AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 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.

Related eMedicine topics:
Hyperviscosity Syndrome
Light Chain-Associated Renal Disorders
Light-Chain Deposition Disease
Multiple Myeloma [in the Radiology section]

Related Medscape topics:
Specialty Site Hematology-Oncology
CME FDA Safety Changes: Metvixia, Clozaril, Velcade
CME Management of Multiple Myeloma Reviewed
CME Strategies for Discovering Novel Cancer Biomarkers Through Utilization of Emerging Technologies
Bortezomib Improves Outcomes in Initial Treatment of Myeloma

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 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.

Frequency

United States

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.

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.^{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.

Related Medscape topics:
Specialty Site Neurology & Neurosurgery
Specialty Site Orthopaedics

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 of multiple myeloma is 3:2.

Age

The median age of patients with multiple myeloma is 68 years for men and 70 years for women.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

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).

• Bone pain
• • 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.
• 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 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.
• 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 multiple myeloma.
• Hyperviscosity
• • 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.
• Neurologic symptoms
• • 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.

Physical

• 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

Causes

• Genetic causes
• • 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
• • 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.

DIFFERENTIALS

Section 4 of 11  

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• Differentials
• Workup
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• Follow-up
• Miscellaneous
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Other Problems to Be Considered

See Special Concerns.

WORKUP

Section 5 of 11  

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Lab Studies

• Perform a complete blood cell (CBC) count to determine if the patient has anemia, thrombocytopenia, or leukopenia.
• Obtain a comprehensive metabolic panel to assess levels of a patient's total protein, albumin and globulin, blood urea nitrogen (BUN), creatinine, and uric acid, which is high if the patient has high cell turnover or is dehydrated.
• Obtain 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).
• Obtain a 24-hour urine collection for the Bence Jones protein (ie, lambda light chains), protein, and creatinine
• • Quantification of proteinuria is useful for the diagnosis of multiple myeloma (>1 g of protein in 24 h is a major criterion) and for monitoring the response to therapy.
  • Creatinine clearance can be useful for defining the severity of the patient's renal impairment.
• Quantitative immunoglobulin levels (ie, IgG, IgA, IgM)
• • A minor diagnostic criterion for multiple myeloma is the suppression of nonmyelomatous immunoglobulin.
  • Also, the level of multiple myeloma protein (ie, M protein level), as documented by the immunoglobulin level, can be useful as a marker to assess the response to therapy.
• Beta-2 microglobulin
• • Beta-2 microglobulin is a very strong predictor of multiple myeloma outcome; some studies suggest it is more powerful than the disease stage.⁶
  • 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 multiple myeloma, which is one reason that it is a useful prognosticator in multiple myeloma. The prognosis of patients with multiple myeloma and impaired renal function is reduced.
• C-reactive protein (CRP)
• • CRP is useful for prognostication.⁶
  • CRP is a surrogate marker of interleukin (IL)-6 activity. IL-6 is often referred to as the plasma cell growth factor.
• Check the serum viscosity in patients with central nervous system (CNS) symptoms, nosebleeds, or very high M protein levels.

Imaging Studies

• Skeletal series
• • Perform a complete skeletal series at multiple myeloma 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 multiple myeloma. Cytokines secreted by multiple myeloma cells suppress osteoblast activity; therefore, typically, no increased uptake is observed.
• Magnetic resonance imaging (MRI)
• • Findings from MRIs 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.
  • Positron emission tomography (PET) scanning
  • • A report in the Nov-Dec 2005 Anticancer Research issue described the utility of PET scanning in the staging of multiple myeloma.⁷ However, this imaging modality has not yet been integrated into standard practice.

Procedures

• Obtain bone marrow aspirate and biopsy samples from patients with multiple myeloma to calculate the percentage of plasma cells in the aspirate (reference range, up to 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 in multiple myeloma. The most significant cytogenetic abnormality appears to be deletion of 17p13. This abnormality is associated with shorter survival, more extramedullary disease, and hypercalcemia. This locus is the site of the p53 tumor suppressor gene. Chromosome 1 abnormalities, and c-myc defects are also significant prognostic factors in multiple myeloma.

Histologic Findings

In patients with multiple 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 multiple 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. Currently 2 staging systems for multiple myeloma are in use: the first described, the Salmon-Durie system, and the second, the International Staging System, developed by the International Myeloma Working Group.

