AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

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

INTRODUCTION

Section 2 of 9  

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

Background

Multiple myeloma (MM) is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow. The disease results in the production of monoclonal immunoglobulins, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP). Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Excessive production of M proteins can lead to renal failure, hyperviscosity, and recurrent infections. MM accounts for 10% of all hematologic cancers.

Pathophysiology

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains. The role of cytokines in the pathogenesis of MM is an important area of current research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems and also general processes.

Regarding skeletal factors, isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia due to production of the osteoclast-activating factor. Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. Among the hematologic processes, bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation. Renal conditions include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy, amyloidosis, and glomerulosclerosis. The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or CNS symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Frequency

United States

MM infrequently occurs, accounting for 1% of all malignancies in the United States and 10% of all hematologic malignancies. More than 13,000 new cases are diagnosed each year.

International

The incidence is 4 cases per 100,000 population per year. MM is rare among the Asian population, with an incidence of 2 cases per 100,000.

Mortality/Morbidity

Survival rates of patients with myeloma vary substantially. See also Workup, Histologic Findings; Follow-up, Complications; and Follow-up, Prognosis.

• In 1999, approximately 13,700 new cases of myeloma were diagnosed, and more than 1,100 people died form the disease in the United States.
• Approximately 3% of patients live longer than 10 years.
• Bacterial infection is the leading cause of death in patients with myeloma.

Race

• In the United States, African Americans are twice as likely as whites to have myeloma, with a ratio of 2:1.
• Myeloma is rare among people of Asian descent, with an incidence of only 1-2 cases per 100,000 population.

Sex

MM occurs slightly more frequently in men than in women.

Age

• Myeloma is age dependent, with less than 2% of cases occurring in individuals younger than 40 years.
• The median patient age at diagnosis is 65 years.
• Only 18% of patients are younger than 50 years, and 3% of patients are younger than 40 years.

CLINICAL

Section 3 of 9  

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

History

• The diagnosis is incidental in 30% of cases. MM is often discovered when patients are being evaluated for unrelated problems.
• In one third of patients, MM is diagnosed after a pathologic fracture occurs; such fractures commonly involve the axial skeleton.
• Two thirds of patients complain of bone pain, commonly with lower back pain. This bone pain is frequently located in the back, long bones, skull, and/or pelvis.
• Patients may complain of nonspecific constitutional symptoms related to hyperviscosity and hypercalcemia.
• Symptoms of hyperviscosity include the following:
• • Generalized malaise
  • Infections
  • Fever
  • Bleeding
  • Headaches
  • Bruising
  • Paresthesia
  • Sensory loss
  • Sluggish mentation
• Symptoms of hypercalcemia include the following:
• • Nausea
  • Fatigue
  • Thirst

Physical

• On head, ears, eyes, nose, and throat (HEENT) examination, the eyes may show exudative macular detachment, retinal hemorrhage, or cotton-wool spots.
• Macroglossia may occur secondary to amyloid deposition in the tongue.
• On evaluation of the abdomen, hepatosplenomegaly may be discovered.
• Cardiovascular system (CVS) examination may reveal cardiomegaly secondary to immunoglobulin deposition.
• On central nervous system (CNS) examination, the patient may have neuropathy, myopathy, a Tinel sign, or a Phalen sign due to carpel tunnel compression secondary to amyloid deposition.
• Bone pain and pathologic fractures may be observed.
• • In general, painful lesions that involve at least 50% of the cortical diameter of a long bone or lesions that involve the femoral neck or calcar femorale are at high (50%) risk for a pathologic fracture.
  • The risk of fracture is lower in lesions of the upper extremity than those of the lower extremity.
  • Even a small cortical defect can decrease torsional strength by as much as 60% (stress riser effect).

Causes

The etiology of MM is not established.

• Radiation may play a role in some patients. An increased risk has been reported in atomic-bomb survivors exposed to more than 50 Gy.
• An increased risk has been reported in farmers, especially in those who use herbicides and insecticides, and in people exposed to benzene and other organic solvents.
• MM has been reported in 2 or more first-degree relatives and in identical twins, although no evidence suggests a hereditary basis for the disease.
• A relationship between MM and preexisting chronic inflammatory diseases has been suggested. However, a case control study provides no support for the role of chronic antigenic stimulation.
• Human herpesvirus 8 (HPV8) infection of bone marrow dendritic cells was found in patients with MM and in some patients with monoclonal gammopathy of undetermined significance (MGUS).

