Myeloma cells proliferate slowly in the marrow (Fig. 27-1; Table 27-1). Less than 1% divide at any one time and myeloma cells do not differentiate. The absolute number of these cells correlates with disease activity and predicts the progression of disease in smoldering multiple myeloma. Circulating myeloma cells may disseminate the tumor within the bone marrow and elsewhere.

Table 27-1

Three Phases of Disease Progression in Multiple Myeloma

Variable	Initial Phase	Medullary Relapse	Extramedullary Relapse
Site of myeloma-cell accumulation or proliferation	Bone marrow	Bone marrow	Blood, pleural effusion, skin, many other sites
Growth fraction^∗	<1%	≥1% (1%-95%)	≥1% (1%-95%)
Genetic or oncogenic events	Deregulation of c-myc Illegitimate switch recombinations	N-ras and K-ras point mutations	p53 point mutations
Phenotypic changes	CD19 loss CD56 overexpression	CD28 expression LFA-1 and VLA-5 loss	CD28 expression CD56 loss
Cytologic changes	Detectable plasmablastic compartment in 15% of cases	Plasmablastic compartment growing	Major plasmablastic compartment
Circulating malignant plasma cells	<1%	Increasing	Increasing

^∗Growth fraction is the rate of atypical cells proliferating in the bone marrow.

From Bataille R, Harousseau JL: Medical progress: multiple myeloma, N Engl J Med 336:1657–1664, 1997.

Figure 27-1 Mechanisms of disease progression in the monoclonal gammopathies. (Adapted from Kyle RA, Rajkumar SV: N Engl J Med 351:1860–1871, 2004.)

Interleukin-6 (IL-6) is essential for the survival and growth of myeloma cells, which express specific receptors for this cytokine. Initially identified as a growth factor for myeloma cells, IL-6 has been shown to promote the survival of myeloma cells by preventing spontaneous or dexamethasone-induced apoptosis. An increased level of IL-6 in the serum of patients with MM can be explained by the overproduction of IL-6 in the marrow. The IL-6 system also has a role in the pathogenesis of bone lesions in MM. IL-6, soluble IL-6 receptor alpha (sIL-6Rα), and interleukin-1 beta (IL-1β) activate osteoclasts in the vicinity of myeloma cells and thus initiate bone resorption. IL-6 may account for MM-associated anemia and for the lack of thrombocytopenia because of its stimulation of megakaryopoiesis.

Epidemiology

Multiple myeloma is the most common form of dysproteinemia. It accounts for 1% of all types of malignant diseases and 10% of hematologic malignancies. The age-adjusted incidence is estimated to be 5.6 cases/100,000 population/year in Western countries. About 10,000 Americans die each year from MM. In Western countries, the frequency of myeloma is likely to increase in the near future as the population ages.

The onset of MM is from 40 to 70 years, with a peak incidence in the seventh decade. It is uncommon (<2% of cases) in patients younger than 40 years. In general, patients with LCD and IgD myeloma are younger than those with IgG or IgA myeloma and have a poorer prognosis because of their high incidence of nephropathy. Males are affected in approximately 62% of cases; the male-to-female ratio is 1.6:1. In addition, blacks are affected twice as often as whites.

IgG myeloma is the most common form of MM (Table 27-2). Four subtypes of IgG heavy chains are known to exist among patients with IgG myeloma. Cases of IgG myeloma are distributed as follows: 65% are gamma G1, 23% gamma G2, 8% gamma G3, and 4% gamma G4 subclass. The only subclass-dependent difference is the greater propensity for patients with IgG3 myeloma to experience hyperviscosity syndrome, similar to the manifestation in WM.

Table 27-2

Distribution of Immunoglobulin Types in Patients With Multiple Myeloma

Type of Protein	Multiple Myeloma (%)
IgM	12
IgG	52
IgA	22
IgD	2
IgE	Rare
Light chains (kappa or lambda)	11
Heavy chains	Rare
Monoclonal proteins	<1
Nonsecretory myeloma	1

Multiple myeloma runs a progressive course, with most patients dying within 1 to 3 years. The β₂-microglobulin level at initial evaluation has been adopted as a predictor of outcome. If the serum β₂-microglobulin level is elevated at the start of therapy, the prognosis is less favorable. The major causes of death are overwhelming infection (sepsis) and renal insufficiency. In patients with sepsis, mortality exceeds 50%, despite antibiotic therapy.

