eMedicine - Multiple Myeloma : Article by Sara Grethlein, MD

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Multiple Myeloma

Last Updated: June 16, 2006

Synonyms and related keywords: myeloma, bone marrow malignancy, bone marrow cancer, myeloma multiple, plasma cell myeloma, Kahler's disease, Kahler disease, plasma cell dyscrasia, plasma cell leukemia, leukopenia, anemia, thrombocytopenia, bone pain, hypercalcemia, spinal cord compression, hyperviscosity, amyloidosis, renal failure, monoclonal gammopathy of unknown significance, MGUS, M and P chemotherapy, leukemia, plasma cell leukemia, VAD chemotherapy, plasmacytoma, renal impairment, compression fracture of vertebral body, shingles, herpes zoster, Haemophilus infections, epistaxis, stroke, myocardial ischemia, myocardial infarction, carpal tunnel syndrome, meningitis, peripheral neuropathies, ecchymoses, purpura, macroglossia

AUTHOR INFORMATION Section 1 of 11

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Author: Sara Grethlein, MD, Associate Dean for Graduate Medical Education, Associate Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York at Upstate

Sara Grethlein, MD, is a member of the following medical societies: American Society of Clinical Oncology, and American Society of Hematology

Editor(s): Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; and Emmanuel C Besa, MD, Professor of Medicine, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University

Disclosure

INTRODUCTION

Section 2 of 11

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Background: 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 this disease is that the antibody-forming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.

Myeloma can be asymptomatic or insidious. The disease can cause systemic ailments, including infections 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.

Pathophysiology: 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 this malignancy 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.

Frequency:

In the US: Age-adjusted annual incidence 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.

Mortality/Morbidity:

Multiple myeloma affects the kidneys in several ways. The most common mechanisms of renal injury are direct tubular injury, amyloidosis, or involvement by plasmacytoma. Physicians manage the acute picture with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but one small randomized study did show a survival advantage with the use of apheresis (Zucchelli, 1988). Conventional therapy may take weeks to months to show benefit. Renal impairment resulting from myeloma is associated with a very poor prognosis.

Spinal cord compression is one of the most severe adverse effects of 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 myeloma, or, rarely, an extradural mass. The dysfunction may be reversible, depending on the duration of cord compression; however, once established, the dysfunction is only rarely fully reversed.

A frequent complication of multiple myeloma is pathologic fractures. Bony involvement typically is 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.
Patients with 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 myeloma.

Race: Multiple myeloma accounts for 1.1% of the malignancies in white US residents and 2.1% of the malignancies in black residents.

Sex: The male-to-female ratio is 3:2.

Age: The median age of patients is 68 years for men and 70 years for women.

CLINICAL

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History: Presenting symptoms 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).

Bone pain

This is the most common presenting symptom. Most 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; 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 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 at some time during the course of disease.

Bleeding

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.

Hypercalcemia

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 at presentation. In most solid malignancies, this carries an ominous prognosis, but in myeloma, its occurrence does not adversely affect survival.

Infection

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 myeloma.

Hyperviscosity

Epistaxis may be a presenting symptom of 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 typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum.

Neurologic symptoms

Carpal tunnel syndrome is a common complication of myeloma.
Meningitis (especially resulting from pneumococcal or meningococcal infection) is more common in patients with myeloma.
Some peripheral neuropathies have been attributed to myeloma.

Physical:

Patients may have pallor resulting from anemia.

Patients may have ecchymoses or purpura resulting from thrombocytopenia.

Bony tenderness is not uncommon, 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 diagnosis 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 G (IgG) peak of greater than 3.5 g/dL or an immunoglobulin A (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 normal immunoglobulin M (IgM) level of less than 50 mg/dL, IgA level of less than 100 mg/dL, or IgG level of less than 600 mg/dL

The following combinations of findings are used to make the diagnosis:

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

Causes:

Genetic causes

The Mayo clinic found disease in 8 siblings out of 440 patients; these 8 siblings had different heavy chains but the same light chains.

Ongoing research is investigating whether HLA-Cw5 or HLA-Cw2 may play a role in the pathogenesis of myeloma.

Environmental or occupational causes: Case-controlled studies have suggested a significant risk of developing 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 myeloma.

MGUS: Approximately 19% of patients with MGUS develop multiple myeloma within 2-19 years.
Radiation:

Radiation has been linked to the development of myeloma.

