Multiple Myeloma
Kathy A. Shane
Brenda K. Shelton
I. Definition:
Multiple myeloma is defined as a malignancy of the plasma cells or their immunoglobulins.
A. Multiple myeloma comprises only 1% of all cancers, and 10% to 12% of hematologic malignancies, with an estimated 14,000 cases per year.
B. Although not a malignancy of high incidence, the number of new cases has increased steadily over the past decade. Whether this reflects the more precise diagnostic criteria, earlier and more specific diagnostic methods, or an actual increase in incidence is unknown. The growing aged population may also contribute to the rising incidence of this disease.
C. Multiple myeloma affects males more commonly than females (3:2).
D. Less than 2% of cases occur before the age of 40, with peak incidence occurring in 50- to 70-year-old people; however, a trend toward disease presentation under the age of 55 has been observed in recent years, implying environmental causes.
E. African Americans develop multiple myeloma twice as commonly as other ethnic groups, although this may be attributable to higher baseline immunoglobulin levels, providing a larger base from which malignant cells can proliferate.
F. The prognosis for patients with multiple myeloma is poor, with 40% to 50% of the patients dying within 3 months of diagnosis, and 85% to 90% within 2 years. There is only a 3% 10-year survival rate despite more effective treatment regimens.
G. Pathophysiology
1. Plasma cells are antibody-forming cells derived from B lymphocytes and act as transcriptionists for the creation of specific antibodies or immunoglobulins.
2. The homogeneous antibody production or monoclonal gammopathy characteristic of multiple myeloma most commonly affects immunoglobulin G or A (52% and 21%, respectively).
3. When plasma cells become malignant, they proliferate uncontrollably, infiltrating the bone marrow, then the bone matrix, causing osteolytic bone lesions.
4. Myeloma cells proliferate outside the bone marrow in all lymphoid tissues where plasma cells normally reside.
5. Paraproteins (referred to as M, myeloma, or monoclonal protein) are secreted in excess by the abnormal plasma cells.
a. May result in hyperviscosity of body fluids, affecting the function of all blood cell lines and many organs.
b. The presence and/or degree of abnormal proteins accounts for the symptomatology, as well as the staging or classification of the disease.
c. Paraproteins may also degrade to amyloid, a proteinaceous substance that deposits between cells; particularly in the heart, liver, spleen, and kidneys.
H. Multiple myeloma is a disease that varies from a smoldering abnormality of immunoglobulin without frank malignant cells, to a highly aggressive malignant disease (Zaidi & Vesole, 2001).
II. Etiology:
The precise cause of multiple myeloma is unknown; however, some factors have been associated with the development of this cancer.
A. Abnormal genetic karyotypes are observed in 50% to 70% of patients.
1. Several chromosomes have been implicated, but the most common are chromosomes 11 and 13.
2. Relapsing or treatment-refractory patients have a higher frequency of chromosomal abnormalities.
3. Dysregulation of oncogenes and tumor suppressor genes controlling cellular proliferation, growth arrest, and apoptosis contribute to the pathogenesis of most malignancies, and multiple myeloma is no exception. The genes thought to be most often affected in multiple myeloma are the p53 tumor suppressor gene, Mip-1 alpha gene, monosomy 13, and IgH translocations (Ho et al., 2002; Magrangeas et al., 2003).
B. The cytokines, interleukin 6 (IL-6), and tumor necrosis factor (TNF) are potent growth and survival factors for myeloma cells.
C. A history of chronic infections or repeat allergic stimulation may place people at risk for the development of multiple myeloma because this cancer involves the antibody-producing cells of the body. In recent years, viruses, particularly hepatitis C and human immunodeficiency virus (HIV), have been identified as possible triggers in the development of multiple myeloma.
D. Exposure to ionizing radiation is considered a risk factor for the disease because of the prevalence of this disease among people with significant exposure to radiation (eg, atomic blast) and those in occupations with chronic low-level radiation exposure.
E. Other suspected risk factors include exposure to wood, rubber, textile, and petroleum processing, hair dye, and asbestos.
III. Patient Management
A. Assessment
1. Bony “tumor sites” are commonly palpable on the skull, jaw, scapulae, sternum, clavicles, vertebrae, pelvis, or ribs. Tumors are pink or reddish looking and fleshy feeling.
2. Bone pain is the most common subjective complaint, occurring in 65% to 75% of patients presenting with multiple myeloma. The proliferation of plasma cells and crowding of the bone marrow produce intractable bone pain that is difficult to differentiate from pain that may be associated with pathologic fractures that can also occur with this disease. In fact, 25% to 35% of patients present with pathologic fractures.
3. Extraskeletal tumor sites (called plasmacytomas) are occasionally noted in the nasopharynx, paranasal sinuses, larynx, thorax, paravertebral or epidural tissues, lymph nodes, and gastrointestinal (GI) tract.
4. Fatigue is a common complaint of patients, occurring as the malignant cells crowd the bone marrow and produce anemia, or related to white blood cell (WBC) dysfunction and infections. Fatigue and muscle weakness are also manifestations of hypercalcemia, a common complication of this disease. At time of diagnosis, 25% to 30% of patients present with symptomatic hypercalcemia.
5. Easy bruising and bleeding occur when the bone marrow becomes crowded with malignant cells, resulting in thrombocytopenia.
6. Mental status changes occur in extensive or progressive disease, and can be due to hypercalcemia, renal dysfunction, hyperviscosity, or an infectious complication. Moderate changes in personality signal a metabolic disorder such as hypercalcemia. More serious focal deficits, such as unequal pupils or single-sided weakness, may be indicative of a thrombotic stroke due to hyperviscosity. Myeloma protein deposition on peripheral nerves can result in both motor and visual deficits and sensory neuropathies.