Diagnostic Evaluation

Hematologic Assessment

A normochromic normocytic anemia is present in about two thirds of patients at diagnosis. In part, anemia is related to the hypervolemia caused by the increase in plasma volume because of monoclonal protein production. Rouleaux formation is a common finding on peripheral blood smears. The leukocyte count can be normal, although about one third of patients have leukopenia. Relative lymphocytosis is usually present. If lymphocyte subsets are examined, a reduction in CD4+ (helper) and an increase in CD8+ (suppressor-cytotoxic) blood lymphocytes can be noted. Defects in the proliferative responses of lymphocytes to mitogens or antigens are explained by the large portion of B cells in MM that originate from the malignant stem cell clone. Few mature plasma cells are seen in the circulation except at the terminal phase of the disease, but the covert presence of the malignant B cell clone can be unmasked by the laboratory use of monoclonal antibodies (MAbs) or by transforming agents such as phorbol esters. In rare cases, in the terminal stages, plasmablasts and proplasmacytes may amount to 50% of the leukocytes in the peripheral blood.

Bleeding is common. Platelet abnormalities, impaired aggregation of platelets, and interference with platelet function by the abnormal monoclonal protein contribute to bleeding. Inhibitors of coagulation factors and thrombocytopenia from marrow infiltration of plasma cells or chemotherapy may also contribute to bleeding. Some patients have a tendency toward thrombosis, which may manifest as a shortened coagulation time and increased levels of fibrinogen and factor VIII.

Diagnosis of MM, however, depends on the demonstration of an increased number (>10%) of plasma cells in a bone marrow aspirate (Fig. 27-3; see Color Plate 12) and/or biopsy and supporting laboratory results. Cytogenetic analysis or fluorescence in situ hybridization (FISH) of bone marrow aspirate is recommended.

Figure 27-3 Myeloma cells in a bone marrow aspirate. (From Bauer JD: Clinical laboratory methods, ed 9, St Louis, 1982, Mosby.)

Bence Jones Proteins

Bence Jones proteins have been important diagnostic markers for MM since the mid-19th century (see later, “Bence Jones Protein Screening Procedure”). In about 10% of MM patients, only BJ proteins are produced, with no complete IgM, IgG, or IgA. BJ proteins are single-peptide chains with a molecular weight of 20 to 22 kkDa, but dimerization occurs spontaneously to form molecules of 40 to 44 kDa.

Bence Jones proteins are monoclonal κ or λ immunoglobulin free light chains (FLCs) not attached to the heavy-chain portion of the immunoglobulin molecule. BJ proteins are seen in two types of syndromes:

• With a typical monoclonal gammopathy

• In free LCD

Serum concentrations of FLCs depend on the balance between production by plasma cells and their precursors and on renal clearance. If there is increased polyclonal immunoglobulin production and/or renal impairment, both κ and λ FLC concentrations can increase by 30% to 40%. Serum FLC tests have been assuming an increasing role in the detection and monitoring of monoclonal gammopathies. Serum FLCs have a short half-life in the blood (κ, 2 to 4 hours; λ, 3 to 6 hours), compared with 21 days for IgG molecules. FLC concentrations allow more rapid assessment of the effects of chemotherapy than monoclonal IgG levels.

Very small amounts of BJ proteins in serum can be associated with significant clinical problems, especially pathologic renal changes. FLCs filter through the glomeruli almost without obstruction because of their small molecular size and accumulate in the tubules. Renal impairment can result from the toxicity of FLCs. Pathologic changes can range from relatively benign tubular proteinuria to ARF or amyloidosis.

