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Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Diagnosis requires demonstration of M-protein (sometimes present in urine and not serum) and either lytic bone lesions, light-chain proteinuria, or excessive plasma cells in bone marrow. A bone marrow biopsy is usually needed. Specific treatment includes conventional chemotherapy with the addition of bortezomib, lenalidomide, thalidomide, corticosteroids, and high-dose melphalan followed by autologous peripheral blood stem cell transplantation.
The incidence of multiple myeloma is 2 to 4/100,000. Male:female ratio is 1.6:1, and the median age is about 65 yr. Prevalence in blacks is twice that in whites. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested.
Pathophysiology
The M-protein produced by the malignant plasma cells is IgG in about 55% of myeloma patients and IgA in about 20%; of patients producing either IgG or IgA, 40% also have Bence Jones proteinuria, which is free monoclonal κ or λ light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein. IgD myeloma accounts for about 1% of cases.
Diffuse osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs, and skull. Lesions are caused by bone replacement by expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells that activate osteoclasts and suppress osteoblasts. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Enhanced bone loss may also lead to hypercalcemia. Extraosseous solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract.
Renal failure (myeloma kidney) occurs in many patients at diagnosis or during the course of the disorder due to many causes, most commonly from deposition of light chains in the distal tubules and hypercalcemia. Patients also often develop anemia usually from kidney disease or suppression of erythropoiesis by cancer cells.
Susceptibility to bacterial infection may occur in some patients. Viral infections, especially herpes infections, are increasingly occurring as a result of newer treatment modalities. Secondary amyloidosis (see Amyloidosis: Secondary amyloidosis (AA)) occurs in 10% of myeloma patients, most often in patients with Bence Jones proteinuria of λ-type.
Variant expressions of multiple myeloma occur (see Table 2: Plasma Cell Disorders: Variant Expressions of Multiple Myeloma ).
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Table 2
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| Variant Expressions of Multiple Myeloma |
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Form
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Characteristics
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Extramedullary plasmacytoma
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Plasmacytomas that occur outside of the medullary system
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Solitary plasmacytoma of bone
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Single bone plasmacytomas, which usually produce no M-protein
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Osteosclerotic myeloma (POEMS syndrome)
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Polyneuropathy (chronic inflammatory polyneuropathy)
Organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy)
Endocrinopathy (eg, gynecomastia, testicular atrophy)
M-protein
Skin changes (eg, hyperpigmentation, excess hair)
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Nonsecretory myeloma
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Absence of M-protein in serum and urine
Presence of M-protein in plasma cells
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Symptoms and Signs
Persistent bone pain (especially in the back or thorax), renal failure, and recurring bacterial infections are the most common problems on presentation, but many patients are identified when routine laboratory tests show an elevated total protein level in the blood or show proteinuria. Pathologic fractures are common, and vertebral collapse may lead to spinal cord compression and paraplegia. Symptoms of anemia predominate or may be the sole reason for evaluation in some patients, and a few patients have manifestations of hyperviscosity syndrome (see Plasma Cell Disorders: Symptoms and Signs). Peripheral neuropathy, carpal tunnel syndrome, abnormal bleeding, and symptoms of hypercalcemia (eg, polydipsia) are common. Patients may also present with renal failure. Lymphadenopathy and hepatosplenomegaly are unusual.
Diagnosis
Multiple myeloma is suspected in patients > 40 yr with persistent unexplained bone pain, particularly at night or at rest, other typical symptoms, or unexplained laboratory abnormalities, such as elevated blood protein or urinary protein, hypercalcemia, renal insufficiency, or anemia. Laboratory evaluation includes routine blood tests, protein electrophoresis, x-rays, and bone marrow examination.
Routine blood tests include CBC, ESR, and chemistry panel. Anemia is present in 80% of patients, usually normocytic-normochromic anemia with formation of rouleau, which are clusters of 3 to 12 RBCs that occur in stacks. WBC and platelet counts are usually normal. ESR usually is > 100 mm/h; BUN, serum creatinine, LDH, and serum uric acid are frequently elevated. Anion gap is sometimes low. Hypercalcemia is present at diagnosis in about 10% of patients.
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Protein electrophoresis is done on a serum sample and on a urine sample concentrated from a 24-h collection to quantify the amount of urinary M-protein. Serum electrophoresis identifies M-protein in about 80 to 90% of patients. The remaining 10 to 20% are usually patients with only free monoclonal light chains (Bence Jones protein) or IgD. They almost always have M-protein detected by urine protein electrophoresis. Immunofixation electrophoresis can identify the immunoglobulin class of the M-protein and can often detect light-chain protein if serum immunoelectrophoresis is falsely negative; immunofixation electrophoresis is done even when the serum test is negative if multiple myeloma is strongly suspected. Light-chain analysis with delineation of κ and λ ratios helps confirm the diagnosis. Light-chain analysis can also be used to monitor efficacy of therapy and provide prognostic data. Serum level of β2-microglobulin is measured if diagnosis is confirmed or very likely; it frequently is elevated, and albumin may be decreased. A new international staging system uses the levels of serum albumin and β2-microglobulin to indicate severity of disease and subsequent prognosis.
X-rays include a skeletal survey. Punched-out lytic lesions or diffuse osteoporosis is present in 80% of cases. Radionuclide bone scans usually are not helpful. MRI can provide more detail and is obtained if specific sites of pain or neurologic symptoms are present.
Bone marrow aspiration and biopsy are done and reveal sheets or clusters of plasma cells; myeloma is diagnosed when > 10% of the cells are of this type. However, bone marrow involvement is patchy; therefore, some samples from patients with myeloma may show < 10% plasma cells. Still, the number of plasma cells in bone marrow is rarely normal. Plasma cell morphology does not correlate with the class of immunoglobulin synthesized. Chromosomal studies on bone marrow may reveal specific karyotypic abnormalities in plasma cells associated with differences in survival.
