Chapter 18: Plasma Cell Disorders

The plasma cell disorders are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the B-lymphocyte lineage. Multiple myeloma, Waldenström’s macroglobulinemia, primary amyloidosis (Chap. 19), and the heavy chain diseases comprise this group and may be designated by a variety of synonyms such as monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias, and dysproteinemias. Mature B lymphocytes destined to produce IgG bear surface immunoglobulin molecules of both M and G heavy chain isotypes with both isotypes having identical idiotypes (variable regions). Under normal circumstances, maturation to antibody-secreting plasma cells and their proliferation is stimulated by exposure to the antigen for which the surface immunoglobulin is specific; however, in the plasma cell disorders, the control over this process is lost. The clinical manifestations of all the plasma cell disorders relate to the expansion of the neoplastic cells, to the secretion of cell products (immunoglobulin molecules or subunits, lymphokines), and to some extent to the host’s response to the tumor. Normal development of B lymphocytes is depicted in Fig. 16-2.

There are three categories of structural variation among immunoglobulin molecules that form antigenic determinants, and these are used to classify immunoglobulins. Isotypes are those determinants that distinguish among the main classes of antibodies of a given species and are the same in all normal individuals of that species. Therefore, isotypic determinants are, by definition, recognized by antibodies from a distinct species (heterologous sera) but not by antibodies from the same species (homologous sera). There are five heavy chain isotypes (M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are distinct determinants that reflect regular small differences between individuals of the same species in the amino acid sequences of otherwise similar immunoglobulins. These differences are determined by allelic genes; by definition, they are detected by antibodies made in the same species. Idiotypes are the third category of antigenic determinants. They are unique to the molecules produced by a given clone of antibody-producing cells. Idiotypes are formed by the unique structure of the antigen-binding portion of the molecule.

Antibody molecules (Fig. 18-1) are composed of two heavy chains (~50,000 mol wt) and two light chains (~25,000 mol wt). Each chain has a constant portion (limited amino acid sequence variability) and a variable region (extensive sequence variability). The light and heavy chains are linked by disulfide bonds and are aligned so that their variable regions are adjacent to one another. This variable region forms the antigen recognition site of the antibody molecule; its unique structural features form idiotypes that are reliable markers for a particular clone of cells because each antibody is formed and secreted by a single clone. Because of the mechanics of the gene rearrangements necessary to specify the immunoglobulin variable regions (VDJ joining for the heavy chain, VJ joining for the light chain), a particular clone rearranges only one of the two chromosomes to produce an immunoglobulin molecule of only one light chain isotype and only one allotype (allelic exclusion) (Fig. 18-1). After exposure to antigen, the variable region may become associated with a new heavy chain isotype (class switch). Each clone of cells performs these sequential gene arrangements in a unique way. This results in each clone producing a unique immunoglobulin molecule. In most plasma cells, light chains are synthesized in slight excess, secreted as free light chains, and cleared by the kidney, but <10 mg of such light chains is excreted per day.

