Multiple Myeloma

A neoplastic disorder resulting from the proliferation and accumulation of neoplastic immature plasma cells in the bone marrow.

In the USA, the annual incidence is about 3/100,000 persons. Multiple myeloma usually occurs in people > 50, and incidence increases with age. The disease is more common in blacks than in whites. It occurs equally in men and women.

Etiology

An increased occurrence of myeloma in first-degree relatives and in blacks and the higher frequency of the 4C complex of HLA antigens in multiple myeloma patients suggest that genetic factors play a role. However, the risk of developing multiple myeloma seems to increase after high radiation exposure, as demonstrated in Hiroshima and Nagasaki atomic bomb survivors. Other possible causes include chronic antigenic stimulation from factors such as cholecystitis, osteomyelitis, repeated allergen injections, rheumatoid arthritis, hereditary spherocytosis, and Gaucher's disease. Asbestos exposure and viral illnesses (eg, human herpesvirus 6) have also been suggested as possible etiologic factors.

The age-related decrease in cell-mediated immunity may play a role. As T-cell numbers decrease, B-cell clones may proliferate excessively. Then, because of this monoclonal expansion, spontaneous or externally induced genetic alteration of the B-cell clone may occur, allowing it to proliferate and produce large amounts of its immunoglobulin. The clone would remain under some control of the immune system and thus would be a benign monoclonal gammopathy. A second external oncogenic event might then result in uncontrolled proliferation of these cells (ie, multiple myeloma).

Pathophysiology

The consequences of abnormal plasma cell growth are plasma cell tumors, osteolytic lesions, bone marrow functional impairment, hypogammaglobulinemia, paraproteinemia, paraproteinuria, and renal disease. Neoplastic plasma cells almost always synthesize abnormal amounts of monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or or light chains. Therefore, they are usually classified according to their immunoglobulin class as determined by immunoelectrophoresis. In rare cases, there is no detectable immunoglobulin production.

Plasma cell tumors usually develop in areas of hematopoietically active bone marrow. They occur in virtually any bone but rarely in extraskeletal sites. Even plasma cell tumors that seem solitary eventually become widespread.

Osteolytic lesions, which are very common, are thought to result from the release of osteoclast-activating factor (interleukin-6) by the neoplastic plasma cells. Interleukin-6 stimulates osteoclasts to resorb bone, which can result in osteolytic lesions or diffuse osteoporosis.

Bone marrow functional impairment occurs in direct proportion to the number of plasma cells in the bone marrow. Anemia is most common, but neutropenia and thrombocytopenia may also occur.

An actual or functional hypogammaglobulinemia occurs, due to a single clone of abnormal plasma cells producing an excess of a single type of immunoglobulin or a portion of the immunoglobulin molecule, thereby suppressing the other normal classes of immunoglobulins. In > 50% of patients with monoclonal gammopathies, the monoclonal protein is IgG; in 20%, IgA; in 12%, IgM (Waldenström's macroglobulinemia); and in 2%, IgD. An IgE monoclonal protein is rare. About 10% of patients produce only light chains, and < 1% produce only heavy chains. About 1% of patients have no monoclonal protein in serum or urine. Rarely, patients produce two or more monoclonal proteins.

Renal disease occurs in about 50% of patients. Glomerular amyloid deposits, urinary tract infections, calcium or uric acid calculi, and plasma cell infiltration of the kidney may occur. However, the major cause of renal failure is the tubular damage associated with the excretion of light chains, called Bence Jones proteins. All light chain proteins are not nephrotoxic, and some patients may excrete large amounts of light chains for years without developing renal failure.

Symptoms and Signs

Multiple myeloma is usually progressive. The abnormal plasma cells are estimated to double in 3 to 10 months. In rare cases, however, the preclinical stage may last for years. The major manifestations of multiple myeloma result from the direct effect of neoplastic cells, the characteristic proteins they produce, and their secondary effects on other organ systems.