Salmon-Durie staging system for multiple myeloma⁸

• Stage I
• • 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
• • 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 less than 2 g/dL.
• Subclassification B involves a creatinine level greater than 2 g/dL.
• Stage I is associated with a median survival of longer than 60 months; stage II, 41 months; and stage III, 23 months. Stage B disease has a significantly worse outcome (eg, 2-12 mo in 4 separate series).

International Staging System for multiple myeloma⁹

• Stage I
• • Beta-2 microglobulin less than or equal to 3.5g/dL and albumin >3.5g/dL
  • CRP >4.0 mg/dL
  • Plasma cell labeling index <1%
  • Absence of chromosome 13 deletion
  • Low serum Il-6 receptor
  • Long duration of initial plateau phase
• Stage II
• • Beta-2 microglobulin <3.5g/dL
  • Albumin <3.5 g/dL
  • Beta-2 microglobulin level >3.5 to <5.5 g/dL
• Stage III
• • Beta-2 microglobulin >5.5 g/dL
• Stage I is associated with a median survival of 62 months; stage II, 44 months; and Stage III, 29 months.

TREATMENT

Section 6 of 11  

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Medical Care

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

An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with multiple myeloma.¹⁰ This study evaluated 638 consecutive untreated subjects with multiple 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 individuals 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 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.¹⁰ 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).

A systematic review by He et al demonstrated a reduction in vertebral compressions and time to progression with early systemic treatment for asymptomatic patients, but this study also revealed an increase in acute leukemia in the early treatment group.¹¹ The failure to demonstrate improved survival may be due to the small number of patients studied.

Patients with multiple myeloma for whom therapy is indicated typically receive chemotherapy. Our understanding of the cell biology of multiple myeloma and the ability to identify prognostic factors has led to the increasing individualization of treatment for affected patients. Physicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation. A randomized prospective study showed that this approach results in higher response rates and better disease-free survival rates. Recent advances in treatment include establishment of thalidomide, lenalidomide, and bortezomib as active agents in multiple myeloma.

Adjunctive therapy for multiple 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 multiple myeloma alone or from chemotherapy and has been shown to improve quality of life.¹²

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 cases of multiple myeloma in which 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 with multiple myeloma who present 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. A report by Ludwig et suggests that bortezomib-based therapy for multiple myeloma with renal failure may lead to reversal.¹

• Transplantation
• • Using the patient's own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense anti–multiple myeloma therapy. Physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then "rescue" patients by infusing patients' own stem cells.

    This process 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.¹³ 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 transplantation has been proposed as a way of overcoming the incomplete response to a single transplant. A 2-arm trial of single versus tandem transplantation revealed no difference in overall survival at 54 months.¹⁴

    In another 2-arm study that compared single versus tandem transplants for newly diagnosed multiple myeloma, Cavo et al showed that double autologous stem cell transplantation effected superior complete response or near complete response rates, relapse-free survival, and event-free survival, but it failed to significantly prolong overall survival.¹⁵ Benefits offered by double autologous stem cell transplantation were particularly evident among patients whose condition failed at least near complete response rates after one autotransplantation.

  • 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 multiple 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 may also 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%).¹⁶ 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 multiple myeloma with allogeneic transplantation less often than with autologous transplantation for several reasons.
  • • First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with multiple myeloma are older than the ideal age for allogeneic transplantation.
    • Second, the transplantation-related mortality rate is quite high in patients with multiple myeloma who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to 56% in different case 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 multiple myeloma allogeneic transplantation is changing the equation. A republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate.¹⁷ Progression-free survival at 18 months was roughly 30%.
• Radiation
• • Multiple 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 they did not observe dramatic success.

Surgical Care

Surgical therapy for multiple myeloma is limited to adjunctive therapy.

Consultations

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

Diet

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

Activity

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

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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, and need for surgery). In addition, erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

Treatment for multiple myeloma is best categorized based on the patient's age and prognostic factors. We will look at 3 separate categories: (1) the young, newly diagnosed patient, who is potentially a transplant candidate; (2) high-risk patients who are potentially transplant candidates; and (3) newly diagnosed elderly patients who are not transplant candidates.

The young, newly diagnosed patient, who is potentially a transplant candidate

Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy has been used to decrease the tumor burden in multiple myeloma to bring patients to transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Because of the infusion, patients require a central venous access catheter. In selected patients, this therapy can be performed in an outpatient setting.

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. 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. This is now considered suboptimal treatment given the higher response rates of new novel agents.