Electrophoretic analysis permits separation of components of the serum proteins (Fig. 18-2). The immunoglobulins move heterogeneously in an electric field and form a broad peak in the gamma region, which is usually increased in the sera of patients with plasma cell tumors. There is a sharp spike in this region called an M component (M for monoclonal). Less commonly, the M component may appear in the β₂ or α₂ globulin region. The monoclonal antibody must be present at a concentration of at least 5 g/L (0.5 g/dL) to be accurately quantitated by this method. This corresponds to ~10⁹ cells producing the antibody. Confirmation of the type of immunoglobulin and that it is truly monoclonal is determined by immunoelectrophoresis that reveals a single heavy and/or light chain type. Hence immunoelectrophoresis and electrophoresis provide qualitative and quantitative assessment of the M component, respectively. Once the presence of an M component has been confirmed, the amount of M component in the serum is a reliable measure of the tumor burden, making M component an excellent tumor marker to manage therapy, yet it is not specific enough to be used to screen asymptomatic patients. In addition to the plasma cell disorders, M components may be detected in other lymphoid neoplasms such as chronic lymphocytic leukemia and lymphomas of B- or T-cell origin; nonlymphoid neoplasms such as chronic myeloid leukemia, breast cancer, and colon cancer; a variety of nonneoplastic conditions such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease, and pyoderma gangrenosum; and a number of autoimmune conditions, including rheumatoid arthritis, myasthenia gravis, and cold agglutinin disease. Monoclonal proteins are also observed in immunosuppressed patients after organ transplant and, rarely, allogeneic transplant. At least two very rare skin diseases—lichen myxedematosus (also known as papular mucinosis) and necrobiotic xanthogranuloma—are associated with a monoclonal gammopathy. In papular mucinosis, highly cationic IgG is deposited in the dermis of patients. This organ specificity may reflect the specificity of the antibody for some antigenic component of the dermis. Necrobiotic xanthogranuloma is a histiocytic infiltration of the skin, usually of the face, that produces red or yellow nodules that can enlarge to plaques. Approximately 10% progress to myeloma. Five percent of patients with sensory motor neuropathy also have a monoclonal paraprotein.

The nature of the M component is variable in plasma cell disorders. It may be an intact antibody molecule of any heavy chain subclass, or it may be an altered antibody or fragment. Isolated light or heavy chains may be produced. In some plasma cell tumors such as extramedullary or solitary bone plasmacytomas, less than one-third of patients will have an M component. In ~20% of myelomas, only light chains are produced and, in most cases, are secreted in the urine as Bence Jones proteins. The frequency of myelomas of a particular heavy chain class is roughly proportional to the serum concentration, and therefore, IgG myelomas are more common than IgA and IgD myelomas. In approximately 1% of patients with myeloma, biclonal or triclonal gammopathy is observed.

DEFINITION

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.

ETIOLOGY

The cause of myeloma is not known. Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency. Myeloma has been seen more commonly than expected among farmers, wood workers, leather workers, and those exposed to petroleum products. A variety of chromosomal alterations have been found in patients with myeloma: hyperdiploidy, 13q14 deletions, translocations t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16), and 17p13 deletions. Evidence is strong that errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the transformation process. However, no common molecular pathogenetic pathway has yet emerged. Genome sequencing studies have failed to identify any recurrent mutation with frequency >20%; N-ras, K-ras, and B-raf mutations are most common and combined occur in over 40% of patients. There is also evidence of complex clusters of subclonal variants at diagnosis that acquire additional mutations over time, indicative of genomic evolution that may drive disease progression. The neoplastic event in myeloma may involve cells earlier in B-cell differentiation than the plasma cell. Interleukin (IL) 6 may play a role in driving myeloma cell proliferation. It remains difficult to distinguish benign from malignant plasma cells based on morphologic criteria in all but a few cases (Fig. 18-3).

INCIDENCE AND PREVALENCE

An estimated 24,050 new cases of myeloma were diagnosed in 2014, and 11,090 people died from the disease in the United States. Myeloma increases in incidence with age. The median age at diagnosis is 70 years; it is uncommon under age 40. Males are more commonly affected than females, and blacks have nearly twice the incidence of whites. Myeloma accounts for 1.3% of all malignancies in whites and 2% in blacks, and 13% of all hematologic cancers in whites and 33% in blacks.

GLOBAL CONSIDERATIONS

The incidence of myeloma is highest in African Americans and Pacific Islanders; intermediate in Europeans and North American whites; and lowest in people from developing countries including Asia. The higher incidence in more developed countries may result from the combination of a longer life expectancy and more frequent medical surveillance. Incidence of multiple myeloma in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area. Chinese and Japanese populations have a lower incidence than whites. Immunoproliferative small-intestinal disease with alpha heavy chain disease is most prevalent in the Mediterranean area. Despite these differences in prevalence, the characteristics, response to therapy, and prognosis of myeloma are similar worldwide.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

Multiple myeloma (MM) cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM), which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu (Fig. 18-4). These effects are due both to direct MM cell–BMSC binding and to induction of various cytokines, including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1α. Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively.

