chain.

EPIDEMIOLOGY

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Monoclonal gammopathy can occur at any age, but it is unusual before puberty, and its frequency increases with age.^14,15 The frequency of a serum paraprotein using zonal electrophoresis is approximately 1 percent in persons older than age 25 years,⁴ approximately 3 percent in those older than age 70 years,^4,9 and approximately 10 percent in those older than age 80 years.³ A much higher prevalence of monoclonal gammopathy has been reported using more sensitive screening methods, such as isoelectric focusing or immunoblotting.^16,17 Prevalence rates differ in different geographic areas and have been somewhat lower in the United States (Minnesota),¹⁵ Iceland,¹⁸ and the Netherlands.¹⁹ The frequency of monoclonal gammopathy is less in Japanese^20,21 and Chinese.²² The prevalence rate among Africans²³ and Americans of African descent^{15,24,25,26,27} is significantly greater than the rate among those of European descent in each comparative age group. Males are more frequently affected than females. Familial occurrence also has been described.^28,29,30,31 An increased incidence of monoclonal gammopathy may be associated with several occupational groups, including farmers and industrial workers, but such associations are not firmly established.³² There is a higher frequency of monoclonal gammopathy among inhabitants of Nagasaki, Japan who were younger than age 20 years when exposed to high doses of radiation from the atomic bomb detonation in 1945 than among inhabitants with lower or no exposure or older than 20 years at time of exposure.²¹

There is a positive association of being overweight or obese with the incidence of a monoclonal gammopathy³³ and a similar positive association exists with the incidence of or mortality from myeloma.^34,35,36

ETIOLOGY AND PATHOGENESIS

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Monoclonal gammopathy can be compared with any benign tumor, such as a colonic adenomatous polyp, which can remain the same size indefinitely or undergo malignant transformation at an unpredictable future time.

Monoclonal gammopathy is caused by the proliferation of a single B lymphocyte, a plasma cell progenitor, leading to a clonal population that reaches a steady-state at approximately 1 to 5 × 10¹⁰ cells. At this cell-population density, marrow lymphocyte or plasma cell prevalence is indistinguishable from that of normal marrow. IgG and IgA monoclonal gammopathy arise from somatically mutated postswitch preplasma cells and may have translocations involving the Ig heavy-chain region on chromosome 14. IgM monoclonal gammopathy arises from a mutated postgerminal center lymphocyte that does not have evidence of isotype switching.³⁷ Not surprisingly, these origins determine the phenotype of the clonal B-lymphocytic diseases that may evolve. For example, IgG or IgA monoclonal gammopathy tend to evolve into myeloma or plasmacytoma (plasma cell phenotypes) and IgM monoclonal gammopathies tend to evolve into lymphomas and Waldenström macroglobulinemia (lymphocytic phenotypes).

The expanded clone secretes monoclonal Ig at a rate per cell sufficient for detection by standard tests. The clonal expansion, however, does not cause osteolysis, hypercalcemia, inhibit hematopoietic proliferation and maturation, or impair differentiation of polyclonal B lymphocytes to plasma cells. Polyclonal Ig synthesis usually is normal, and patients do not incur an increased risk of infection. The cells in the stable (benign) clone do not accumulate further and do not elaborate significant amounts of osteoclast-activating factors that are responsible for bone destruction.

Despite these significant differences from myeloma in the behavior of the neoplastic B cells, cytogenetic abnormalities akin to those seen in myeloma may be present in plasma cells derived from patients with essential monoclonal gammopathy.^37–47 G-banding cytogenetic evaluation usually is normal in patients with monoclonal gammopathy, presumably related to the unavailability of cells in the cell cycle (metaphase). However, clones containing numerical abnormalities (e.g., trisomy or monosomy) and translocations have been identified with fluorescence in situ hybridization of interphase cells (see “Cytogenetic Analysis” below). The presence of clonal cytogenetic changes does not necessarily predict clonal evolution and progression. It was initially thought that 25 to 30 percent of patients with myeloma had an identified antecedent period of essential monoclonal gammopathy which underwent clonal evolution to myeloma^43,46; whereas more recent studies suggest that an antecedent period of monoclonal gammopathy may precede all patients who develop myeloma.^48,49 The presence of clonal cytogenetic abnormalities does not correlate with such evolution, however.^37,38,45 Gene-expression studies of plasma cells isolated from normal marrow and marrow from patients with essential monoclonal gammopathy have identified several hundred genes that are differentially expressed.^50,51 The predominate finding was a gradient of overexpression of 41 of 52 genes studied in plasma cells from normal subjects, from patients with monoclonal gammopathy, and from patients with myeloma, respectively.⁵¹ In addition, myeloma patients could be stratified into those with gene-expression profiles that were more or less similar to that of essential monoclonal gammopathy. The group more similar to monoclonal gammopathy constituted approximately 30 percent of myeloma patients.