In 109,000 survivors of the bombing of Nagasaki, 29 died from myeloma from 1950-1976; however, some recent studies do not confirm that these survivors have an increased risk of developing myeloma.

DIFFERENTIALS

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Monoclonal Gammopathies of Uncertain Origin
Waldenstrom Hypergammaglobulinemia

Other Problems to be Considered:

See Special Concerns.

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Monoclonal Gammopathies of Uncertain Origin

Waldenstrom Hypergammaglobulinemia

Patient Education

Blood and Lymphatic System Center

Myeloma Overview

Myeloma Causes

Myeloma Symptoms

Myeloma Treatment

WORKUP

Section 5 of 11

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Lab Studies:

Complete blood count to determine if the patient has anemia, thrombocytopenia, or leukopenia

Comprehensive metabolic panel to assess a patient's total protein, albumin and globulin, BUN, creatinine, and uric acid, which is high if the patient has high cell turnover or is dehydrated

Serum protein electrophoresis, urine protein electrophoresis, and immunofixation

Serum protein electrophoresis is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed).

Urine protein electrophoresis is used to identify the presence of the Bence Jones protein in urine.

Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

A 24-hour urine collection for the Bence Jones protein (ie, lambda light chains), protein, and creatinine

Quantification of proteinuria is useful for diagnosis (>1 g of protein in 24 h is a major criterion) and for monitoring the patient's response to therapy.
Creatinine clearance can be useful for defining the severity of the patient's renal impairment.

Quantitative immunoglobulin (ie, IgG, IgA, IgM) levels

A minor diagnostic criterion for myeloma is the suppression of nonmyelomatous immunoglobulin.
Also, the level of myeloma protein (ie, M protein level), as documented by the immunoglobulin level, can be useful as a marker to assess the patient's response to therapy.

Beta-2 microglobulin

Beta-2 microglobulin is a very strong predictor of outcome; some studies suggest it is more powerful than stage.
Beta-2 microglobulin is a surrogate marker for the overall body tumor burden.
The level of beta-2 microglobulin is increased in patients with renal insufficiency without myeloma, which is one reason that it is a useful prognosticator in myeloma. The prognosis of patients with myeloma and impaired renal function is reduced.

C-reactive protein

C-reactive protein is useful for prognostication.

C-reactive protein is a surrogate marker of interleukin 6 activity. Interleukin 6 is often referred to as the plasma cell growth factor.

Check serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels.

Imaging Studies:

Skeletal series

Perform a complete skeletal series at diagnosis, including the skull (a very common site of bone lesions in persons with multiple myeloma), the long bones (looking for impending fractures), and the spine.
Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent.
Findings from this evaluation may be used to identify impending pathologic fractures, allowing physicians the opportunity to repair debilities and prevent further morbidity.
Do not use bone scans to evaluate myeloma. Cytokines secreted by myeloma cells suppress osteoblast activity; therefore, typically, no increased uptake is observed.

MRI scan

Findings from MRI scans of the vertebrae are often positive when plain radiographs are not.

For this reason, evaluate symptomatic patients with MRI to obtain a clear view of the spinal column and to assess the integrity of the spinal cord.

Procedures:

Obtain bone marrow aspirate and biopsy samples to calculate the percent of plasma cells in the aspirate (reference range, <3%) and to look for sheets or clusters of plasma cells in the biopsy specimen.

Cytogenetic analysis of the bone marrow may contribute significant prognostic information. Abnormalities of chromosome 13 (predominantly monosomy 13) predict a poor outcome. In addition, in persons with MGUS, the presence of monosomy 13 may correlate with the subsequent development of myeloma.

Histologic Findings: In patients with myeloma, plasma cells proliferate within the bone marrow, typically in sheets. Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are smooth (round or oval) in contour with clumped chromatin and have a perinuclear halo or pale zone. The cytoplasm is basophilic. Many descriptions of myeloma cells include characteristic, but not diagnostic, cytoplasmic inclusions, usually containing immunoglobulin. The variants include Mott cells, Russell bodies, grape cells, and morula cells. Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps. This infiltration is different from the lymphoplasmacytic infiltration observed in patients with Waldenström macroglobulinemia.

Staging: Staging is a cumulative evaluation of all of the diagnostic information garnered and is a useful tool for stratifying the severity of patients' disease. The staging system for myeloma is somewhat complex, but it is well correlated with outcome.

Stage I involves all of the following:

Hemoglobin level greater than 10 g/dL
Calcium level less than 12 mg/dL
Radiograph showing normal bones or solitary plasmacytoma
Low M protein values (ie, IgG <5 g/dL, IgA <3 g/dL, urine <4 g/24 h)

Stage II involves criteria that fit neither stage I nor stage III.
Stage III involves any one of the following:

Hemoglobin level less than 8.5 g/dL
Calcium level greater than 12 mg/dL
Radiograph showing advanced lytic bone disease
High M protein value (ie, IgG >7 g/dL, IgA >5 g/dL, urine >12 g/24 h)

Subclassification A involves a creatinine level of less than 2 g/dL.

Subclassification B involves a creatinine level greater than 2 g/dL.

Stage I is associated with median survival of longer than 60 months, stage II is 41 months, and stage III is 23 months. Stage B disease has a significantly worse outcome (eg, 2-12 mo in 4 separate series).

TREATMENT

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Medical Care: Physicians must understand both the natural history of the disease and the limitations of current therapy in the treatment of multiple myeloma.

An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with multiple myeloma. This study evaluated 638 consecutive untreated subjects with myeloma. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of bone disease. The subjects in this group were designated as either low risk (ie, no bone disease, M protein level <3 g/dL, or Bence Jones protein level <5 g/24 h) or high risk (ie, lytic bone disease and serum M protein level >3 g/dL or Bence Jones protein level >5 g/24 h). Intermediate-risk subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones protein level of greater than 5 g/24 h. The patients were evaluated every 2 months.

The median time for disease progression was 10 months in the high-risk group, 25 months in the intermediate-risk group, and 61 months in the low-risk group. At the time of progression, subjects were treated with standard chemotherapy. The subjects' response rates did not significantly differ from those of unselected populations. The median survival time from the institution of chemotherapy did not differ among the groups. To summarize, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect the efficacy of the treatment (ie, survival).

Patients for whom therapy is indicated typically receive chemotherapy. Physicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation. A randomized prospective study shows that this approach results in higher response rates and better disease-free survival rates.

Adjunctive therapy for myeloma includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture, need for surgery, need for radiation). Erythropoietin may ameliorate anemia resulting from either myeloma alone or from chemotherapy and has been shown to improve quality of life.

Patients with spinal cord compression due to multiple myeloma should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to reverse or maintain neurologic function. Although surgical decompression is sometimes appropriate, posterior laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be superior to radiation. This surgical approach is probably best reserved for patients in whom radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected into compressed vertebrae, have been shown to improve function with few complications, although the studies reported have been small.

Patients presenting with acute renal failure may benefit from plasmapheresis. Hydration (to maintain a urine output of >3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors.

Transplantation

Using the patient's own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense antimyeloma therapy. Physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then "rescue" patients by infusing patients' own stem cells. This sequence of myeloablative therapy, followed by the reinfusion of stem cells, is termed an autologous stem cell transplantation. This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times higher dose than is used in standard therapy. In autologous transplantation, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.
Tandem autologous transplants have been proposed as a way of overcoming the incomplete response to a single transplant. A recently reported 2 arm trial of single versus tandem transplants revealed no difference in overall survival at 54 months (Moreau, 2005).
In highly selected patients with multiple myeloma, physicians may use allogeneic (ie, from someone else) transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably an HLA-identical sibling. The advantage of this approach is that the patient is not at risk of being reinfused with myeloma cells. Also, the donor's immune system may fight the recipient's cancer (ie, graft vs myeloma effect). Unfortunately, the donor's immune system also may attack the recipient's body (ie, graft vs host effect).
Two randomized prospective studies compared standard chemotherapy with high-dose autologous transplantation. In the first study of 200 subjects, researchers observed better response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated group) and better 5-year event-free survival rates (ie, 28% vs 10%). The second study also showed a significant improvement in event-free survival rates and superior quality of life for subjects treated with the high-dose approach.
Physicians treat myeloma with allogeneic transplantation less often than autologous transplantation for several reasons.
- First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with myeloma are older than the ideal age for allogeneic transplantation.
- Second, the transplantation-related mortality rate is quite high in patients with myeloma who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10-56% in different series.
- Third, although some survivors experience long-term disease-free results after allogeneic transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation showed a median survival of 34 months for the autologous transplantation group and 18 months for the allogeneic group.
The exception to this rule is the rare patient with a twin donor. In a limited study of 25 transplantations involving twins, outcomes with syngeneic transplantations were superior, with reduced transplantation-related mortality.
The development of a nonmyeloablative preparative regimen for myeloma allogeneic transplantation is changing the equation. A recently republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate. Progression-free survival at 18 months was roughly 30% (Gerull, 2005).