BJ proteins can be detected in serum, urine, or both. The level of monoclonal light chains in serum or urine is related to filtration, resorption, or catabolism of the protein by the kidneys. During the early stages of renal disease, when the kidneys are only mildly affected, excretion and reabsorption continue normally, but only partial catabolism occurs. At this point, BJ proteins may be detected in the serum but not in the urine. Progressive renal involvement impairs reabsorption, and diminished reabsorption with decreased catabolism results in FLCs in serum and urine. Later, as resorption is totally blocked, FLCs are present in urine only. In terminal stages of renal disease, uremia occurs, renal clearance is affected, and BJ proteins again appear in the serum.

BJ proteins are unusual in their response to heating. They are soluble at room temperature, become insoluble (forms a precipitate around 60° C to 70° C, and then dissolves at 100° C). This pattern reverses when the temperature is lowered, which is unique to BJ protein.

Serologically, all BJ proteins are not identical, although there are κ and λ types. BJ proteins will react with antisera to the λ chains of IgG and λ chains react with antisera to BJ protein.

Approximately 80% of patients with MM produce intact immunoglobulin monoclonal proteins, of which 46% have excess monoclonal FLCs in the urine by immunofixation electrophoresis. Serum protein electrophoresis is positive less often because of low serum concentrations of FLCs. From 3% to 4% of MM patients have nonsecretory disease. These patients have no detectable monoclonal proteins with serum and urine electrophoretic testing because their tumor cells produce small amounts of monoclonal protein. Their FLC concentrations are below the sensitivity of serum electrophoretic tests and below the threshold for clearance into the urine. These patients can be monitored by serum FLC tests rather than by repeated bone marrow biopsies or whole-body scans.

Free Light Chains

Free light chains are incorporated into immunoglobulin molecules during B lymphocyte development and expressed initially on the surface of immature B cells. Production of FLCs occurs throughout the rest of B cell development and in plasma cells, in which secretion is highest. Tumors associated with the different stages of B cell maturation will secrete monoclonal FLCs into the serum, where they may be detected by FLC immunoassays (Box 27-1; Table 27-3).

Box 27-1 Benefits of Serum Free Light-Chain Immunoassays

• Better sensitivity and precision than current electrophoretic assays

• Numeric results for disease monitoring

• Convenience of serum as a test medium

• Identification of AL amyloidosis and NSMM patients who have detectable monoclonal proteins by conventional tests

• More accurate marker of complete disease remission than existing assays

• Short half-life marker for rapid assessment of treatment responses

• Identification of progression risk in individuals with MGUS

• Better screening of symptomatic patients

From Bradwell AR: Serum free light chain analysis, Birmingham, England, 2006, Binding Site, p 4.

FLC, Free light chain; AL, immunocyte derived; NSMM, nonsecretory multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance.

Table 27-3

Assays for Free Light Chains

Assay	Advantages	Disadvantages
Total urine protein	Simple, inexpensive, widely used	Inadequate sensitivity for FLC detection
Urine dipstick	Simple, inexpensive, widely used	Inadequate sensitivity for FLC detection
Serum protein electrophoresis	Simple, manual or semiautomated method Well established, inexpensive Monoclonal bands observed Quantitative results with scanning	Insensitive (<500-2000 mg/L) Cannot detect FLCs at low concentration Subjective interpretation of results
Urine protein electrophoresis	Simple, manual, or semiautomated method Well established, inexpensive Monoclonal bands observed Sensitive in concentrated urine (10 mg/L) Quantitative results with scanning	Subjective interpretation of results Urine may require concentration, with possible protein loss False bands from concentrating urine Heavy proteinuria obscures results Cumbersome 24-hour urine collection
Immunofixation electrophoresis (IFE) on serum and urine	Well established Good sensitivity for serum, very sensitive for concentrated urine (5-30 mg/L)	Nonquantitative Serum sensitivity (150-500 mg/L) inadequate for normal serum FLC levels Rather laborious to perform Visual interpretation may be difficult Expensive use of antisera Cannot be used to quantify monoclonal immunoglobulins because of precipitating antibody
Capillary zone electrophoresis	Automated technology Quantitative	Less sensitive (400 mg/L) than IFE for serum FLCs Can fail to detect 5% of positive samples (false-negatives)
Total serum κ and λ assays	Automated immunoassay	Not sensitive enough for routine testing Specificity inadequate for detecting many patients with light-chain multiple myeloma

Adapted from Bradwell AR: Serum free light chain analysis, Birmingham, UK, 2006, Binding Site, pp 23, 47-52.

Production of FLCs in normal individuals is approximately 500 mg/day from bone marrow and lymph node cells. The molecules enter the blood and are readily partitioned between the intravascular and extravascular compartments. In normal individuals, serum FLCs are rapidly cleared and metabolized by the kidneys, depending on their molecular size.

Immunologic Testing

Traditionally, laboratories have detected the monoclonal immunoglobulins by protein electrophoresis, which began in the 1930s, and have characterized the proteins by immunofixation electrophoresis (IFE), which was developed in the 1980s.

The identification of κ and λ molecules has been accomplished with the use of antibodies specific for each type of protein. Immunodiffusion was initially used, followed by immunoelectrophoresis (in 1953), radial immunodiffusion, and ultimately nephelometry and turbidimetry. An automated nephelometric assay, described in 2001, represented a major breakthrough. This methodology allows for the quantitation of both κ and λ free light chains and can be performed using automated chemistry analyzers (e.g., Dade Behring [now Siemens AG], Beckman Coulter, Roche Hitachi, Olympus) (see Chapter 13).

Each monoclonal protein (M protein or paraprotein) consists of two heavy-chain polypeptides of the same class and subclass and two light-chain polypeptides of the same type. The different monoclonal proteins are designated by capital letters corresponding to the class of their heavy chains, which are designated by Greek letters: gamma (γ) in IgG, alpha (α) in IgA, mu (µ) in IgM, delta (δ) in IgD, and epsilon (ε) in IgE. The subclasses are IgG1, IgG2, IgG, and IgG4, or IgA1 and IgA2, and their light-chain types are κ and λ. A monoclonal protein is characterized by a narrow peak or localized band on electrophoresis, by a thickened bowed arc on immunoelectrophoresis, and by a localized band on immunofixation. Many different entities are associated with M proteins (monoclonal gammopathies; Box 27-2).

Electrophoresis of the serum or urine reveals a tall sharp peak on the densitometer tracing or a dense localized band in most cases of multiple myeloma (Fig. 27-4). A monoclonal protein is demonstrable in the serum and urine in 90% of patients. In all, 60% of patients exhibit IgG, 20% IgA, 10% light chain only (BJ proteinemia), and 1% IgD. Electrophoresis of urine shows a globulin peak in 75% of cases, mainly albumin in 10% of patients, and a normal pattern in 15%. When an M spike is observed on serum protein electrophoresis, the suggested sequence of testing includes testing by immunoelectrophoresis and immunofixation (Table 27-4). Screening for cryoglobulins and viscosity may also be warranted.

Table 27-4

M Spike on Serum Protein Electrophoresis
Serum	Urine
Immunoelectrophoresis	Screening of urine for increased protein, (e.g., sulfosalicylic acid)
Immunofixation	Total protein assay of a 24-hr urine specimen
Quantitation of immunoglobulins by radial immunodiffusion or nephelometry	Urinary protein electrophoresis
Screening for cryoglobulins	Urinary immunoelectrophoresis
Determination of serum viscosity if IgM, IgA, or IgG or signs and symptoms suggestive of hyperviscosity	Immunofixation

Figure 27-4 Serum electrophoretic patterns.
A, Normal patient. B, Patient with multiple myeloma. C, Patient with Waldenström’s macroglobulinemia.

Immunoelectrophoresis, also called gamma globulin electrophoresis or immunoglobulin electrophoresis, is a method of determining the blood levels of three major immunoglobulins—IgM, IgG, and IgA—based on their combined electrophoretic and immunologic properties (see Chapter 11). Immunoelectrophoresis is also used frequently to diagnose MM, which affects the bone marrow. Drugs that may cause increased immunoglobulin levels include therapeutic gamma globulin, hydralazine, isoniazid, phenytoin (Dilantin), procainamide, oral contraceptives, methadone, steroids, and tetanus toxoid and antitoxin. The laboratory should be notified if the patient has received any vaccinations or immunizations in the 6 months before the test. Prior immunizations lead to increased immunoglobulin levels, resulting in false-positive results. Because immunoelectrophoresis is not quantitative, it is being replaced by immunofixation, which is more sensitive and easier to interpret.

Prognosis

In patients diagnosed when they are younger than 60 years, the 10-year survival is approximately 30%. Staging of the disease, according to the International Staging System, defines three risk groups on the basis of serum β₂-microglobulin and albumin levels. Any chromosomal abnormality detected on standard cytogenetic analysis is associated with a worse outcome than that associated with a normal karyotype. Translocations such as t(4;14), deletion 17p13, and chromosome 1 abnormalities are associated with a poor prognosis.

Standard-risk disease is defined by the presence of hyperdiploidy or t(11;14), normal levels of serum β₂-microglobulin or lactate dehydrogenase, and International Staging System stage I. High-risk disease and a poor prognosis are defined by the presence of one of the following in each category: hypodiploidy, t(4;14), or deletion 17p13; high levels of serum β₂-microglobulin or lactate dehydrogenase, and International Staging System stage III.

The CD200 membrane glycoprotein imparts an immunoregulatory signal that leads to the suppression of T cell–mediated immune responses. Patients with CD200^absent MM cells have an increased event-free survival of 24 months; patients with CD200^present demonstrate an event-free survival of 14 months after high-dose therapy and stem cell transplantation. The presence or absence of CD200 expression in MM cells is considered a predictor of event-free survival for patients who are independent of the stage of disease or β₂M serum levels.

Treatment

Asymptomatic (smoldering) myeloma requires only clinical observation because early treatment with conventional chemotherapy has shown no benefit. Recently, the introduction of autologous stem cell transplantation (see Chapter 32) as a mainstay of myeloma therapy and the availability of agents such as thalidomide, lenalidomide, and bortezomib have changed the medical management of active (symptomatic) myeloma and extended overall survival. New proteasome inhibitors, immunomodulatory drugs (pomalidomide), targeted therapies, epigenetic agents, and humanized monoclonal antibodies are currently undergoing clinical trial investigations.

When a patient undergoes chemotherapy, the number of myeloma cells in the bone marrow and the amount of monoclonal protein in the blood and urine are closely monitored. A stable monoclonal protein level indicates that the disease is stable, often the result of effective treatment. The monoclonal protein rarely disappears completely from blood and urine.

Vaccination with the myeloma idiotype of a monoclonal immunoglobulin is an investigational means of immunotherapy. DNA hybridization or blotting technology is the newest technology available and can be used to detect abnormal gene arrangements and mutations in cellular oncogenes. Although the gene product of MAbs is the method of detection, DNA probes that can detect the abnormal gene are now available. Blotting techniques may replace the current approach to the laboratory evaluation of monoclonal gammopathies.

Strategies are being investigated to develop risk-adapted approaches to treatment based on knowledge of genetic polymorphisms or mutations that modulate the molecular pathways that underlie the pathogenesis of the disease.

Waldenström’s Primary Macroglobulinemia

Etiology

Waldenström’s primary macroglobulinemia (WM), or simply macroglobulinemia, is a B cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. WM is considered to be a lymphoplasmacytic lymphoma, as defined by the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classification systems. WM is a malignant lymphocyte–plasma cell proliferative disorder that exhibits abnormally large amounts of immunoglobulin of the 19S IgM type.

The cause of WM is unknown but a possible genetic predisposition may exist. About 20% of WM patients have a familial predisposition to the disease and related B cell malignancies. A greater frequency of IgM monoclonal proteins and quantitative abnormalities have been observed in some relatives of patients with WM. In addition, research has suggested a significantly increased risk of WM after infections—hepatitis B virus, immunodeficiency virus, and rickettsiosis—and found an increased risk of WM in patients with a personal history of autoimmune disease.

Because WM is a malignant offshoot of B cell development before the myelomas, the sole gene product is IgM. Patients with WM have chromosomal rearrangements characteristic of B cell neoplasia, including t(8:14) and trisomy 12.

Epidemiology

Waldenström’s macroglobulinemia occurs about 10% as frequently as multiple myeloma. WM has an age-specific incidence; it is most often found in older individuals, with a mean age of onset of 60 to 64 years. No significant gender differences exist in the incidence of WM. Disease onset is usually insidious; the median survival is approximately 3 years after diagnosis.

Signs and Symptoms

The signs and symptoms of WM have an indolent progression over many years. Initially, disease onset is slow and insidious, with the pace of manifestations determined by the rate of proliferation of the IgM-secreting clone. Most clinical signs and symptoms of disease stem from intravascular accumulation of high levels of IgM macroglobulin. When the IgM is precipitable at cold temperatures, as it is in 37% of cases, clinical manifestations of cold sensitivity such as Raynaud’s phenomenon, arthralgias, purpura of the extremities, renal insufficiency, and peripheral vascular occlusions may develop. Cold hypersensitivity can occur when serum IgM levels exceed 2 to 3 g/dL and the protein precipitates at temperatures exceeding 20° C (68° F).

Although the patient experiences weakness and fatigue, it is usually the onset of bleeding from the gums or nose that arouses concern. Patients undergo weight loss and the incidence of infection is twice the normal rate. As the disease progresses, about 40% of patients develop hepatomegaly, splenomegaly, and lymphadenopathy. Occasionally, the clinical manifestations may simulate those of diffuse lymphoma. Specific dysfunctions and abnormalities occur in a variety of body systems.

Skeletal Features

In contrast to multiple myeloma, bone pain is almost nonexistent in WM. Diffuse osteoporosis may be seen, but bone lesions are extremely rare.

Hematologic Abnormalities

Patients with WM usually have chronic anemia and bleeding episodes. Bleeding problems in the form of bruising, purpura, and bleeding from the mouth, gums, nose, and gastrointestinal tract are common. The quantities of circulating platelets may be normal or decreased, but the most notable alteration is a disturbance in platelet function. Therefore, thrombocytopenia or hyperviscosity may contribute to the bleeding disorder.

In addition to anemia caused by chronic or recurrent bleeding, the decrease in red blood cells (RBCs) becomes more severe as the disease progresses because of a dilutional effect caused by increased immunoglobulin production. In addition, the presence of macroglobulin also produces an increased erythrocyte sedimentation rate (ESR). Microscopic examination of a peripheral blood smear usually reveals normocytic and frequently hypochromic RBCs with striking rouleaux (rolled coin) formation. The total blood leukocyte count is normal or slightly decreased because of moderate neutropenia. In a terminal patient, the blood may be inundated with malignant lymphoplasmacytic cells.

Renal Dysfunction

Renal function becomes mildly or moderately impaired in about 15% of WM patients. Nephrosis is uncommon. BJ proteinuria, however, is present in about 70% of WM patients, although the quantity of light chains excreted is much less than in multiple myeloma.

Glomerular lesions are the predominant form of renal injury. IgM collects on the endothelial side of the basement membrane of the kidney; sometimes these macroglobulin accumulations obstruct glomerular capillaries.

Ocular Manifestations

Blurred vision is a frequent abnormality of WM. Rouleaux induced by elevations of IgM causes distention of veins and capillaries; retinal oxygenation diminishes as rouleaux-inducing IgM rises. As a result of increased IgM levels, retinal hemorrhage, exudate formation, and varicosities develop, which can lead to more permanent retinal damage unless IgM levels are lowered by therapy.

Neuropsychiatric Problems

The most common serious neurologic consequence of the slowed cerebral perfusion caused by macroglobulinemia is acute cerebral malfunction, beginning with headache, fluctuating confusion, forgetfulness, and slowed mentation. This can progress to somnolence, stupor, and coma–diffuse brain syndrome, sometimes termed coma paraproteinaemicum. Neurologic abnormalities can be improved by a reduction of plasma viscosity.

Polyneuropathy affects 5% to 10% of patients with WM. This condition is associated with an increase in spinal fluid protein and deposits of monoclonal IgM on myelin sheaths. Monoclonal IgM found in the plasma and attached to damaged nerves has been shown in some cases to share idiotypic determinants. This suggests that the polyneuropathy of WM may be an autoimmune process caused by monoclonal IgM possessing antibody activity for a component of nerve tissue.

Cardiopulmonary Abnormalities

Congestive heart failure becomes a serious problem in patients with chronic uncontrolled WM. About 90% of IgM remains trapped in the circulating plasma and exerts an unbalanced transendothelial osmotic effect sufficient to cause marked expansion of the plasma volume. This in turn creates a dilutional anemia and augments cardiac filling and cardiac output. As a result, increased cardiac output and blood viscosity overwork the myocardium.

About 10% of patients develop pulmonary lesions. Pulmonary tumors, diffuse infiltrates, and pleural involvement are all about equally represented. The signs and symptoms of pulmonary dysfunction include coughing and dyspnea.

Cutaneous Manifestations

Cold sensitivity is a frequent manifestation of WM; however, skin lesions are uncommon. A small number of patients develop flat, violaceous, macular skin lesions resulting from dense infiltration by lymphoplasmacytoid cells. Pink, pearly-looking papules caused by dense deposits of IgM may be seen.

Immunologic Manifestations

The basic abnormality in this macroglobulinemia is uncontrolled proliferation of B lymphocytes and plasma cells. As a result, there is a heavy accumulation of monoclonal IgM in the circulating plasma and plasmacytoid lymphocytes in the bone marrow.

In many cases, WM is associated with mixed cryoglobulinemia, which reflects the binding of IgG or IgA antiidiotypic antibody to the mutant IgM. In a small number of patients, dysplastic tumor cells secrete 7S IgM monomers, µ chains, or other monoclonal immunoglobulins or fragments. Therefore, the major IgM production indicates that the immunoglobulin (gene) lesion sometimes degenerates and codes for more than one M component.

Diagnostic Evaluation

Hematologic Assessment

Microscopic examination of a bone marrow aspirate reveals that the lymphoplasmacytic cells vary morphologically from small lymphocytes to obvious plasma cells. Frequently, the cellular cytoplasm is ragged and may contain material staining positive with periodic acid–Schiff (PAS) stain, probably identical to the circulating macroglobulin.

The total peripheral blood leukocyte count is usually normal, with an absolute lymphocytosis. Moderate to severe degrees of anemia are frequently observed on peripheral blood smears, as well as rouleaux formation. The patient’s plasma volume may be greatly increased and the ESR is also increased.

Platelet counts are usually normal. Faulty platelet aggregation and release of platelet factor 3 are caused by the nonspecific coating of platelets by IgM. The most common coagulation defect is a prolonged thrombin time, resulting from the binding of M component to fibrin monomers and consequent gel clotting of IgM-coated fibrin. Bleeding abnormalities can be demonstrated by the following:

• Faulty platelet adhesiveness

• Defective platelet aggregation

• Abnormal release of platelet factor 3

• Impaired clot retraction

• Prolonged bleeding time

• Positive tourniquet test

• Prolonged thrombin-prothrombin time test

• Decreased levels of factor VIII

Immunologic Assessment

Serum electrophoresis usually demonstrates the overproduction of IgM (19S) antibodies. Diagnosis is made by the demonstration of a homogeneous M component composed of monoclonal IgM. Quantitation of immunoglobulins reveals IgM levels ranging from 1 to 12 g/dL (usually, >3 g/dL), accounting for 20% to 70% of total protein. Characteristically, blood samples are described as having hyperviscosity.