DIFFERENTIALS

Section 4 of 9  

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

Other Problems to be Considered

MGUS
Smoldering MM
Primary amyloidosis
Heavy chain disease
Plasma cell leukemia

WORKUP

Section 5 of 9  

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

Lab Studies

• The CBC count and differential may show pancytopenia, abnormal coagulation, and an increased erythrocyte sedimentation rate (ESR). The reticulocyte count is typically low.
• Peripheral blood smears may show Rouleau formation.
• Chemical screening, including calcium and creatinine SPEP, immunofixation, immunoglobulin quantitation may show azotemia, hypercalcemia, an elevated alkaline phosphatase level, and hypoalbuminemia. A high lactic dehydrogenase (LDH) level is predictive of an aggressive lymphomalike course.
• SPEP is a useful screening test for detecting M proteins.
• • An M component is usually detected by means of high-resolution SPEP. The kappa-to-lambda ratio has been recommended recently as a screening tool for detecting M-component abnormalities.
  • An M-component serum concentration of 30 g/L is a minimal diagnostic criterion for MM.
  • In about 25% of patients, M protein cannot be detected by using SPEP.
• Routine urinalysis may not indicate the presence of Bence Jones proteinuria. Therefore, a 24-hour urinalysis by means of UPEP or immunoelectrophoresis may be required.
• • UPEP or immunoelectrophoresis can also be used to detect an M component and kappa or lambda light chains.
  • The most important means of detecting MM is electrophoretic measurement of immunoglobulins in both serum and urine.

Imaging Studies

• Simple radiography is indicated for the evaluation of skeleton lesions, and a skeletal survey is performed when myeloma is in the differential diagnosis.
• • Conventional plain radiography can usually depict lytic lesions.
  • Plain radiographs can be supplemented by CT scanning to assess cortical involvement and risk of fracture.
  • Lytic bone lesions appear as multiple, rounded, punched-out areas found in the skull, vertebral column ribs, and/or pelvis. Less common but not rare sites of involvement include the long bones.
• MRI is useful in detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression. MRI can depict as many as 40% of spinal abnormalities in patients with asymptomatic gammopathies in whom radiographic studies are normal.
• On technetium bone scanning, more than 50% of lesions can be missed.

Procedures

• Bone-marrow biopsy enables a more accurate evaluation of malignancies than does bone marrow aspiration.
• MM is characterized by an increased number of bone marrow plasma cells.
• Plasma cell shows low proliferative activity, as measured by using the labeling index.
• • This index is a reliable parameter for the diagnosis of MM.
  • High values are strongly correlated with progression of the disease.

Histologic Findings

Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic histologic findings. With the plasmacytic type, median survival is approximately 39.7 months. With the mixed cellular type, survival is 16.1 months, and with the plasmablastic type, survival is 9.8 months.

Staging

The Durie and Salmon classification of MM is based on 3 stages and additional subclassifications.

• In stage I, the MM cell mass is less than 0.6 cells X 10¹²m², and all of the following are present:
• • Hemoglobin value greater than 10 g/100 mL
  • Serum calcium value less than 12 mg/100 mL (normal)
  • Normal bone structure (scale 0) or only a solitary bone plasmacytoma on radiographs
  • Low M-component production rates
    • IgG value less than 5 g/100 mL
    • IgA value less than 3 g/100 mL
    • Urine light-chain M component on electrophoresis less than 4 g/24 h
• In stage II, the MM cell mass 0.6-1.2 cells per 10¹²m². The other values fit neither those of stage I nor those of stage III.
• In stage III, the MM cell mass greater than 1.2 cells per 10¹²m², and all of the following are present:
• • Hemoglobin value equal to 8.5 g/100 mL
  • Serum calcium value greater than 12 mg/100 mL
  • Advanced lytic bone lesions (scale 3)
  • High M-component production rates
    • IgG value greater than 7 g/100 mL
    • IgA value greater than 5 g/100 mL
    • Urine light-chain M component on electrophoresis greater than 12 g/24 h
• Subclassifications include the following:
• • Relatively normal renal function (serum creatinine value <2 mg/100 mL)
  • Abnormal renal function (serum creatinine value > 2 mg/100 mL)

TREATMENT

Section 6 of 9  

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

Medical Care

Although MM remains incurable, several drug therapies are valuable in the treatment of patients with MM. A combination of melphalan and prednisone remains the standard chemotherapy. As monotherapy or in combination, interferon alfa-2b and prednisone modestly prolong the disease-free interval. Early evidence suggests that bisphosphonates may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence.