Radiation

Myeloma is extremely sensitive to radiation.

Physicians use radiation to treat symptomatic lesions and to stabilize bones at risk for fracture.

Physicians also use radiation to treat spinal cord compression.
Some researchers tried low-dose, double-hemibody irradiation as systemic therapy but did not observe dramatic success.

Surgical Care: Surgical therapy for myeloma is limited to adjunctive therapy.

Consultations: Patients often benefit from the expertise of an orthopedic surgeon versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

Diet: Patients with myeloma who are receiving bisphosphonate therapy should include adequate calcium in their diet.

Activity: Encourage patients with myeloma to be physically active, as appropriate to their individual bone status. Physical activity may help maintain bone strength.

MEDICATION Section 7 of 11

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Multiple myeloma is treated with several categories of medications. Chemotherapeutic agents are used to reduce the disease burden, and bisphosphonates are used to promote bone healing and to provide secondary prophylaxis against skeletal-related events (eg, hypercalcemia, bone fracture, spinal cord compression, need for radiation, need for surgery). In addition, erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

The regimen used most often is melphalan and prednisone (M and P). Both drugs are typically administered by mouth for 4-7 days; the cycle is repeated every 4-6 weeks, depending on count recovery. Patients tolerate this therapy extremely well, but, rarely, patients report nausea or fatigue. Patients almost never develop emesis. Patients' overall response rates are approximately 50%, and alopecia is exceedingly uncommon.

All patients' disease eventually becomes refractory. Although many other combinations of chemotherapy regimens (eg, vincristine, bischloroethylnitrosourea, melphalan, cyclophosphamide, and prednisone; vincristine, doxorubicin [Adriamycin], and dexamethasone [VAD]; vincristine, bischloroethylnitrosourea, melphalan, cyclophosphamide, and prednisone plus vincristine, bischloroethylnitrosourea, doxorubicin, and prednisone) have been developed, a meta-analysis published in Lancet compared M and P with combination chemotherapy and found no significant advantage in response rate, response duration, or survival rates with combination chemotherapy. However, patients had a quicker response with VAD than with M and P. Patients who are potential candidates for autologous bone marrow or peripheral blood stem cell transplantation typically are not treated with melphalan because stem cell injury may occur with this drug.

VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin (Adriamycin), with 4 daily oral doses of dexamethasone (Decadron). Because of the infusion, patients require a central venous access catheter. In selected patients, this therapy can be performed in an outpatient setting. A pegylated liposomal form of doxorubicin, Doxil, has been used to alter the distribution of the drug within the body. This changes the toxicity and efficacy profile. It has been substituted for standard doxorubicin in the VAD combination.

Patients tolerate this therapy well, and nausea is usually minimal. Patients typically experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation) are usually mild. Pancytopenia is expected, although patients do usually not require hospitalization for infection or transfusion solely from the chemotherapy. Because patients are at risk of developing Pneumocystis carinii pneumonia, some physicians drop the latter 2 courses of steroids. The use of trimethoprim-sulfamethoxazole as prophylaxis for P carinii pneumonia is also common.

Significant concerns with the use of infusion therapy include the risk of soft tissue injury if the chemotherapy infiltrates, the risk of cardiac injury from the doxorubicin, and the risk of infection or hyperglycemia from the high-dose steroids. Some patients also experience adverse CNS effects from the high-dose steroids.

Many researchers feel that the high-dose steroid component of VAD accounts for much of its efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical responses.

Thalidomide has been found to be an active agent in the management of multiple myeloma. A published report demonstrates a significant response rate in 32% of subjects whose disease progressed following other therapy. Two of the 84 subjects treated had complete remission with this therapy. The optimal timing for using this agent remains undetermined. Toxicity of the drug is predominantly sensory neuropathy, and because of the drugs teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy. Combinations of thalidomide with dexamethasone and clarithromycin (ie, clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone [Decadron]) have been reported to have extremely high response rates. Thalidomide is now often used as first-line therapy either as a single agent or in combination with steroids. An analogue of thalidomide (Revlimid) is being evaluated for approval by the FDA based on promising studies.