7. Spontaneous pathologic fractures occur due to bone invasion by myeloma cells. Fractures of long bones with minimal activity (eg, femur, humerus) are common, although vertebral collapse with spinal cord compression is also prevalent. Pathologic fractures and spinal cord compression impair patient mobility.
8. Oliguria and impaired renal function can result from damage to renal tubules by myeloma protein, and is a presenting symptom in 25% to 40% of patients.
9. Despite the wide array of symptoms that can signal a diagnosis of multiple myeloma, 30% of patients are diagnosed on routine examination.
B. Diagnostic Parameters
1. Serum tests
a. There is one specific serum test to diagnose multiple myeloma (serum protein electrophoresis) and the specific type of gammopathy. On electrophoresis, the abnormal immunoglobulin separates differently than normal immunoglobulins found in the serum.
b. Serum immunofixation determines the type of myeloma protein, light or heavy chain.
c. Tests to detect common complications of the disease (complete blood count, serum calcium)
(1) The complete blood count is performed to detect the severity of bone marrow infiltration with malignant plasma cells. There are usually a large number of lymphocytes (40% to 50% of total WBC count) and not less than 3% plasma cells. In severe disease, anemia and thrombocytopenia are present.
(2) Serum calcium levels are elevated above 10.5 mg/dL, or 4.5 mEq/L due to abnormal bone resorption when myeloma invades the bony matrix.
d. Tests to monitor the disease’s response to therapy (eg, serum viscosity, erythrocyte sedimentation rate)
(1) Serum viscosity levels (plasma/saline ratio) are elevated above 1.9 due to excess immunoglobulin.
(2) Hyperuricemia (uric acid >4 mg/dL) is present when there is a large tumor burden and rapid cell turnover.
(3) The erythrocyte sedimentation rate (ESR) is increased due to inflammation and abnormal levels of immunoglobulin. This test may be used to monitor response to treatment.
e. Tests to assess severity of disease or disease progression (Beta 2 microglobulin, C-reactive protein, lactate dehydrogenase [LDH], plasma cell labeling index values, cytogenetics)
(1) Beta 2 microglobulin is a protein normally found on the surface of myeloma cells; a level >3 μg/mL indicates extensive disease.
(2) C-reactive protein is produced by the liver; a level >6 μg/mL is indicative of a poorer prognosis.
(3) LDH is a measure of tumor cell burden; increasing levels may indicate disease progression.
(4) Plasma cell labeling index is the percentage of plasma cells actively growing; a normal value is <1%.
(5) Cytogenetic testing assesses the number and normalcy of chromosomes.
2. Urine Tests
a. A 24-hour urine test for Bence Jones protein (the light chain of the immunoglobulin molecule) detects the presence of abnormal immunoglobulin. The kidneys normally resorb abnormal immunoglobulin, but when it is present in large amounts, it will spill into the urine. Its absence may not rule out disease, but its presence does confirm diagnosis.
b. On urinalysis, plasma cells may be present in urine sediment.
c. Hypercalciuria (any detectable urine calcium) is present when there is serum hypercalcemia, and it is present in many patients with multiple myeloma.
3. Other Tests
a. A bone marrow aspiration shows abnormal numbers of immature plasma cells, as well as decreased WBC, red blood cells (RBC), and platelets.
b. Computed tomography (CT) scans or magnetic resonance imaging (MRI) scans will demonstrate amyloid plaquelike lesions on the liver, spleen, lymph nodes, adrenal glands, kidneys, and GI tract.
c. X-rays initially show osteoporosis and eventually demonstrate multiple, sharply circumscribed osteolytic (punched out) lesions, particularly on the skull, pelvis, and spine.
C. Treatment: The three major considerations in staging multiple myeloma are the IgG or IgA levels, renal function, and isolation of discrete tumors. A summary of the staging criteria for multiple myeloma are noted in Box 19-1. Classifications of monoclonal gammopathies are noted in Table 19-1.
BOX 19-1 Myeloma Staging SystemStage | Criteria | ||
I | All of the following: | ||
Hgb value > 10 g/dL | |||
Serum calcium value normal (< 12 mg/dL) | |||
On roentgenogram, normal bone structure or solitary bone plasmacytoma only | |||
Low M-component production rates | |||
IgG value < 5 g/dL | |||
IgA value < 3 g/dL | |||
Urine light chain M-component on electrophoresis < 4 g/24 hr | |||
II | Overall data not as minimally abnormal as shown for Stage I, and no single value as abnormal as defined for Stage III | ||
III | One or more of the following: | ||
Hgb value < 8.5 g/dL | |||
Serum calcium value > 12 mg/dL | |||
Advanced lytic bone lesions | |||
High M-component production rates | |||
IgG value > 7 g/dL | |||
IgA value > 5 g/dL | |||
Urine light chain M-component on electrophoresis > 12 g/24 hr | |||
Subclassification | |||
A = relatively normal renal function (serum creatinine value < 2.0 mg/dL) | |||
B = abnormal renal function (serum creatinine value > 2.0 mg/dL) | |||
Examples | |||
Stage IA = low cell mass with normal renal function | |||
Stage IIIB = high cell mass with abnormal renal function | |||
Source: Alexanian, R., Balcerzak, S., Bonnet, J. D., et al. (1975). Prognostic factors in multiple myeloma. Cancer, 36, 1192-1201. Copyright © 1975 American Cancer Society. Reprinted by permission by Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. | |||
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