Multiple myeloma is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, multiple myeloma is a disease characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein. An intriguing feature of multiple myeloma is that the antibody-forming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.
The presentation of multiple myeloma can range from asymptomatic to very symptomatic with complications requiring emergent treatment. Systemic ailments include bleeding, infection and renal failure, and local catastrophes, including pathologic fractures and spinal cord compression. Although patients benefit from treatment (ie, longer life, less pain, fewer complications), currently no cure exists. Recent advances in therapy have helped to lessen the occurrence and severity of adverse effects of multiple myeloma.
For excellent patient education resources, visit eMedicine’s Blood and Lymphatic System Center. Also, see eMedicine’s patient education article Myeloma.
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Multiple myeloma can cause a wide variety of problems. The proliferation of plasma cells may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions in the skeleton. Feared complications of multiple myeloma are bone pain, hypercalcemia, and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity, and patients have a high prevalence of infection, especially with encapsulated organisms. The overproduction of these antibodies may lead to hyperviscosity, amyloidosis, and renal failure.
The age-adjusted annual incidence of multiple myeloma is 4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women.
Multiple myeloma affects the kidneys in several ways. The most common mechanisms of renal injury are direct tubular injury, amyloidosis, or involvement by plasmacytoma.1, 2 Physicians manage the acute clinical condition with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis.2 Conventional therapy may take weeks to months to show a benefit. Renal impairment resulting from multiple myeloma is associated with a very poor prognosis.
Spinal cord compression is one of the most severe adverse effects of multiple myeloma. Reports indicate that as many as 20% of patients develop spinal cord compression at some point during the course of their disease. Symptoms typically include back pain, weakness or paralysis in the legs, numbness, or dysesthesias in the lower extremities. However, depending on the level of involvement, patients may present with upper extremity symptoms.The mechanism of these symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed.
A frequent complication of multiple myeloma is pathologic fractures. Bony involvement is typically lytic in nature. Physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient’s bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures.3, 4, 5
Patients with multiple myeloma commonly develop hypercalcemia. The mechanisms include bony involvement and, possibly, humoral mechanisms. Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in multiple myeloma.
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Multiple myeloma accounts for 1.1% of the malignancies in white US residents and 2.1% of the malignancies in black residents.
The male-to-female ratio of multiple myeloma is 3:2.
The median age of patients with multiple myeloma is 68 years for men and 70 years for women.
Presenting symptoms of multiple myeloma include bone pain, pathologic fractures, weakness, anemia, infection (often resulting from pneumococcal infection), hypercalcemia, spinal cord compression, or renal failure. Increasingly, physicians are identifying asymptomatic patients through routine blood screening. Typically, a large gap between the total protein and the albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).
This is the most common presenting symptom in multiple myeloma. Most case series report that 70% of patients have bone pain at presentation.
The lumbar vertebrae are one of the most common sites of pain.
Pathologic fractures and bone lesions
Pathologic fractures are very common in multiple myeloma; 93% of patients have more than one site of bony involvement.
A common presentation is a severe bony event.
Spinal cord compression
The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. The most common cause of weakness in patients with multiple myeloma is anemia, which may be quite severe.
Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis.
This complication occurs in approximately 10-20% of patients with multiple myeloma at some time during the course of disease.
Occasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia.
In some patients, monoclonal protein may absorb clotting factors and lead to bleeding, but this development is rare.
Patients may have hypercalcemia if they present with confusion, somnolence, bone pain, constipation, nausea, and thirst.
This complication may be present in as many as 30% of patients with multiple myeloma at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in multiple myeloma, its occurrence does not adversely affect survival.
Abnormal humoral immunity and leukopenia may lead to infection.
Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common among patients with multiple myeloma.
Epistaxis may be a presenting symptom of multiple myeloma with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction.
Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with multiple myeloma typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum.
Carpal tunnel syndrome is a common complication of myeloma.
Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with multiple myeloma.
Some peripheral neuropathies have been attributed to multiple myeloma.
Patients with multiple myeloma may have pallor resulting from anemia.
Patients may have ecchymoses or purpura resulting from thrombocytopenia.
Bony tenderness is not uncommon in multiple myeloma, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical.
Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), weakness, or carpal tunnel syndrome.
Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions.
Amyloidosis may develop in some patients with multiple myeloma. The characteristic physical examination findings that suggest amyloidosis include the following:
The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules.
Macroglossia is a common finding in patients with amyloidosis.
Skin lesions that have been described as wax papules or nodules may occur on the torso, ears, or lips.
Postprotoscopic peripalpebral purpura strongly suggests amyloidosis. Patients may develop raccoonlike dark circles around their eyes following any procedure that parallels a prolonged Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this observation. The correlation was observed when patients in the past underwent rectal biopsies to make the diagnosis.
The most widely accepted schema for the diagnosis of multiple myeloma is as follows:
I = Plasmacytoma on tissue biopsy
II = Bone marrow with greater than 30% plasma cells
III = Monoclonal globulin spike on serum protein electrophoresis, with an immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis) result of greater than 1 g/24 h
a = Bone marrow with 10-30% plasma cells
b = Monoclonal globulin spike present but less than category III
c = Lytic bone lesions
d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or IgG level less than 600 mg/dL
The following combinations of findings are used to make the diagnosis of multiple myeloma:
I plus b
I plus c
I plus d
II plus b
II plus c
II plus d
III plus a
III plus c
III plus d
a plus b plus c or a plus b plus d
A study by the Mayo clinic found multiple myeloma in 8 siblings from a group of 440 patients; these 8 siblings had different heavy chains but the same light chains.
Ongoing research is investigating whether human leukocyte antigen (HLA)-Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.
Environmental or occupational causes: Case-controlled studies have suggested a significant risk of developing multiple myeloma in individuals with significant exposures in the agriculture, food, and petrochemical industries. Long-term (>20 y) exposure to hair dyes has been tied to an excessive risk of developing multiple myeloma.
MGUS: Approximately 19% of patients with MGUS develop multiple myeloma within 2-19 years.
Radiation has been linked to the development of multiple myeloma.
In 109,000 survivors of the bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976; however, some more recent studies do not confirm that these survivors have an increased risk of developing multiple myeloma.