Bone pain is the most common symptom in myeloma, affecting nearly 70% of patients. Unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone, and suppression of osteoblasts that form new bone. The increased osteoclast activity is mediated by osteoclast activating factors (OAFs) made by the myeloma cells (OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-κB [RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor necrosis factor [TNF]). The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation due to their suppression by dickhoff-1 (DKK-1) produced by myeloma cells. Therefore, radioisotopic bone scanning is less useful in diagnosis than is plain radiography. The bony lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia may dominate the clinical picture (see below). Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull (Fig. 18-5), clavicles, and sternum; and the collapse of vertebrae may lead to spinal cord compression. The next most common clinical problem in patients with myeloma is susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. In ~25% of patients, recurrent infections are the presenting features, and >75% of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results in fractional catabolic rates of 8–16% instead of the normal 2%. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Most measures of T-cell function in myeloma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a tumor product. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients. Some commonly used therapeutic agents, e.g., dexamethasone, suppress immune responses and increase susceptibility to bacterial and fungal infection, and bortezomib predisposes to herpesvirus reactivation.

Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in more than 50%. Many factors contribute to this. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the kidney by myeloma cells all may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal. When the glomeruli are involved, nonselective proteinuria is also observed. Patients with myeloma also have a decreased anion gap [i.e., Na⁺ – (Cl⁻ + HCO₃⁻)] because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Renal dysfunction due to light chain deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.

Normocytic and normochromic anemia occurs in ~80% of myeloma patients. It is usually related to the replacement of normal marrow by expanding tumor cells, to the inhibition of hematopoiesis by factors made by the tumor, to reduced production of erythropoietin by the kidney, and to the effects of long-term therapy. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B₁₂ deficiency. Granulocytopenia and thrombocytopenia are rare except when therapy-induced. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly; the interaction of the M component with clotting factors I, II, V, VII, or VIII; antibody to clotting factors; or amyloid damage of endothelium. Deep venous thrombosis is also observed with use of thalidomide, lenalidomide, or pomalidomide in combination with dexamethasone. Raynaud’s phenomenon and impaired circulation may result if the M component forms cryoglobulins, and hyperviscosity syndromes may develop depending on the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined based on the relative viscosity of serum as compared with water. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA; however, depending on chemical and physical properties of the paraprotein molecule, it can occasionally be observed at lower levels.

Although neurologic symptoms occur in a minority of patients, they may have many causes. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, and coma. Bony damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and other sensorimotor mono- and polyneuropathies. Neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) and myeloma is more frequently sensory than motor neuropathy and is associated with IgM more than other isotypes. In >50% of patients with neuropathy, the IgM monoclonal protein is directed against myelin-associated globulin (MAG). Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy.

Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can present as medical emergencies. Despite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic tissue.

DIAGNOSIS AND STAGING

The diagnosis of myeloma requires marrow plasmacytosis (>10%), a serum and/or urine M component, and end organ damage detailed in Table 18-1. Bone marrow plasma cells are CD138 and either monoclonal kappa or lambda light chain positive. The most important differential diagnosis in patients with myeloma involves their separation from individuals with MGUS or smoldering multiple myeloma (SMM). MGUS is vastly more common than myeloma, occurring in 1% of the population older than age 50 years and in up to 10% of individuals older than age 75 years. The diagnostic criteria for MGUS, SMM, and myeloma are described in Table 18-1. Although ~1% of patients per year with MGUS go on to develop myeloma, all myeloma is preceded by MGUS. Non-IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. Absence of all three features predicts a 5% chance of progression, whereas higher risk MGUS with the presence of all three features predicts a 60% chance of progression over 20 years. The features responsible for higher risk of progression from SMM to MM are bone marrow plasmacytosis >10%, abnormal kappa/lambda free light chain ratio, and serum M protein >30 g/L (3 g/dL). Patients with only one of these three features have a 25% chance of progression to MM in 5 years, whereas patients with high-risk SMM with all three features have a 76% chance of progression. There are two important variants of myeloma—solitary bone plasmacytoma and solitary extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress.

The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare patients (~1%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis. A 24-h urine specimen is necessary to quantitate Bence Jones protein excretion. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum β₂-microglobulin and albumin (see below).

The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains is unclear. The heavy chain isotype may have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2–4% of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature-dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations.

PROGNOSIS

Serum β₂-microglobulin is the single most powerful predictor of survival and can substitute for staging. β₂-Microglobulin is a protein of 11,000 mol wt with homologies to the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Patients with β₂-microglobulin levels <0.004 g/L have a median survival of 43 months, and those with levels >0.004 g/L have a survival of only 12 months. Combination of serum β₂-microglobulin and albumin levels forms the basis for a three-stage International Staging System (ISS) (Table 18-2) that predicts survival. With the use of high-dose therapy and the newer agents, the Durie-Salmon staging system is unable to predict outcome and thus is no longer used. High labeling index, circulating plasma cells, performance status, and high levels of lactate dehydrogenase are also associated with poor prognosis.

Other factors that may influence prognosis are the presence of cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent in situ hybridization (FISH)–identified chromosome 17p deletion, and translocations t(4;14), (14;16), and t(14;20). Chromosome 13q deletion, previously thought to predict poor outcome, is not a predictor following the use of newer agents. Microarray profiling and comparative genomic hybridization have formed the basis for RNA- and DNA-based prognostic staging systems, respectively. The ISS system, along with cytogenetic changes, is the most widely used method for assessing prognosis (Table 18-2).

TREATMENT

In 1948, Waldenström described a malignancy of lymphoplasmacytoid cells that secreted IgM. In contrast to myeloma, the disease was associated with lymphadenopathy and hepatosplenomegaly, but the major clinical manifestation was hyperviscosity syndrome. The disease resembles the related diseases chronic lymphocytic leukemia, myeloma, and lymphocytic lymphoma. It originates from a post–germinal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-bearing memory B cell. Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a similar clinical course, but therapeutic options are different. The diagnosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells in the bone marrow. Such patients are at greater risk of pathologic fractures than patients with WM.

A familial occurrence is common in WM, but its molecular bases are yet unclear. A distinct MYD88 L265P somatic mutation has been reported in over 90% of patients with WM and the majority of IgM MGUS. Presence of this mutation is now used as a diagnostic test to discriminate WM from marginal zone lymphomas (MZLs), IgM-secreting myeloma, and chronic lymphocytic leukemia (CLL) with plasmacytic differentiation. This mutation also explains the molecular pathogenesis of the disease, with involvement of Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling leading to activation of IL-1R–associated kinase (IRAK) 4 and IRAK1 followed by nuclear factor-κB (NF-κB) activation. The disease is similar to myeloma in being slightly more common in men and occurring with increased incidence with increasing age (median 64 years). There have been reports that the IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a greater extent than the better known myelin basic protein in patients with multiple sclerosis. Sometimes patients with macroglobulinemia develop a peripheral neuropathy, and half of these patients are positive for anti-MAG antibody. The neuropathy may precede the appearance of the neoplasm. There is speculation that the whole process begins with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component.

Like myeloma, the disease involves the bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Bone marrow shows >10% infiltration with lymphoplasmacytic cells (surface IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and CD23−) with an increase in number of mast cells. Like myeloma, an M component is present in the serum in excess of 30 g/L (3 g/dL), but unlike myeloma, the size of the IgM paraprotein results in little renal excretion, and only ~20% of patients excrete light chains. Therefore, renal disease is not common. The light chain isotype is kappa in 80% of the cases. Patients present with weakness, fatigue, and recurrent infections similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms such as peripheral neuropathy, dizziness, headache, and transient paresis are much more common in macroglobulinemia. Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic examination may reveal vascular segmentation and dilation of the retinal veins characteristic of hyperviscosity states. Patients may have a normocytic, normochromic anemia, but rouleaux formation and a positive Coombs’ test are much more common than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10% of macroglobulins are cryoglobulins. These are pure M components and are not the mixed cryoglobulins seen in rheumatoid arthritis and other autoimmune diseases. Mixed cryoglobulins are composed of IgM or IgA complexed with IgG, for which they are specific. In both cases, Raynaud’s phenomenon and serious vascular symptoms precipitated by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood drawn into a warm syringe and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin.