An exciting new chemotherapy approved for myeloma, bortezomib (Velcade), is a reversible proteosome inhibitor. This was the first approved drug in a new class of anticancer therapy. Bortezomib has produced some remarkable results in persons with myeloma, with as high as 27.7% objective responses in the trial that led to its approval. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. The above results were in heavily pretreated patients, and the exact timing of bortezomib administration in the treatment plan of patients with myeloma is still evolving through ongoing research. Later studies have reported as high as 80% response rates when bortezomib was combined with melphalan.

Several promising new agents are under study for myeloma, including a Bcl-2 antisense oligodeoxynucleotide.

Intense research has focused on the use of interferon alfa to treat myeloma. This drug does not appear to be effective for inducing remission, and a randomized controlled trial showed that patients do not benefit from the addition of interferon to M and P. Interferon alfa appears to prolong remission in selected patients. For this use, interferon alfa may be administered after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been completed.

Bisphosphonates have a role in the secondary prevention of bony complications, including hypercalcemia, pathologic fracture, and spinal cord compression. A randomized placebo-controlled trial of pamidronate (eg, Aredia) in subjects with myeloma who had experienced one skeletal event demonstrated that the medication reduced the likelihood of a second skeletal event from 41% to 24% after 9 months of therapy. The report also noted improvements in pain, narcotic usage, and quality of life scores.

Zoledronic acid (Zometa) may be significantly more potent than pamidronate. Recent evidence suggests that osteonecrosis of the jaw may occur in some patients receiving bisphosphonate therapy.

Further Inpatient Care:

Patients may require hospitalization for treatment of pain or bony pathology.

Further Outpatient Care:

Patients with myeloma are at high risk of infection, especially from encapsulated organisms. Vaccinations against pneumococcal organisms and influenza are recommended. Consider vaccinating patients against Haemophilus influenzae B.

In/Out Patient Meds:

Medications include chemotherapy, zoledronic acid, pain medications, and erythropoietin.

Transfer:

Patients who may have spinal cord compression need a rapid evaluation, which may necessitate urgently transferring the patient to a center equipped with MRI for diagnosis or a center with a radiation oncologist for urgent therapy.

Deterrence/Prevention:

No preventative measures are known.

Complications:

Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal cord compression)

Infection

Anemia

Renal failure

Amyloidosis

Prognosis:

Many schemas have been published to aid in determining the prognosis of patients with multiple myeloma. One schema uses C-reactive protein and beta-2 microglobulin.

If levels of both are less than 6 mg/L, the median survival is 54 months.
If the level of only one component is less than 6 mg/L, the median survival is 27 months.
If levels of both values are greater than 6 mg/L, the median survival is 6 months.

Renal impairment (ie, stage B disease or creatinine level >2 mg/dL at diagnosis) is indicative of a poor outcome.

The prognosis for survival in unselected patients with multiple myeloma is 3 years (ie, median survival).

Patient Education:

Patient education is very important in the management of multiple myeloma. The International Myeloma Foundation offers educational resources, a quarterly newsletter, and conferences. Patients or physicians can contact the International Myeloma Foundation by phone at (800) 452-CURE or on the World Wide Web at International Myeloma Foundation.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Myeloma.

MISCELLANEOUS

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Medical/Legal Pitfalls:

Failure to consider spinal cord compression in patients with multiple myeloma who report back pain, bowel or bladder control problems, or neuropathy because as many as 20% of patients with myeloma may experience a spinal cord compression during the course of their illness

Failure to recognize that long-term neurologic function is directly related to the rapidity of diagnosis and the institution of appropriate therapy

Special Concerns:

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, M protein deviations, and skin changes.

Amyloidosis is often secondary to myeloma but may develop without myeloma. The absence of sufficient numbers of plasma cells in the bone marrow or M protein to meet diagnostic criteria is typical for amyloidosis.

Indolent myeloma is the same as myeloma except patients with indolent myeloma have no (or very limited) bone disease, a performance status greater than 70%, a hemoglobin level greater than 10 g/dL, calcium within the reference range, a creatinine level of less than 2 mg/dL, no infections, and low (ie, <7 g/dL for IgG, <5 g/dL for IgA) M protein levels.

Smoldering myeloma is the same as indolent myeloma except that patients with smoldering myeloma have less than 30% plasma cells in their bone marrow and they have no bone disease.

PICTURES

Section 10 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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Caption: Picture 2. Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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Caption: Picture 3. Radiograph of the skull demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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Picture Type: CT

Caption: Picture 4. Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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BIBLIOGRAPHY Section 11 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Multiple Myeloma excerpt