In addition, cryoglobulins can be detected in the patient’s serum. Cryoglobulins are proteins that precipitate or gel when cooled to 0° C (32° F) and dissolve when heated. In most cases, monoclonal cryoglobulins are IgM or IgG. Occasionally, the macroglobulin is cryoprecipitable and capable of cold-induced, anti-I–mediated agglutination of RBCs. IgM may also occasionally be a pyroglobulin, which precipitates on heating to 50° C to 60° C (122° F to 140° F) but does not redissolve on cooling or intensified heating, as do typical BJ pyroglobulins. Many cryoglobulins have the ability to fix complement and initiate an inflammatory reaction similar to that of antigen-antibody complexes. Cryoglobulins have been classified into the following three types:

• Type I is composed of a single class. IgM and IgG classes are most common; IgA or light-chain, single cryoglobulins are seen less frequently. Type I constitutes about 25% of cryoglobulins and is generally associated with multiple myeloma, macroglobulinemia, and other, rarer neoplastic proliferations of plasma cells and lymphocytes.

• Type II cryoglobulins consist of two forms. The monoclonal form always has rheumatoid factor activity and usually is an IgM with κ light chains. The second form is polyclonal IgG, which reacts with the monoclonal IgM rheumatoid factor.

• Type III is a mixed cryoglobulin in which both constituent immunoglobulins are polyclonal. More than 90% of type III cryoglobulins contain IgM rheumatoid factor and IgG. Type III cryoglobulins are seen in a variety of autoimmune, systemic rheumatic diseases and persistent infections with immune complexes (e.g., bacterial endocarditis).

Treatment

Current treatment of WM includes single-agent alkylator, nucleoside analogue, or standard-dose rituximab therapy. Newer studies have suggested that extended-dose rituximab and other treatment options are likely to yield as good or even better results than currently recommended therapy. These include therapy with nucleoside analogues or alkylator agents, rituximab in combination with nucleoside analogues, nucleoside analogues plus alkylator agents, and combination chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]) or cyclophosphamide and dexamethasone.

Other Monoclonal Disorders

Monoclonal Gammopathy of Undetermined Significance

MGUS represents the presence of a monoclonal protein in patients with no features of multiple myeloma or related malignant disorders (e.g., WM, B cell lymphoma, chronic lymphocytic leukemia). MGUS was originally considered a benign monoclonal gammopathy, but it is now known that this disorder can evolve into a malignant monoclonal gammopathy.

The International Myeloma Working Group has established the differences between MGUS and plasma cell neoplasms (Table 27-5). Characteristics of MGUS include the following:

Table 27-5

Diagnostic Criteria for Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Waldenström’s Macroglobulinemia

	MGUS	Smoldering Multiple Myeloma	Multiple Myeloma	Waldenström’s Macroglobulinemia
Bone marrow plasma cells	<10% and	≥10% and/or	≥10% and/or	>10% and <10% lymphoplasmacytoid cells
Circulating monoclonal protein	<3 g/dL	≥3 g/dL	≥3 g/dL	>3 g/dL
Clinical signs and symptoms	Absent	Absent	Present	Present

Adapted from International Myeloma Working Group: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders, Br J Haematol 121:749–757, 2003.

• Serum monoclonal protein concentration less than 3 g/dL

• Fewer than 10% plasma cells in the bone marrow

• Absence of lytic bone lesions

• Anemia

• Hypercalcemia

• Renal insufficiency

• No clinical signs or symptoms related to the monoclonal gammopathy

In terms of incidence, 50% of patients with a monoclonal gammopathy have MGUS and 15% to 20% have multiple myeloma. The incidence of MGUS increases with age. The median age at diagnosis is about 70 years. MGUS occurs more frequently in men than women and more often in blacks than in whites. IgG is the most common immunoglobulin affected, followed by IgM. The cause is unknown.

The monoclonal gammopathies are characterized by a rearrangement of immunoglobulin genes that result in the production of a monoclonal protein. There are two populations of plasma cells in patients with MGUS: (1) normal and polyclonal (CD38+, CD56+, CD19−); and (2) clonal with an abnormal immunophenotype (CD38+, CD56+, CD19−). The plasma cell clone and associated monoclonal protein concentrations usually remain stable for many years. After a prolonged period, a substantial number of patients with MGUS progress to a malignant plasma cell disorder (e.g., MM, B cell lymphoma, chronic lymphocytic leukemia).

• Hemoglobin concentration

• Serum calcium concentration

• Creatinine concentration