Thalidomide has been found to be an active agent in the management of multiple myeloma. Several randomized trials have compared thalidomide to VAD-like regimens, showing its superiority as an induction regimen. When VAD was compared with thalidomide plus dexamethasone¹⁸; thalidomide, doxorubicin, plus dexamethasone¹³; and thalidomide plus VAD,¹⁹ the thalidomide-containing regimens showed better response rates.

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids in patients with multiple myeloma. The toxicity of this drug is predominantly sensory neuropathy, and because of the drug's teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy.

Bortezomib, a proteosome inhibitor, has shown striking anti–multiple myeloma activity, with objective responses as high as 27.7% observed in a phase II trial which led to its approval by the Food and Drug Administration (FDA) in 2003. This was studied in patients with relapsed and heavily pretreated multiple myeloma.²⁰ Later studies have reported response rates as high as 80% when bortezomib is combined with melphalan.

A randomized trial from the Intergroupe Franςais du Myélome (IFM) compared bortezomib plus dexamethasone with VAD for induction, showing response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD arm (P < .001).²¹ This regimen has been shown to be active not only in the pretransplantation setting but also posttransplantation. Following high-dose therapy and autologous transplantation, the very good partial response (VGPR) or better rate continued to favor bortezomib plus dexamethasone (61.7% vs. 41.7%, P < .001). This benefit was observed independent of beta-2 microglobulin or adverse cytogenetic risk groups.

Similarly, a superior response rate was seen when bortezomib, thalidomide, plus dexamethasone was compared with thalidomide plus dexamethasone in a large phase 3 study from the Italian GIMEMA group (Gruppo Italiano Malattie e Matologiche dell' Adulto [Italian Group for Adult Hematologic Diseases]); 93% in the when bortezomib, thalidomide, plus dexamethasone arm versus 80% in the thalidomide plus dexamethasone arm, in which patients went on to receive tandem autologous stem cell transplantation.²² As before, response was independent of adverse prognostic risk factors.

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and renal failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. Despite these results, the exact timing of bortezomib administration in the treatment plan of patients with newly diagnosed multiple myeloma is still evolving through ongoing research.

An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of multiple myeloma therapy. In the randomized, double-blinded, placebo-controlled SWOG trial S0232A, lenalidomide plus high-dose dexamethasone was compared with high-dose dexamethasone alone as treatment for newly-diagnosed multiple myeloma.¹⁸ This study showed the superiority of the lenalidomide plus high-dose dexamethasone arm.

The overall response rate was 84% in the lenalidomide plus high-dose dexamethasone group versus 53% in the high-dose dexamethasone group, with 22% of patients achieving complete remission in the lenalidomide plus high-dose dexamethasone arm.¹⁸ Progression-free survival and overall survival favored lenalidomide plus high-dose dexamethasone, but 12-month survival for both arms was >90%. A very important observation however, was the high incidence of deep venous thrombosis in the lenalidomide plus high-dose dexamethasone arm.

In another randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide (LD) plus low-dose dexamethasone (Ld) in newly diagnosed multiple myeloma, the overall response rate for LD was superior (82%) to that for Ld (70%), with an improvement in the VGPR-or-better rate for LD (44% vs 26%) evaluated after 4 months.²³ When best overall response was compared, LD again was superior, with an overall response rate of 82% compared with 71% for Ld. However, there was no difference in progression-free survival between the 2 arms. Overall survival continued to favor the Ld arm; however, for patients younger than 65 years, there was no benefit in survival for Ld over LD.²³ 

Although these data are very encouraging and promising, we will need further studies to help define the exact timing and role of novel agents in the treatment of multiple myeloma. Patients tolerate lenalidomide 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 not it does not require hospitalization for infection or transfusion solely from the chemotherapy.

High-risk patients who are potentially transplant candidates

High-risk multiple myeloma patients are those with advanced stage disease, according to the International Staging System stage III; those with poor cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome 13, inactivation of P53; and those with a complex karyotype. Patients with very high proliferative rates are also included in this classification. This group represents about 25% of those with newly diagnosed multiple myeloma, with an expected median survival of 2 years or less. Although they respond to traditional therapies for induction, these individuals tend to relapse rapidly. Therefore, novel agents should be considered up front for these patients.