Americans of African descent have a much higher frequency of an autosomal dominant inherited risk factor for monoclonal gammopathy and myeloma. Hyperphosphorylated paratarg-7 (pP-7) results from an inability to inactivate protein phosphatase 2A, which leads to the inability to dephosphorylate p-7 at serine 17. The pP-7 carrier state is associated with an increased risk of monoclonal gammopathy and myeloma. The carrier state is more than twice as prevalent in Americans of African descent as those of European descent and is much less prevalent in Americans of Asian descent than those of European descent, a gradient similar to the incidence of monoclonal gammopathy in those populations.⁵²

Common single nucleotide polymorphisms at 2p23.3(rs6746082), 3p22.1(rs1052501), 3q26.2(rs10936599), 6p21.33(rs2285803), 7p15.3 (rs4487645), 17p11.2(rs4273077), and 22q13.1(rs877529) are associated with increased risk of myeloma. Similarly these polymorphisms independently increased the risk of monoclonal gammopathy. Polymorphism associations were independent; risk increased with a larger number of risk alleles carried, supporting a polygenic model of disease susceptibility to monoclonal gammopathy and, therefore, to myeloma.⁵³

MYD88 L265 is a somatic mutation found in approximately 50 percent of individuals with IgM monoclonal gammopathy and in more than 90 percent of patients with Waldenström macroglobulinemia. It is thought to represent an early oncogenic event in monoclonal gammopathy contributing to evolution to macroglobulinemia.^54,55

The C57BL mouse provides a model of essential monoclonal gammopathy. The frequency of monoclonal gammopathy increases with age in these mice.⁵⁶ The gammopathy can be transferred to either irradiated or nonirradiated mice by marrow or spleen cells.⁵⁷ The transfer can be accomplished only during the first four consecutive transplantations, and no effect is seen on the survival of the recipient compared with that of appropriate control animals. In contrast, if mouse B-cell lymphoma or myeloma cells are transplanted into normal mice, the engraftment frequency is higher than that of B cells from mice with essential monoclonal gammopathy. Passage from the original recipient to a new recipient is unlimited. Progressive disease develops, and survival of the recipient animals is impaired. Thus, an intrinsic difference exists in the growth potential (degree of malignancy) of these B-cell clones.⁴³ The frequency of monoclonal gammopathy increases with age, but progression to myeloma in the C57BL mouse is a rare event.⁵⁸ Studies in transgenic mice and their litter mates replicate the increased incidence of B-cell clones and gammopathy with aging.⁵⁹

Occasionally, monoclonal gammopathy is the result of exaggerated production of natural antibody by a B-lymphocyte clone.⁶⁰ For example, patients with cold agglutinins may have monoclonal IgM for years. A few monoclonal IgM antibodies act as rheumatoid factors and may form cryoglobulins through complex formation with IgG molecules.

CLINICAL FEATURES

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BLOOD CELLS AND MARROW

Blood counts and the marrow examination are normal. Notably anemia is not present and the proportion of plasma cells in marrow is less than 10 percent. Although an increased percent of plasma cells is the most constant morphologic feature of myeloma, the presence of cytologic atypia as judged by frequent binucleate plasma cells and large plasma cell nucleoli are findings more specific for myeloma.⁶¹ Quantitative microscopy of the number of marrow microvessels per high-power field, using immunohistochemistry, indicates microvessel density on average is threefold greater than in normal persons, but far less than in patients with myeloma, although some overlap with myeloma occurs.⁶²

CYTOGENETIC ANALYSIS

Hyperdiploidy, assessed by DNA content, is present in about half the cases and hypodiploidy is present in approximately 10 percent of cases of monoclonal gammopathy.⁴² Use of interphase fluorescence in situ hybridization has uncovered numerical chromosome abnormalities in the plasma cells of more than 50 percent of subjects. Clones containing trisomy or monosomy involving chromosomes 3, 6, 7, 9, 11, 13, 17, and 18 have been identified.^{38,39,40,41,44,45} Deletions of 13q14 are present in about one-quarter of patients and abnormalities involving 14q32, the site of the Ig heavy-chain genes, are present in approximately 60 percent of subjects.^38,39,40,41 Chromosomal changes do not appear to be correlated with progression.