In patients without serum M protein, myeloma is indicated by Bence Jones proteinuria > 300 mg/24 h, osteolytic lesions (without evidence of metastatic cancer or granulomatous disease), and sheets or clusters of plasma cells in the bone marrow.
Prognosis
The disease is progressive and incurable, but median survival has recently improved to > 5 yr as a result of advances in treatment. Unfavorable prognostic signs at diagnosis are lower serum albumin and higher β2-microglobulin levels. Patients presenting with renal failure also do poorly unless kidney function improves with therapy.
Because multiple myeloma is ultimately fatal, patients are likely to benefit from discussions of end-of-life care that involve their doctors and appropriate family and friends. Points for discussion may include advance directives, the use of feeding tubes, and pain relief.
Treatment
Treatment of myeloma has improved in the past decade, and long-term survival is a reasonable therapeutic target. Therapy involves direct treatment of malignant cells in symptomatic patients and the treatment of the complications. Asymptomatic patients probably do not benefit from treatment, which is usually withheld until symptoms or complications develop. However, patients with evidence of lytic lesions or bone loss (osteopenia or osteoporosis) should be treated with monthly infusions of zoledronic acid or pamidronate to reduce the risk of skeletal complications.
Treatment of malignant cells:
Until recently, conventional chemotherapy consisted only of oral melphalan and prednisone given in cycles of 4 to 6 wk with monthly evaluation of response. Recent studies show superior outcome with the addition of either bortezomib or thalidomide. Other chemotherapeutic drugs, including other alkylating drugs (eg, cyclophosphamide, doxorubicin and its newer analog liposomal pegylated doxorubicin) also are more effective when combined with thalidomide or bortezomib. Many other patients are effectively treated with bortezomib, thalidomide, or lenalidomide plus glucocorticoids and/or chemotherapy.
Chemotherapy response is indicated by decreases in serum or urine M-protein, increases in RBCs, and improvement in renal function among patients presenting with kidney failure.
Autologous peripheral blood stem cell transplantation may be considered for patients who have adequate cardiac, hepatic, pulmonary, and renal function, particularly those whose disease is stable or responsive after several cycles of initial therapy. Allogeneic stem cell transplantation after non-myeloablative chemotherapy (eg, low-dose cyclophosphamide and fludarabine) or low-dose radiation therapy can produce myeloma-free survival of 5 to 10 yr in some patients. However, allogeneic stem cell transplantation remains experimental because of the high morbidity and mortality from graft vs. host disease.
In relapsed or refractory myeloma, combinations of bortezomib, thalidomide, or its newer analog lenalidomide with chemotherapy or corticosteroids may be used. These drugs are usually combined with other effective drugs that the patient has not yet been treated with, although patients with prolonged remissions may respond to retreatment with the same regimen that led to the remission.
Maintenance therapy has been tried with nonchemotherapeutic drugs, including interferon alfa, which prolongs remission but does not improve survival and is associated with significant adverse effects. Following a response to corticosteroid-based regimens, corticosteroids alone are effective as a maintenance treatment. Thalidomide may also be effective as a maintenance treatment, and studies are evaluating maintenance therapy with bortezomib and lenalidomide among patients who have responded to these drugs alone or in combination therapeutic regimens.
Treatment of complications:
In addition to direct treatment of malignant cells, therapy must also be directed at complications, which include anemia, hypercalcemia, renal insufficiency, infections, and skeletal lesions.
Anemia can be treated with recombinant erythropoietin (40,000 units sc once/wk) in patients whose anemia is inadequately relieved by chemotherapy. If anemia causes cardiovascular or significant systemic symptoms, packed RBCs are transfused. Plasmapheresis is indicated if hyperviscosity develops (see Plasma Cell Disorders: Symptoms and Signs).
Hypercalcemia is treated with saluresis, IV bisphosphonates, and sometimes with prednisone. Most patients do not require allopurinol. However, allopurinol is indicated for patients with high levels of serum uric acid or high tumor burden and a high risk of tumor lysis syndrome with treatment.
Renal compromise can be ameliorated with adequate hydration. Even patients with prolonged, massive Bence Jones proteinuria (≥ 10 to 30 g/day) may have intact renal function if they maintain urine output > 2000 mL/day. Dehydration combined with high-osmolar IV contrast may precipitate acute oliguric renal failure in patients with Bence Jones proteinuria.
Infection is more likely during chemotherapy-induced neutropenia. In addition, infections with the herpes zoster virus are occurring more frequently in patients treated with newer antimyeloma drugs. Documented bacterial infections should be treated with antibiotics; however, prophylactic use of antibiotics is not routinely recommended. Prophylactic use of antiviral drugs may be indicated for patients receiving specific drugs. Prophylactic IV immune globulin may reduce the risk of infection but is generally reserved for patients with recurring infections. Pneumococcal and influenza vaccines are indicated to prevent infection.
Skeletal lesions require multiple supportive measures. Maintenance of ambulation and supplemental Ca and vitamin D help preserve bone density. Analgesics and palliative doses of radiation therapy (18 to 24 Gy) can relieve bone pain. However, radiation therapy may impair the patient's ability to receive cytotoxic doses of systemic chemotherapy. Most patients, especially those with lytic lesions and generalized osteoporosis or osteopenia, should receive a monthly IV bisphosphonate (either pamidronate or zoledronic acid). Bisphosphonates reduce skeletal complications and lessen bone pain and may have an antitumor effect.
Last full review/revision July 2008 by James R. Berenson, MD
Content last modified April 2012
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