Polyclonal Gammopathies

A polyclonal gammopathy is a common protein abnormality. It is defined as an increase in more than one immunoglobulin and involves several clones of plasma cells. In contrast to a monoclonal protein, a polyclonal protein consists of one or more heavy-chain classes and both light-chain types. Polyclonal increases are exhibited as secondary manifestations of infection or inflammation. They are often seen in chronic infections, chronic liver disease, especially chronic active hepatitis, rheumatoid connective tissue (autoimmune) diseases, and lymphoproliferative disorders.

A polyclonal protein is characterized by a broad peak or band, usually of gamma mobility, on electrophoresis, by a thickening and elongation of all heavy-chain and light-chain arcs on immunoelectrophoresis, and by the absence of a localized band on immunofixation. A polyclonal gammopathy therefore resembles a normal pattern, with the serum staining more intensely. A selective polyclonal increase is of special interest because only the level of one class of immunoglobulin is significantly elevated; however, the increase is polyclonal because immunoglobulin is produced by several clones of plasma cells and both kappa and lambda types are produced. Immunoglobulin quantitation by specific assay procedures demonstrates which immunoglobulin is increased. Immunofixation is not recommended in cases of polyclonal gammopathy because it presents no additional information.

Etiology

The cause of MM is unknown. Radiation may be a factor in some cases and a viral cause has been suggested. Other factors may include environmental stimulants, such as exposure to asbestos, benzene, or industrial toxins. The likelihood of a genetic factor in some cases has been supported by well-documented reports of familial clusters with MM.

Pathophysiology

Myelomas arise from an asymptomatic premalignant proliferation of monoclonal plasma cells derived from postgerminal center B cells. In contrast to normal plasma cells, myeloma cells are often immature and may have the appearance of plasmablasts. These cells usually are CD19-CD56^bright, CD38, and syndecan-1, and produce very low amounts of immunoglobulins.

Most patients demonstrate complex karyotype abnormalities with chromosomal gains, deletions, and translocations, some of which are identical to those observed in certain B cell lymphomas. Many numeric and structural abnormalities occur. Primary early chromosomal translocations occur at the immunoglobulin switch region on chromosome 14 (q32.33). This process results in the deregulation of two adjacent genes. Secondary late-onset translocations and gene mutation are implicated in disease progression and include complex karyotypic abnormalities. These genetic abnormalities may prevent the differentiation and apoptosis of myeloma cells, which continue to proliferate and accumulate in the bone marrow. Chromosomal aberrations are of sufficient number to be detected on flow analysis of DNA content, which is aneuploid in about 80% of patients.

Most patients exhibit a slight nuclear DNA excess of 5% to 10%; hypoploidy is observed in only 5% to 10% of patients and is strongly associated with resistance to standard chemotherapy. Deletions of chromosomes 13 and 17 have been observed. The morphologic immaturity, hypodiploidy, and 13q− and 14q+ abnormalities correlate with the resistance to treatment and short survival that are characteristic of aggressive disease.

The somatic mutations of the immunoglobulin genes of myeloma cells indicate that the putative myeloma cell precursors are stimulated by antigens and are memory B cells or migrating plasmablasts.

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.

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.

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.

Signs and Symptoms

The signs and symptoms of MM include bone pain, typically in the back or chest, and weakness, fatigue, and pallor associated with anemia or abnormal bleeding. In all, 20% of patients exhibit hepatomegaly and 5% demonstrate splenomegaly. In some cases, the major manifestations of disease result from acute infection, renal insufficiency, hypercalcemia, or amyloidosis. Weight loss and night sweats are not prominent until the disease is advanced. Bone pain, anemia, and renal insufficiency constitute a triad of signs and symptoms strongly suggestive of MM.

In 1975 a staging system for myeloma was developed. This system defines indolent versus severe disease and determines a basis for therapy. Patients are divided into three groups, with classification based on the production of IgG by plasma cells and the total quantity of IgG in the body. The number of abnormal plasma cells is correlated with the hemoglobin value, serum calcium level, serum IgG peak, and presence or absence of lytic bone lesions. Renal function is also considered an important factor, not only because it is essential to survival, but also because IgG light chains can damage the kidneys.

Some physicians use a simpler system of staging based on serum albumin, hemoglobin, and β₂-microglobulin levels.