Bone pain is the most common symptom of multiple myeloma, occurring in about 70% of patients. Pain often occurs in the lower back or ribs and gradually increases in intensity. A sudden onset may mean that a vertebra has collapsed or that a spontaneous pathologic fracture has occurred (eg, in the shaft of a long bone, the pelvis, a rib, or a clavicle).

Systemic symptoms and signs include pallor, weakness, fatigue, dyspnea on exertion, and palpitations--all due to normochromic-normocytic anemia, which is present in about 70% of patients at diagnosis. Signs of thrombocytopenia (eg, ecchymoses, purpura, epistaxis, excessive bleeding from trauma) are common. Infection also occurs frequently because of neutropenia and immunoglobulin deficiency, and the patient may present with pneumonia, pyoderma, or pyelonephritis. Cold sensitivity and urticaria may result from cryoglobulinemia. Rarely, patients present with nephrotic syndrome.

Hypercalcemia, common in patients with destructive bone lesions, may result in anorexia, nausea, vomiting, polyuria, polydipsia, constipation, and dehydration. Particularly in the elderly, hypercalcemia may produce drowsiness, confusion, and coma.

Renal disease may be acute or chronic. Acute disease is usually accompanied by azotemia and may be caused by hypercalcemia, hyperuricemia, hypotension, dehydration, infections, or treatment with nephrotoxic drugs. Dehydration often results from fluid deprivation or IV use of hypertonic contrast media during a diagnostic procedure. Procedures such as IV or retrograde urograms or open bone biopsies should not be performed unless urine production is ample and hypercalcemia and hyperuricemia have been corrected.

Hyperviscosity syndrome occurs in about 50% of cases in which the monoclonal immunoglobulin is IgM (Waldenström's macroglobulinemia). The syndrome is uncommon in multiple myeloma with other immunoglobulin classes. Purpura, ecchymoses, epistaxis, gastrointestinal bleeding, blurred vision (resulting from venous congestion, intraocular hemorrhages, and exudates), and ischemic neurologic symptoms are common.

Neurologic symptoms and signs in multiple myeloma include mental confusion from hypercalcemia, spinal cord and nerve root compression, myelomatous meningitis, carpal tunnel syndrome from amyloid deposits, and sensorimotor polyneuropathy not due to amyloid or plasma cell infiltration. Less commonly, CNS symptoms may result from intracerebral plasmacytomas, herpes zoster, and multifocal leukoencephalopathy.

Diagnosis

Virtually all patients have normochromic-normocytic anemia. Elderly patients with unexplained normochromic-normocytic anemia should be evaluated for multiple myeloma. Many also have thrombocytopenia in the range of 80,000 to 130,000/µL and leukopenia in the range of 3000 to 4000/µL.

Multiple myeloma is diagnosed by the presence of osteolytic bone lesions or osteoporosis, monoclonal proteins in serum, and > 10% mature and immature plasma cells in the bone marrow. Daily excretion of light chains (Bence Jones protein) into the urine of > 60 mg/24 hours and serum levels of monoclonal protein > 2 g/dL are highly suggestive of multiple myeloma. If bone marrow plasmacytosis is not demonstrated along with these findings, repeated bone marrow aspirations and a search for an extraskeletal plasma cell tumor should be undertaken. Idiopathic monoclonal components may occur with other cancers.

Prognosis and Treatment

Once a diagnosis of multiple myeloma is made, the patient may be classified as a good or a poor risk. Good-risk patients have laboratory values of Hb >= 9.0 g/dL, serum creatinine < 2 mg/dL (< 177 µmol/L), and calcium <= 12 mg/dL (<= 3 mmol/L) after hydration. With therapy, the good-risk group has a median survival of 42 months; the poor-risk group, only 21 months. The groups respond equally well to initial therapy. In some good-risk elderly patients, the disease progresses slowly (smoldering myeloma). If the patient is asymptomatic or only mildly symptomatic, the disease can be followed over time to determine its pace. Occasionally, elderly patients with advanced-stage multiple myeloma do well.

Because multiple myeloma is a disseminated neoplastic disorder, the mainstay of treatment is chemotherapy. Many chemotherapeutic regimens are used for multiple myeloma. In elderly persons, the two most common regimens are intermittent melphalan with prednisone and low-dose continuous melphalan. In the intermittent regimen, the dosage of melphalan is 0.25 mg/kg/day po for 4 days, and the dosage of prednisone is 2 mg/kg/day for 4 days. This dosage is repeated every 4 to 6 weeks, depending on the degree of bone marrow suppression. In the continuous regimen, the patient is generally first given melphalan 8 to 10 mg/day for about 1 week (loading dose). The dosage is then reduced to 2 mg/day but must be adjusted frequently, depending on bone marrow sensitivity. In the very old, the loading dose is usually reduced to 4 mg/day for 1 week.

Radiation is useful for localized tumor burden and is widely used to relieve back pain from osteolytic lesions. Large osteolytic lesions should be irradiated before fractures occur. A fracture through a lytic lesion requires placement of an intramedullary pin and radiation therapy. However, if back pain results from extensive demineralization of bone, radiation usually will not relieve it, and chemotherapy should be begun promptly.

Autologous transplantation with peripheral blood stem cells is often being performed for people up to age 70 and occasionally even up to age 78, depending on the patient's functional status. The preferred initial chemotherapy for people in whom transplantation is being considered is vincristine, doxorubicin, and dexamethasone, rather than melphalan. Chemotherapy (usually high-dose cyclophosphamide followed by granulocyte colony-stimulating factor and then high-dose melphalan) and bone marrow transplantation can improve survival, even though the malignant clone of plasma is rarely eliminated. Some newer therapies are being tried. Thalidomide, still considered experimental therapy, is sometimes helpful. High-dose pulse dexamethasone by itself is sometimes used, and seems to be as effective as more toxic combination chemotherapy regimens. Cyclosporine may reverse drug-resistance. Maintenance therapy with interferon can be used for the patient who has achieved a stable tumor level (as measured by M protein).

All patients should be encouraged to stay active to prevent further bone demineralization. Lumbar corsets and braces may help relieve pain and reduce the risk of pathologic fractures. All infections must be treated promptly. Patients must drink sufficient fluid (2 to 3 L/day) to increase urine output and increase the excretion of light chains, calcium, uric acid, and other metabolites. Hydration with saline or saline plus furosemide IV may also be used temporarily. Hyperuricemia should be treated with allopurinol 300 mg/day. For hyperviscosity, treatment with plasmapheresis may be effective in the short term.

Hypercalcemia is usually treated with pamidronate (90 mg diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride or 5% dextrose administered over a 4-hour period on a monthly basis) and corticosteroids (40 to 100 mg for 4 to 5 days). This combination of drugs is also used in patients with osteolytic lesions, even without hypercalcemia. Vigorous saline hydration is an integral part of treatment. The patient's blood volume must be adequate prior to therapy, particularly if there is Bence Jones proteinuria. Pamidronate should never be mixed with a calcium-containing solution (eg, Ringer's lactate) and should be given in its own separate IV line. An alternative--calcitonin 4 to 8 IU/kg sc q 12 h, often with corticosteroids--can be used, but it is very expensive. Plicamycin 25 µg/kg IV over 4 to 6 hours may be used if pamidronate and calcitonin fail. Sodium or potassium phosphate 2 g/day may also be useful in some patients with mild or moderate hypercalcemia.

End-of-Life Issues

Multiple myeloma involves a great deal of pain and is ultimately fatal. Because this disease occurs mainly in the elderly, treatment protocols were devised with this age group in mind. Treatment, therefore, is not a harder burden for the elderly to bear compared with younger patients. However, treatment eventually fails, and death is inevitable. It is essential to prepare the patient for dying and to discuss such issues as advance directives, resuscitation, feeding tubes, and pain relief.