MONOCLONAL PROTEIN

Characteristically, individuals are detected by the unexpected identification of a monoclonal IgG or light chain in the serum in the absence of symptoms or signs (e.g., anemia, marrow plasmacytosis, lymph node enlargement, plasmacytoma, bone lesions, or amyloid deposits) caused by diseases associated with monoclonal proteins.^{6,7,8,9,10,60,63–71} Although classically a serum Ig or urine monoclonal light chain was the standard for diagnosis, the ability to measure serum free light chains with high specificity and sensitivity has replaced the necessity to measure urine light chain excretion for diagnosis as the latter is less sensitive than the former.⁷²

Monoclonal IgG gammopathy occurs in approximately 70 percent of persons and IgM and IgA in approximately 20 percent and 10 percent, respectively. A few percent of persons may have biclonal or triclonal gammopathy (see Table 106–1).^{6,7,8,9,10,12,60,63–71}

Most patients with essential monoclonal gammopathy have a monoclonal protein concentration of less than 30 g/L, but exceptions occur. The diagnosis reflects the sum of (1) the monoclonal protein level, (2) the marrow plasma cell concentration (<10 percent), (3) the absence of other features of progressive plasma cell neoplasm (e.g., hypercalcemia, osteolysis, otherwise unexplained anemia, otherwise unexplained renal disease), and (4) the absence of progression on periodic long-term followup.

A developing consensus favors measurement of serum protein gel electrophoresis and serum free light chain levels (and the κ:λ ratio), and serum protein immunofixation electrophoresis without urinary Ig measurements to detect monoclonal gammopathies.^73,74,75 Some pathologists are still reluctant to give up urinary measurements because of the uncommon occurrence of urinary monoclonal light chains in the absence of evidence of an abnormality of serum monoclonal light chains.⁷⁶ Followup of these cases has not shown any clinical consequence of these uncommon false-negative serum light-chain measurements. Serum protein gel electrophoresis has a limit of detection of approximately 0.03 g/dL, if the monoclonal protein migrates in the γ-globulin fraction. Small monoclonal proteins that migrate in the α- or β-globulin fraction are more difficult to identify on electrophoresis. Immunofixation electrophoresis is used to confirm a monoclonal protein found on gel electrophoresis. Immunofixation electrophoresis may also detect a monoclonal protein not evident on serum protein gel electrophoresis, usually because the protein is in too low a concentration or is embedded in the normal polyclonal α- or β-globulin peak. Monoclonal proteins identified by immunofixation electrophoresis may be transient (approximately 15 to 20 percent) and have a greater likelihood to progress to a disease if they are of an IgA or IgM isotype.⁷⁷ In the future, mass spectroscopy may be a more sensitive and specific method to identify monoclonal proteins.⁷⁸

In individuals with a serum monoclonal IgG of less than 1.5 g/dL, especially if of an older age and with no overt end-organ abnormality, marrow examination and radiographic examination of the bones have a very low diagnostic yield and can be omitted. A presumptive diagnosis of essential monoclonal gammopathy can be made with reexamination at approximately 6 months and at appropriate intervals, thereafter.^79,80

FUNCTIONAL IMPAIRMENT FROM A MONOCLONAL PROTEIN

Interaction with Plasma Protein or Blood Cells

Some patients have monoclonal proteins with antibody specificity directed against plasma or cell proteins, resulting in symptomatic pathophysiologic effects, such as immune hemolytic anemia,⁸¹ acquired von Willebrand disease,^82,83,84 immune neutropenia,^85,86 and other functional manifestations^{87,88,89,90,91,92} (Table 106–2).

Table 106–2.Functional Abnormalities Associated with Essential Monoclonal Gammopathy

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Table 106–2. Functional Abnormalities Associated with Essential Monoclonal Gammopathy

Plasma protein and blood cell disturbances

Antierythrocyte antibodies,⁸¹ acquired von Willebrand disease,^82,83,84 immune neutropenia,^85,86 cryoglobulinemia,¹⁰ cryofibrinogenemia,¹⁰ acquired C1 esterase inhibitor deficiency (angioedema),¹⁰ acquired antithrombin,⁸⁷ insulin antibodies,^88,89 antiacetylcholine receptor antibodies,⁹⁰ “antiphospholipid” antibodies,⁹¹ dysfibrinogenemia⁹²

Renal disease^93–100

Oculopathies^{102,103,104,105,106}

Neuropathies^{107,108,109,110,111}

Deep venous thrombosis^136,137

Renal Injury

Occasional patients may have severe renal disease associated with monoclonal gammopathy.^{93,94,95,96,97,98,99,100} The renal disease my take the form of a tubular disorder, mimicking Fanconi syndrome (glycosuria, hypouricemia, proteinuria, asymptomatic renal insufficiency)^93,96 or a glomerular deposition disorder resulting from the deleterious interaction of the monoclonal Ig or a light chain and the renal parenchyma resulting in renal insufficiency.^94,95,97,100 The term “dangerous small B-cell clone” has been applied to a monoclonal gammopathy that can produce disease, often quite serious, without lymphoproliferation and progression of the neoplastic cell population. The principal approach to therapy is to attempt to suppress the small B-cell clone and, thereby, its monoclonal protein secretion with chemotherapy. Cyclophosphamide, thalidomide, bortezomib, or bendamustine are favored because they have much less renal toxicity than congeners such as melphalan or lenalidomide. A glucocorticoid and rituximab can, also, be useful.^100,101 One should also consider the possibility that the monoclonal protein may be secreted by a solitary plasmacytoma, which would be amenable to local radiation therapy. Thus, in the face of significant renal impairment a careful evaluation, including positron emission tomography, should be considered to exclude a solitary lesion. In exceptional cases, ablative therapy with an autologous hematopoietic stem cell transplant may be considered.¹⁰¹

Ophthalmic Injury

Corneal deposits of crystalline Ig^102,103 and a monoclonal copper binding Ig resulting in copper deposits in the eye,^104,105 each associated with classical monoclonal gammopathy, have led to loss of visual acuity. Remarkably, despite very high serum copper levels in the latter cases, no other organ damage ensued. Iritis, vitritus, and maculopathy with loss of visual acuity have also been described in association with a monoclonal gammopathy.¹⁰⁶

NEUROPATHIES

Frequency of Occurrence

A significant association exists between the incidence of neuropathies and essential monoclonal gammopathy.^{107,108,109,110,111,112,113,114} Approximately 10 percent of patients with idiopathic neuropathy have a monoclonal Ig, a frequency about eight times that of age-adjusted healthy comparison groups.^{107,108,109,110,111} The frequency of neuropathy among patients with monoclonal gammopathy varies depending on the distribution of Ig classes, but is in the range of 3 to 5 percent. IgM monoclonal gammopathy has a significantly higher frequency of neuropathy than does IgG or IgA monoclonal gammopathy.^107,108

Mechanisms of Nerve Damage

Monoclonal antibodies, especially IgM, can react with peripheral nerve myelin, specifically with myelin-associated glycoprotein, glycolipids, or sulfatides.^{112,113,114,115,116,117} Although various antinerve antibodies are present in approximately 40 percent of patients with neuropathy and IgG monoclonal gammopathy, a similar frequency has been found in such patients without neuropathy.¹¹⁸ Neuropathy in the absence of reactivity of the monoclonal protein with nerve antigens implies other mechanisms also operate to cause nerve damage.^107,109,116 Deposition of monoclonal protein in the epineurium has been proposed as an alternative mechanism of nerve injury.¹¹⁹ Also, in one report, four of 16 patients with IgG monoclonal gammopathy and neuropathy had polyclonal, not monoclonal, antibodies against neurofilament protein.¹¹⁶ In addition, a proportion of patients develop a detectable monoclonal protein after the onset of the neuropathy, sometimes years later.¹¹⁸

Signs and Symptoms

Patients with essential IgM monoclonal gammopathy and neuropathy can have dysesthesia of the hands and feet, loss of vibration and position sense, atrophy of distal muscles, ataxia, and intention tremor.^114,115,117 The monoclonal antibodies reactive with nerve antigens usually are of the IgM type. Serum often contains antibodies to myelin-associated glycoprotein.^107,108 In contrast, patients with IgG or IgA monoclonal gammopathy usually have chronic inflammatory demyelinating polyneuropathy; a minority have sensory axonal or mixed neuropathy.^{108,118,120,121,122} The neuropathy may be (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.¹¹⁸ The course may be relapsing and remitting or progressive. IgA gammopathy is associated with dysautonomia.¹²³ The presence or absence of antibody to myelin-associated glycoprotein may have an effect on the specific nature of the neuropathic manifestations.^{108,109,114,115,116,117}

Diagnostic Findings

Demyelinization is reflected in decreased nerve conduction velocity. Axonal loss is reflected in decreased sensory potentials.^{109,113,114,120,121,122,123,124} Electromyography may show denervation of muscles.^109,113 Immunofluorescence studies of sural nerve or of skin biopsies may uncover Ig binding to nerve.^109,114 Morphologic studies of nerve biopsies may show decreased or absent myelinated fibers or axonal degeneration. A rare case of crystal formation in the epineurium has been described.¹²⁵