TREATMENT

The features of this syndrome are polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS). Diagnostic criteria are described in Table 18-1. Patients usually have a severe, progressive sensorimotor polyneuropathy associated with sclerotic bone lesions from myeloma. Polyneuropathy occurs in ~1.4% of myelomas, but the POEMS syndrome is only a rare subset of that group. Unlike typical myeloma, hepatomegaly and lymphadenopathy occur in about two-thirds of patients, and splenomegaly is seen in one-third. The lymphadenopathy frequently resembles Castleman’s disease histologically, a condition that has been linked to IL-6 overproduction. The endocrine manifestations include amenorrhea in women and impotence and gynecomastia in men. Hyperprolactinemia due to loss of normal inhibitory control by the hypothalamus may be associated with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in about one-third of patients. Hypothyroidism and adrenal insufficiency are occasionally noted. Skin changes are diverse: hyperpigmentation, hypertrichosis, skin thickening, and digital clubbing. Other manifestations include peripheral edema, ascites, pleural effusions, fever, and thrombocytosis. Not all the components of POEMS syndrome may be present initially.

The pathogenesis of the disease is unclear, but high circulating levels of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have been documented, and levels of the inhibitory cytokine transforming growth factor β are lower than expected. Treatment of the myeloma may result in an improvement in the other disease manifestations.

Patients are often treated similarly to those with myeloma. Plasmapheresis does not appear to be of benefit in POEMS syndrome. Patients presenting with isolated sclerotic lesions may have resolution of neuropathic symptoms after local therapy for plasmacytoma with radiotherapy. Similar to multiple myeloma, novel agents and high-dose therapy with autologous stem cell transplantation have been pursued in selected patients and have been associated with prolonged progression-free survival.

The heavy chain diseases are rare lymphoplasmacytic malignancies. Their clinical manifestations vary with the heavy chain isotype. Patients have absence of light chain and secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared. Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted.

GAMMA HEAVY CHAIN DISEASE (FRANKLIN’S DISEASE)

This disease affects individuals of widely different age groups and countries of origin. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. It is frequently associated with autoimmune diseases, especially rheumatoid arthritis. Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer’s ring, and this may progress to produce respiratory compromise. The diagnosis depends on the demonstration of an anomalous serum M component (often <20 g/L [<2 g/dL]) that reacts with anti-IgG but not anti–light chain reagents. The M component is typically present in both serum and urine. Most of the paraproteins have been of the γ₁ subclass, but other subclasses have been seen. The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow that may show increased numbers of lymphocytes or plasma cells that do not stain for light chain. Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy. Therapy is indicated when symptomatic and involves chemotherapeutic combinations used in low-grade lymphoma. Rituximab has also been reported to show efficacy.

ALPHA HEAVY CHAIN DISEASE (SELIGMANN’S DISEASE)

This is the most common of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America. The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains. Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease. Without J chain–facilitated dimerization, viscosity does not increase dramatically. Light chains are absent from serum and urine. The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may develop diffuse aggressive histologies of malignant lymphoma. Chemotherapy may produce long-term remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone. Immunoproliferative small-intestinal disease (IPSID) is recognized as an infectious pathogen–associated human lymphoma that has association with Campylobacter jejuni. It involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. Early-stage IPSID responds to antibiotics (30–70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma. Patients not responding to antibiotic therapy are considered for treatment with combination chemotherapy used to treat low-grade lymphoma.

MU HEAVY CHAIN DISEASE

The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with CLL. The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine. The diagnosis requires ultracentrifugation or gel filtration to confirm the nonreactivity of the paraprotein with the light chain reagents, because some intact macroglobulins fail to interact with these serums. The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm. There is no evidence that such patients should be treated differently from other patients with CLL (Chap. 16).