Skeletal Abnormalities

About 90% of patients with MM have broadly disseminated destruction of the skeleton, which is responsible for the predominance of bone pain. These abnormalities consist of punched-out lytic areas (Fig. 27-2), osteoporosis, and fractures in about 80% of patients. The vertebrae, skull, thoracic cage, pelvis, and proximal humeri and femurs are the most frequent sites of involvement.

Immunologic Manifestations

In approximately 20% of patients, multiple myeloma is diagnosed by chance in the absence of symptoms, usually after screening laboratory studies have revealed an increased serum protein concentration. MM cells express not only cytoplasmic immunoglobulins, the hallmark of plasma cells, but early B, T, natural killer (NK), myeloid, erythroid, and megakaryocytic cell markers as well. These phenotypic features are consistent with the hypothesis that MM may originate from a transformed early hematopoietic progenitor cell, which explains the occasional coexistence of MM and acute myelogenous leukemia (AML).

Patients with MM have defects in humoral but not cellular immunity. Humoral immunity is disrupted because plasma cell tumors induce the suppression of antibody synthesis by normal immunoglobulin-secreting cells and the production of antiidiotype antibodies declines proportionately. In addition, selective impairment occurs in the formation of normal antibodies because of increased immunoglobulin catabolism and the release of a protein that incites macrophages to suppress synthesis of normal immunoglobulins by myeloma cells. Depression of normal humoral immunity accounts for the high susceptibility of MM patients to bacterial infection. The normal functioning of cellular immunity is demonstrated by normal resistance to fungal and most viral infections and by normal delayed-type hypersensitivity to skin testing antigens.

Initially, in vivo myeloma clones are subject to control by the immune network via specific idiotype-antiidiotype mechanisms. Each of the million or more potential immunoglobulin variants in every individual carries singular determinants of designated idiotypes. Antiidiotypic antibodies directed against autologous immunoglobulin are elicited during a normal immune response. The presumed mission of antiidiotypic antibodies is to help terminate the immune response by binding complementary idiotypes to form endogenous immune complexes that are removed from the circulation. The antiidiotypic antibodies in turn stimulate production of antibodies to antiidiotype, and so on, to create a modulating network that includes T cells, which recognize idiotype antigens through unique antigen receptors. Antiidiotype- and idiotype-sensitized T cells collaborate most efficiently during highly restricted responses, during which both antibodies and lymphocytes that specifically recognize the dominant idiotype are activated. These can inhibit or enhance the response of lymphocytes to receptors expressing the idiotype. The overall net direction of the response is determined by the functional influence of T cells linked by antiidiotype receptor interactions to their molecular targets on B cells. In MM, idiotype expression is carried to an extreme. Monoclonal paraproteins secreted by plasma cell tumors induce many immunologic responses capable of acting in concert to contain or modulate tumor growth.

The earliest detectable monoclonal B cell, as identified by idiotypic structures of the myeloma protein, is the transitional form bearing surface IgM, IgD, and IgG. This and the finding that precursor (early) B cells destined to become myeloma cells possess surface IgG (sIgG) indicate that the myeloma tumor clone includes memory B cells that can mature into plasma cells. The use of antiidiotypic antibodies for identifying IgA myeloma clones has revealed clonal expression at the pre–B state, a finding supported by the observation that B cells in the circulation of myeloma patients are clonally frozen at the pre–B stage. As maturing B cell members of the malignant clone differentiate in the marrow, they lose IgD and IgM, in that order, accumulate sIgG, and finally shed sIg to become IgG-producing mature plasma cells, as programmed by the mutant precursor cell. Thus, the mature myeloma cell contains abundant cytoplasmic (secretory) IgG but no sIgG. IgA myeloma cells proceed along the same normal differentiation scheme of B cell maturation. Although MM-associated tumors disseminate widely, the disease is spread through the release of clonal precursors into the blood circulation that show lymphoid rather than plasma cell morphology.

The most consistent immunologic feature of multiple myeloma is the incessant synthesis of a dysfunctional single monoclonal protein or of immunoglobulin chains of fragments, with concurrent suppression of the synthesis of normal functional antibody. In 99% of myeloma patients, an M component is usually found in serum, urine, or both. Different types of M components are associated with various clinical syndromes.