Management

At least seven treatment approaches have been used to ameliorate the neuropathies: (1) intravenous Ig administration; (2) glucocorticoids alone; (3) immunoadsorption of perfused blood with staphylococcal protein A; (4) plasma exchange or plasmapheresis; (5) immunosuppressive cytotoxic chemotherapy, such as cyclophosphamide, chlorambucil, or fludarabine with or without added glucocorticoids; (6) rituximab (anti–cluster of differentiation [CD]20 antibody) to deplete B cells; and (7) high-dose cytotoxic therapy with autologous hematopoietic stem cell rescue.^{107,108,109,117,118,124,126–135} In some cases, use of plasmapheresis has been followed by cytotoxic therapy in an effort to produce a sustained effect. Plasma exchange has shown benefit in a small clinical trial. The other modalities of treatment await such studies.¹⁰⁷ Response rates to each form of therapy are low and duration of response is variable,^{109,118,126,127,128,129,130,131} but some patients obtain coincidental significant improvement for prolonged periods. A recommendation has been made to start therapy with intravenous Ig, especially in essential monoclonal IgM-associated neuropathy, because of the relative safety of this approach.¹⁰⁷ Mild symptoms and signs may not be an indication for treatment because of the low response rate and the potential noxious effects of therapy.¹⁰⁷

COINCIDING DISORDERS

Monoclonal gammopathy unrelated to a clinically evident proliferation of B lymphocytes or plasma cells has been observed in association with a wide variety of conditions (Table 106–3).^136–201 Although they are grouped under the designation monoclonal gammopathy with a coincidental disease, few such reports have examined whether the coincidence is greater than expected in a control group matched for age and ethnicity, the two variables having the greatest impact on the incidence of monoclonal gammopathy. Non–B-cell malignancies, including solid tumors,^{3,5,6,18,178,179,180,181} myeloproliferative disorders,^{182,183,184,185,186,187,188,189} and Hodgkin and T-cell lymphomas,^{190,191,192,193} are associated with monoclonal Ig. These relationships could result from various factors: (1) patients with a monoclonal Ig have an increased risk of developing cancer; (2) the monoclonal Ig is an antibody against some antigen associated with the cancer; (3) the monoclonal Ig is the product of cancer cells; or (4) coincidence. The last possibility is favored by two epidemiologic studies that found the same frequency of monoclonal gammopathy in a matched control group as in cancer patients.^9,18 Furthermore, when the monoclonal Ig is associated with a cancer, it usually persists after successful resection of the tumor. A convincing case for an association of acute myelogenous leukemia and myelodysplasia with monoclonal gammopathy was made by one group of scientists^183,184 but a large longitudinal study did not find this association.¹² Some observers propose that in clonal myeloid diseases the monoclonal protein reflects B-cell lineage involvement.

Table 106–3.Disorders Reported in Coincidence with Monoclonal Gammopathy

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Table 106–3. Disorders Reported in Coincidence with Monoclonal Gammopathy

Axial bone fracture^138,139

Connective tissue diseases and autoimmune diseases: Crohn disease, cryoglobulinemia, Hashimoto thyroiditis, lupus erythematosus, myasthenia gravis, pernicious anemia, polymyalgia rheumatica, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren disease^140–149

Corneal and other ocular diseases: pseudo–Kayser-Fleischer ring,²⁴³ corneal gammopathy^{102,103,104,105,106,244}

Cutaneous diseases: Schnitzler syndrome, urticaria, hyperkeratotic spicules, pyoderma gangrenosum (neutrophilic dermatoses), psoriasis, scleromyxedema^{150,151,152,153,154,155,156}

Diffuse idiopathic skeletal hyperostosis¹⁵⁷

Endocrine diseases: hyperparathyroidism^158,159

Gaucher disease, type I^160,161,162

Hepatic disease: cirrhosis,¹⁴⁸ hepatitis,^163,164

Hereditary spherocytosis¹⁶⁵

Infectious diseases: bacterial endocarditis, Corynebacterium species, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, Mycobacterium tuberculosis, purpura fulminans^{19,148,166,167,168,169,212,215}

Metabolic disease: hyperlipidemia¹⁷⁰

Neutropenia, chronic^85,86,171

Osteoporosis^172,174,175

Pituitary macroadenoma¹⁷³

Pregnancy¹⁷⁴

Systemic capillary leak syndrome¹⁷⁷

Carcinomas: colon, lung, prostate, other^{3,5,6,178,179,180,181}

Myeloproliferative diseases: acute and chronic myelogenous leukemia,^182,183,184 chronic neutrophilic leukemia, polycythemia vera^{185,186,187,188,189}

T-cell lymphomas, Hodgkin lymphoma^{190,191,192,193}

After chemotherapy, radiotherapy, or marrow, kidney, or liver transplantation^{194,195,196,197,198,213,214,215}

Miscellaneous diseases^200,201,202

Transient, monoclonal, or oligoclonal gammopathies^204,205,206

Factitious hyperferremia²⁰⁷

Factitious increase in C-reactive protein²⁰⁸

Vitamin B₁₂ deficiency^140,209

Chemotherapy, radiotherapy, organ or marrow transplantation,^{194,195,196,197,198,199} and other miscellaneous disorders^{5,7,10,24,25,26,147,148,200,201,202} are associated with a transient or persistent monoclonal Ig (see Table 106–3). The high prevalence of monoclonal proteins and associated diseases, especially after age 50 years, indicates some of these associations are coincidental. Thus, although surgical correction of hyperparathyroidism is associated with disappearance of the plasma monoclonal protein,¹⁵⁸ statistical studies of this disorder suggest a coincidental relationship in most patients.¹⁵⁹ Gaucher disease type I has a higher-than-expected frequency of polyclonal (approximately 40 percent) and monoclonal (approximately 20 percent) gammopathy, and, probably, of myeloma.^160,161,162 Elaboration of proinflammatory cytokines, growth factors, and chemokines, several involved in B-cell function, is disturbed in type I Gaucher disease. An increase of interleukin (IL)-10 and pulmonary and activation-regulated chemokine is notable. A high frequency of B-cell clonality and IgH gene rearrangements have also been described.¹⁶² The administration of recombinant glucocerebrosidase therapy may decrease the occurrence and progression of gammopathies.¹⁶¹

In inflammatory, autoimmune, and infectious diseases, the association is viewed as an unusual expansion of a restricted population of B lymphocytes. Following marrow transplantation, the presence of oligoclonal blood B-lymphocyte populations often reflects the process of reconstitution of the B-cell population.

LABORATORY FEATURES

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PLASMA AND URINARY MONOCLONAL IMMUNOGLOBULINS

The monoclonal protein usually is an IgG; however, IgM, IgA, IgD, and IgE, urinary light chains, double gammopathy involving IgA and IgG or IgM and IgA, and triple gammopathy can occur. Rare cases may have the isotype IgD or IgE (see Table 106–1).^{12,63,64,65,66,178,203} By definition, no findings other than a serum monoclonal Ig or monoclonal light chain is present with no other features of a B-lymphocyte or plasma cell malignancy.

In monoclonal gammopathy of the IgG type, the concentration of monoclonal Ig usually is less than 3 g/dL. In the IgA or IgM type, the concentration usually is less than 2.5 g/dL.^10,12,203 However, dramatic exceptions to this rule exist. Occasional patients with essential monoclonal gammopathy have concentrations as high as 6 g/dL. Some patients have urinary monoclonal light chain excretion (Bence Jones proteinuria) as the sole manifestation of monoclonal gammopathy.^1,10 The amount of urinary light chains excreted occasionally is so large (>1.0 g/day) that renal dysfunction may develop.^93,96,97

Most patients with myeloma or macroglobulinemia have significantly depressed nonmonoclonal Ig levels. For example, patients with IgG myeloma usually have very low IgA and IgM concentrations and a reduced polyclonal IgG level. Patients with monoclonal gammopathy usually have normal polyclonal Ig levels; and, if a decrease of their polyclonal Ig levels is present, it is usually not as severe as in myeloma.^{10,12,203,210}

Depression of normal polyclonal immunoglobulin concentrations is considered one of several factors that may portend the likelihood of progression to a B-cell malignancy.

OLIGOCLONAL IMMUNOGLOBULINS

Oligoclonal or monoclonal serum Ig levels have been detected with high-resolution agarose gel electrophoresis in hospitalized patients with acute-phase reactions or polyclonal hyperglobulinemia.²⁰⁶ Oligoclonal Ig bands are frequently seen in the cerebrospinal fluid and serum of patients with a variety of neurologic conditions, especially multiple sclerosis, when the fluids are analyzed by isoelectric focusing.²¹¹ Patients with AIDS have B-cell activation and aberrancies of B-cell regulation. High-resolution electrophoresis indicates most AIDS patients with advanced disease have monoclonal or oligoclonal serum Ig bands. Persons with AIDS, lymphadenopathy syndrome, or antibody to the human immunodeficiency virus also have oligoclonal or monoclonal Ig bands by standard zonal electrophoresis.^167,168 These monoclonal proteins are typically IgG. In about half the patients with AIDS who receive antiviral therapy the monoclonal protein disappears by 5 years of treatment.²¹² Oligoclonal or monoclonal serum Ig has also been associated with Epstein-Barr virus infection and in patients after liver,²¹³ heart,²¹⁴ and marrow transplantation.²¹⁵

LYMPHOCYTE AND PLASMA CELL PHENOTYPES

The concentration of plasma cells in the marrow is less than 10 percent, and the incorporation of tritiated thymidine into marrow plasma cells is negligible (<1 percent) in essential monoclonal gammopathy. Marrow plasma cells in monoclonal gammopathy do not express neural cell adhesion molecule (CD56), whereas myeloma cells strongly express this surface protein.²¹⁶ Blood T-lymphocyte subset levels are normal in monoclonal gammopathy, whereas CD4+ T-cell levels are lower and CD8+ T-cell levels higher in myeloma and macroglobulinemia.^{217,218,219,220} Blood B-cell concentration is normal in monoclonal gammopathy, but often is decreased in myeloma patients. Clonally restricted, idiotype-positive blood B cells are characteristic of myeloma but not of monoclonal gammopathy.²²¹

β₂-Microglobulin is the light chain of cell surface human leukocyte antigen (HLA) molecules and is present in low concentrations in normal serum. Its concentration in serum frequently is elevated in myeloma, and the magnitude of the elevation is positively correlated with tumor mass. β₂-Microglobulin concentration is not elevated in essential monoclonal gammopathy.^222,223

The distinction between stable essential monoclonal gammopathy and emerging (so-called “larval” myeloma) or low-infiltrate myeloma (so-called “smoldering” myeloma) with a very low tumor burden is not easily discerned except by following the patient’s clinical status. This finding has not kept investigators from looking for a distinguishing test. More than 40 variables have been studied as an index for discriminating a stable (benign) from progressive (malignant) clone (Table 106–4). No single test is sufficiently sensitive and specific to be useful in an individual patient. Periodic examination of the patient is the best method for detecting the emergence of myeloma or lymphoma or a related disease. Measurement of the concentration of the serum monoclonal protein, serum polyclonal proteins, serum free Ig light chains, serum β₂-microglobulin, and hemoglobin concentration at appropriate intervals is required. The marrow should be reexamined if the monoclonal protein level increases or hemoglobin concentration decreases significantly. Practical and sensitive methods for measuring bone density would be an additional useful measure of stability or progression.

Table 106–4.Variables Used in an Attempt to Distinguish Essential Monoclonal Gammopathy from Myeloma or Lymphoma

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Table 106–4. Variables Used in an Attempt to Distinguish Essential Monoclonal Gammopathy from Myeloma or Lymphoma

LYMPHOCYTES AND IMMUNOGLOBULINS

Igκ light-chain expression²⁴⁵

Ig light chains in urine²⁴⁵

Polyclonal Ig serum concentration²⁴⁵

β₂-Microglobulin or C-reactive protein serum concentration²⁴⁶

Ig-secreting cells in blood²⁴⁷

Idiotype-reactive blood T lymphocytes^248,249

CD4-to-CD8 lymphocyte ratio in blood or marrow^217,250,251

Clonally restricted B lymphocytes^{221,252,253,254}

Immunofluorescence of lymphocytes²¹⁸

Natural killer cell frequency²⁵⁵

PLASMA CELLS

Frequency^{6,7,9,10,15,203}

Morphology^{219,256,257,258}

MB2 antibody reactivity²⁵⁹

Proliferative index^{219,220,250,256,260}

Asynchronous replication²⁶¹

DNA content or interphase fluorescent in situ hybridization^{38,39,43,219,256}

Gene-expression profile^51,237

Ratio of monoclonal CD19–/CD38+/CD56++ to polyclonal CD19+/CD38++/CD56– cells²⁶²

Blood or marrow concentration^{10,219,220,221,253}

J chains²⁶³

Acid phosphatase²⁶⁴

Multidrug resistance expression²⁶⁵

CD19 expression²⁶⁶

CD56/neural cell adhesion molecule expression²¹⁶

Proportion of CD19+/CD56– plasma cells in marrow²⁶⁷

5′ Nucleotidase²⁶⁸

BONE INTEGRITY

Magnetic resonance imaging^269,270

Dual-energy x-ray absorptiometry²⁷¹

Histomorphometry²⁷²

Urinary pyridinium-collagen complexes²⁷³

MISCELLANEOUS

Marrow microvessel density⁶²

Neural cell adhesion molecules²⁷⁴

Serum IL-1β²⁷⁵

Serum IL-6, IL-10, soluble CD16, soluble IL-6 receptor, IL-1β^{276,277,278,279,280,281}

Serum transforming growth factor-β²⁸²

Urinary deoxypyridinoline excretion rate²⁸²

Hemoglobin concentration^8,148,178

Mononuclear cell E-cadherin gene methylation²⁸³

COURSE, PROGNOSIS, AND THERAPY

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Longitudinal studies have reported three major patterns of outcome for patients with essential monoclonal gammopathy.^{10,224,225,226} Approximately 25 percent of patients do not progress to a lymphocytic neoplasm over 25 to 30 years of observation. In this group, occasional patients experience increases in monoclonal protein concentration of up to 50 percent of their initial diagnostic value. However, these patients restabilize and do not develop signs of myeloma, macroglobulinemia, amyloidosis, or lymphoma. About half of patients die of an unrelated cause over the 25- to 30-year period of observation. The remaining 25 percent of patients develop a plasmacytoma, myeloma, amyloidosis, macroglobulinemia, lymphoma, or chronic lymphocytic leukemia over several decades of observation. The occurrence of a lymphoma or myeloma in the latter group of patients continues to increase slowly without reaching a plateau. Evolution to a progressive clonal B-cell disorder has been observed more than 25 years after the diagnosis of monoclonal gammopathy. The actuarial risk of progressing to a clonal B-cell malignancy for all classes of monoclonal protein is approximately 0.5 to 1.0 percent per year depending on the population studied.^{12,224,225,226} IgM gammopathy usually progresses to lymphoma, macroglobulinemia, amyloidosis, or chronic lymphocytic leukemia.²²⁷ Although one large study found that IgM monoclonal gammopathy evolved to a progressive clonal lymphoid disorder at a rate of approximately 1.5 percent per year,²²⁸ two other large studies found no significant difference in the rate of progression when patients with IgG or IgM were compared.^229,230 IgG or IgA monoclonal gammopathy evolves principally into myeloma, plasmacytoma, or amyloidosis.^231,232 Several studies have found a somewhat higher progression rate in persons with IgA monoclonal gammopathy.^18,233

Patients with a higher percentage of plasma cells in the marrow, higher monoclonal Ig levels at the time of diagnosis, lower levels of polyclonal Ig, an elevated erythrocyte sedimentation rate, a more disturbed serum light chain ratio, a lower relative proportion of CD19+ plasma cells, and more than one focal lesion in marrow as determined by whole-body magnetic resonance imaging evolve to a progressive clonal B-lymphocyte disease more frequently.^{12,229,230,231,232,233,234,235,236} None of these variables have the specificity and sensitivity to be highly accurate in predicting the behavior of an individual patient. Neither the plasma cell gene-expression profile nor the cell population cytogenetic findings are sufficiently specific to predict progression from a stable to an unstable clone based on current studies.^41,237 These findings indicate, not surprisingly, that the qualitative leap is between normal, polyclonal plasma cells (B lymphocytes) and the emergence of a monoclonal population (either stable or progressively growing) and that the distinctions between the latter two states are subtle, complex, and as yet unidentified. In rare patients, the monoclonal protein appears transiently in relation to a disease (e.g., infection)^202,204,205 or disappears spontaneously even when not associated with a disease (clonal exhaustion).³

Generally, the diagnosis of essential monoclonal gammopathy cannot be made with certainty at the time of the initial evaluation. Periodic reexamination is required to document a stable clinical course. One of the most subtle interfaces is between essential monoclonal gammopathy and smoldering myeloma (Chap. 107). In the latter, the marrow plasma cell concentration is between 10 and 20 percent or the monoclonal protein concentration is greater than 3 g/dL or both. There is no anemia, increase in serum calcium, or evident bone or kidney disease.²³⁸ Careful observation of patients with presumed essential monoclonal gammopathy should permit identification of those who are better categorized as smoldering myeloma. Although at this time treatment is not recommended for smoldering myeloma until progression, calls for clinical trials to assess whether early treatment may improve outcome have been made.²³⁹ Therapy is not required for essential monoclonal gammopathy without a confirmed diagnosis of myeloma, macroglobulinemia, amyloidosis, or lymphoma with evidence of progressive disease. Therapy may be indicated, however, if the monoclonal protein interferes with the vital function of a normal plasma or tissue constituent, induces kidney disease, or is associated with a disabling neuropathy.

A better understanding and an ability to identify the somatic mutations that underlie the evolution of monoclonal gammopathy to a progressive and potentially fatal B-cell neoplasm may permit the application of therapy at an earlier time when curability or sustained remissions would be more frequent.^240,241,242

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Chapter 106: Essential Monoclonal Gammopathy

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INTRODUCTION

DEFINITION AND HISTORY

EPIDEMIOLOGY

ETIOLOGY AND PATHOGENESIS

CLINICAL FEATURES

BLOOD CELLS AND MARROW

CYTOGENETIC ANALYSIS

MONOCLONAL PROTEIN

FUNCTIONAL IMPAIRMENT FROM A MONOCLONAL PROTEIN

Interaction with Plasma Protein or Blood Cells

Renal Injury

Ophthalmic Injury

NEUROPATHIES

Frequency of Occurrence

Mechanisms of Nerve Damage

Signs and Symptoms

Diagnostic Findings

Management

COINCIDING DISORDERS

LABORATORY FEATURES

PLASMA AND URINARY MONOCLONAL IMMUNOGLOBULINS

OLIGOCLONAL IMMUNOGLOBULINS

LYMPHOCYTE AND PLASMA CELL PHENOTYPES

COURSE, PROGNOSIS, AND THERAPY

REFERENCES

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