The advent of novel agents (thalidomide, lenalidomide, and bortezomib) has substantially improved outcomes in these high-risk groups. In fact, they appear to overcome the influence contributed by poor cytogenetics.^{24, 25} Once a response has been achieved, then these patients can be brought to autologous stem cell transplantation.

Newly diagnosed elderly patients who are not transplant candidates

All of the above regimens may be used in patients who are not being considered for autologous stem cell transplantation. The following, however, can only be used in patients not going for transplantation, as they impair stem cell reserve. The gold standard has been melphalan and prednisone (M and P) as far back as the 1950's. A meta-analysis of 4930 patients from 20 randomized trials compared melphalan and prednisone to other drug combinations and showed a significantly higher response rate (60%) with this combination, with a response duration of 18 months and overall survival of 24 to 36 months.²⁶

A 3-arm study looked at melphalan and prednisone plus thalidomide versus melphalan and prednisone versus VAD induction, followed by high-dose melphalan and autologous stem cell transplantation in 447 patients between ages 65 and 75 years.²⁷ The patients were randomized, with overall survival as the primary endpoint. The response rate in the melphalan and prednisone plus thalidomide arm and transplantation arm was similar; the complete responses was significantly better in the melphalan and prednisone plus thalidomide and the transplantation arms than the melphalan and prednisone arm.²⁷ Melphalan and prednisone plus thalidomide is now recommended as first-line treatment.

Intense research has focused on the use of interferon alfa to treat multiple 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 melphalan and prednisone.²⁸ Interferon alfa appears to prolong remission in selected patients with multiple myeloma. For this use, interferon alfa may be administered after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been completed. The toxicity of interferon and the availability of alternate interventions has significantly limited the role of interferon alfa.

Bisphosphonates have a role in the secondary prevention of bony complications in multiple myeloma, including hypercalcemia, pathologic fracture, and spinal cord compression. A randomized placebo-controlled trial of pamidronate (eg, Aredia) in subjects with multiple 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.²⁹ The investigators also noted improvements in pain, narcotic usage, and quality of life scores. A 2007 systematic review of the use of bisphosphonates in multiple myeloma confirmed a number-needed-to-treat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was seen.³

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.³⁰ The management of osteonecrosis of the jaw is evolving, and no definitive data have yet been published. Collaboration with knowledgeable dentists and oral surgeons is essential. Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.  

Refractory or relapsed multiple myeloma

Patients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the multiple myeloma relapse occurs greater than 6 months from the initial therapy, then the initial regimen can be used again. Bortezomib has a well-established role as salvage therapy based on a phase III randomized trial showing a response rate of 38% relative to 18% in patients receiving dexamethasone only.²⁰ Median progression-free survival was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group.

An important prospective placebo controlled trial of the addition of lenalidomide to dexamethasone in relapsed cases of multiple myeloma demonstrated spectacular results.³¹ The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 in the lenalidomide plus dexamethasone group vs 4.7% in the placebo group). Overall survival was significantly improved.³¹

Drug Category: Chemotherapeutic Agents

The choice of chemotherapy depends on several factors, including the patient's performance status, age, renal function, desire for inpatient or outpatient therapy, and likelihood of receiving future autologous stem cell transplantation. In patients with renal failure or highly aggressive disease, VAD may be preferred. In elderly patients or patients in whom autologous transplantation is not possible in the future, M and P is preferred because of its ease of administration and low toxicity.

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Interferons

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally.

Drug Category: Bisphosphonates

Bisphosphonates inhibit bone resorption via action on osteoclast or osteoclast precursors.

Drug Category: Colony-stimulating Factors

Colony-stimulating factors induce erythropoiesis.

Drug Category: Antibiotics

Therapy with antibiotic agents must cover all the likely pathogens in the context of the multiple myeloma clinical setting.

Drug Category: Immunosuppressant Agents

Immunosuppressant agents inhibit key factors in the immune system that are responsible for immune reactions.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients with multiple myeloma may require hospitalization for the treatment of pain or bony pathology.

Further Outpatient Care

• Patients with multiple 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. Consideration of the use of the herpes zoster vaccine should be given.

In/Out Patient Meds

• Medications for the treatment of multiple myeloma include chemotherapy, zoledronic acid, pain medications, and erythropoietin.

Transfer

• Patients with multiple myeloma 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 for multiple myeloma 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 CRP and beta-2 microglobulin.
• • If levels of both proteins 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 protein 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 (800-452-2873) in the US and Canada or on the World Wide Web at International Myeloma Foundation.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials