Multiple Myeloma

Posted by Alex

Multiple myeloma is a malignant proliferation of plasma cells. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms of bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and vascular 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. In contrast to most other B cell tumors, consistent chromosomal alterations have not been found in patients with myeloma, though cytogenetic abnormalities are noted in a substantial fraction of cases. Overexpression of myc or ras genes has been noted in some cases. Mutations in p53 and Rb-1 have also been described, but no common molecular pathogenesis has yet emerged. The murine plasmacytoma models suggest that the induction of plasmacytomas (e.g., with mineral oil injection) may require exposure to foreign antigens as well as a cellular event. Thus chronic antigenic stimulation may play a role in the transformation of a particular B cell clone. This is supported by evidence that M proteins from different persons sometimes share idiotypes. There is also some evidence for a genetic predisposition to myeloma in humans. Myeloma has been seen more commonly than expected among farmers, wood workers, leather workers, and those exposed to petroleum products. The neoplastic event in myeloma may involve cells earlier in B cell differentiation than the plasma cell. Circulating B cells bearing surface immunoglobulin that share the idiotype of the M component are present in myeloma patients. It is possible that the malignant clone escapes normal control mechanisms at a pre-plasma cell stage of differentiation and the chronic exposure to a particular antigenic stimulus drives the cell to terminal differentiation. Interleukin (IL) 6 may play a role in driving myeloma cell proliferation; a large fraction of myeloma cells exposed to IL-6 in vitro respond by proliferating. It remains difficult to distinguish benign from malignant plasma cells on the basis of morphologic criteria in all but a few cases.

Incidence And Prevalence About 14,400 cases of myeloma were diagnosed in 2006, and 10,400 people died from the disease. Myeloma increases in incidence with age. The median age at diagnosis is 68 years. It is rare under age 40. The yearly incidence is around 4 per 100,000 and remarkably similar in countries throughout the world. Males are slightly more commonly affected than females, and blacks have nearly twice the incidence of whites. In the age group over 25 the incidence is 30 per 100,000. Myeloma accounts for about 1 percent of all malignancies in whites and 2 percent in blacks; 13 percent of all hematologic cancers in whites and 33 percent in blacks.

Pathogenesis And Clinical Manifestations Bone pain is the most common symptom in myeloma, affecting nearly 70 percent of patients. The pain usually involves the back and ribs, and 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 the tumor cells and the activation of osteoclasts that destroy the bone. The osteoclasts respond to osteoclast activating factors (OAF) made by the myeloma cells [OAF activity can be mediated by several cytokines, including IL-1, lymphotoxin, and tumor necrosis factor (TNF)]. However, production of these factors stops following administration of glucocorticoids or interferon (IFN)-g. The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation; therefore, radioisotopic bone scanning is less useful in diagnosis than 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, clavicles, and sternum, and the collapse of vertebrae may lead to symptoms of 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 about 25 percent of patients, recurrent infections are the presenting features, and over 75 percent 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 to 16 percent instead of the normal 2 percent. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Such responses are normally T cell-independent. 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 product of the tumor. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients.

Renal failure occurs in nearly 25 percent of myeloma patients, and some renal pathology is noted in over half. There are many contributing factors. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, 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 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 syndrome (a type 2 proximal renal tubular acidosis) with increased loss of glucose, amino acids, and 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, there is very little albumin in the urine because glomerular function is usually normal. When the glomeruli are involved, the proteinuria is nonselective. 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. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.

Anemia occurs in about 80 percent of myeloma patients. It is usually normocytic and normochromic and related both to the replacement of normal marrow by expanding tumor cells and to the inhibition of hematopoiesis by factors made by the tumor. 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 very rare. Clotting abnormalities may be seen due to the failure of antibody-coated platelets to function properly or to the interaction of the M component with clotting factors I, II, V, VII, or VIII. 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 on the basis of 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 of 5 to 6, a level usually reached at paraprotein concentrations of around 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.

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, visual disturbances, and retinopathy. 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.

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 classic triad of myeloma is marrow plasmacytosis (>10 percent), lytic bone lesions, and a serum and/or urine M component. The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop. There are two important variants of myeloma, solitary bone plasmacytoma and extramedullary plasmacytoma. These lesions are associated with an M component in fewer than 30 percent of the cases, they may affect younger individuals, and both are associated with median survivals of 10 or more 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 most difficult differential diagnosis in patients with myeloma involves their separation from individuals with benign monoclonal gammopathies or monoclonal gammopathies of uncertain significance (MGUS). MGUS are vastly more common than myeloma, occurring in 1 percent of the population over age 50 and in up to 10 percent over age 75. Patients with MGUS usually have <10 percent bone marrow plasma cells; <30 g/L (3 g/dL) of M components; no urinary Bence Jones protein; and no anemia, renal failure, lytic bone lesions, or hypercalcemia. When bone marrow cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labeling index <1 percent and patients with myeloma always have a labeling index >1 percent. Other discriminators include plasma cell acid phosphatase and b-glucuronidase, both of which are low in MGUS patients, and the salmon calcitonin stimulation test, which is positive only in patients with active ongoing bone destruction. With long-term follow-up, about 25 percent of patients with MGUS go on to develop myeloma. Typically, patients with MGUS require no therapy. Their survival is about 2 years shorter than age-matched controls without MGUS.

The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. It is paradoxical that only a small minority of patients have an enlargement of the spleen and lymph nodes, the physiologic sites of antibody production. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Very rare patients (~2 percent) may have plasma cell leukemia with more than 2000 plasma cells per microliter. This may be seen in disproportionate frequency in IgD (~12 percent) and IgE (~25 percent) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins 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 protein excretion, and a concentrated aliquot is used for electrophoresis and immunologic typing of any M component. 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 b2-microglobulin (see below). Serum-soluble IL-6 receptor levels and C-reactive protein may reflect physiologic IL-6 levels in the patient.

The serum M component will be IgG in 53 percent of patients, IgA in 25 percent, and IgD in 1 percent, and 20 percent 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 about 50 percent of patients with light chain myeloma. Fewer than 1 percent of patients have no identifiable M component, and these patients usually have light chain myelomas in which renal catabolism has made the light chains undetectable in the urine. IgD myeloma may also present as light chain myeloma. 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. It is not clear 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. 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 to 4 percent 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.

The staging system for patients with myeloma is a functional system for predicting survival and is based on a variety of clinical and laboratory tests, unlike the anatomic staging systems for solid tumors. Details of the staging system are given in Table 114-2. Based on the hemoglobin, calcium, M component, and degree of skeletal involvement, the total-body tumor burden is estimated to be low (stage I, < 0.6 ´ 1012 cells per square meter), intermediate (stage II, 0.6 to 1.2 ´ 1012 cells per square meter), or high (stage III, > 1.2 ´ 1012 cells per square meter), and the stages are further subdivided on the basis of renal function [A if serum creatinine < 177 umol/L (< 2 mg/dL), B if > 177 (>2)]. Patients in stage IA have a median survival of more than 5 years and those in stage IIIB about 15 months. b2-Microglobulin is a protein of 11,000 mol wt with homologies with 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. Serum b2-microglobulin is the single most powerful predictor of survival and can substitute for staging. Patients with b2-microglobulin levels less than 0.004 g/L have a median survival of 43 months and those with levels higher than 0.004 g/L only 12 months. It is also felt that once the diagnosis of myeloma is firm, histologic features of atypia may also exert an influence on prognosis. IL-6 may be an autocrine and/or paracrine growth factor for myeloma cells; elevated levels are associated with more aggressive disease. High labeling index and high levels of lactate dehydrogenase and thymidine kinase are also associated with poor prognosis.