The resistance mechanisms to chemotherapy in MM are reduced drug concentration at the target site of action, alterations in the drug target, and inhibition of drug-induced apoptosis. Factors mediating myeloma cell growth, patient survival rates, and the complex interaction of myeloma cells with the bone marrow microenvironment have provided a framework for the rational design of therapeutic agents that may ultimately lead to improved disease-free survival and, potentially, a cure Overall, the care of patients with MM is complex and should focus on treatment of the disease process and any associated complications.

Chemotherapy

Patients with symptomatic MM require chemotherapy. In asymptomatic patients with MM, treatment is delayed until disease clinically progresses or until serum or urine levels of M protein substantially increase.

Chemotherapy with melphalan-prednisone (MP) is the standard treatment for MM. It consists of melphalan 9 mg/m² and prednisone 100 mg given on days 1-4, with courses repeated at 4- to 6-week intervals for at least 1 year.

The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction after chemotherapy is used as a sign of response. A 50% reduction in M-component is considered a good clinical response (according to the Chronic Leukemia-Myeloma Task Force). MP induces a response in 50-60% of patients with MM. Disappearance of the M component on electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.

Combination chemotherapies may be appropriate. Vincristine, Adriamycin, and dexamethasone (VAD) chemotherapy is a new tool in MM treatment. It is the best standard-dose treatment for patients in whom relapse occurs. The following treatments may be helpful: high-dose chemotherapy (melphalan) with stem cell transplantation, low-dose therapy with melphalan (essentially palliative), immunotherapy with bortezomib (promising preliminary phase I/II study result with Velcade [bortezomib] combined with thalidomide to treat advance myeloma in which previous therapies failed).

For MM therapy, the MP regimen no longer is the criterion standard, as it is suitable for less than 50% of patients. Alternative approaches, such as VAD-based regimens and high-dose chemotherapies with stem-cell support are preferred for most patients.

High-dose chemotherapy in cases of autotransplantation has shown encouraging complete remission rates over several years in phase 1 studies, and it was superior to conventional therapy in a randomized study. Autologous peripheral blood stem cells (PBSCs) in support of high-dose melphalan is now considered standard therapy for young patients with myeloma. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ) and the proteosome inhibitor PS 341 (Velcade; Millenium, Cambridge, Mass).

Radiation therapy

Myeloma is sensitive to radiation therapy. If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated. Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing should be limited for the first 4-6 weeks.

American Society of Clinical Oncology (ASCO) patient guide

For bone resorption, bisphosphonates are specific inhibitors of osteoclastic activity. They are used to treat bone resorption. Intravenous pamidronate is effective in preventing skeletal complications.

Lytic disease or fracture may be observed on plain radiographs.

Pamidronate at 90 mg delivered intravenously over at least 2 hours or zoledronic acid at 4 mg given over 15 minutes every 3-4 weeks are recommended. For all patients receiving chronic pamidronate or zoledronic acid therapy, the ASCO panel recommends urinalysis every 3-6 months to test for albuminuria and azotemia. In patients with preexisting renal disease and a serum creatinine value of less than 265 µmol/L or less than 3 mg/dL, no change in dose, infusion time, or interval is required.

Thalidomide therapy

Nearly one third of patients with advanced MMs in which current standard chemotherapy or stem cell transplantation fail respond to thalidomide for a median duration of nearly 1 year, as shown in a Mayo Clinic study. Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm.

Allotransplants

Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens (mini-allotransplantation) may hold promise for more widely exploiting this feature.

Surgical Care

Surgical care consists of prophylactic fixation of pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic fractures.

Prophylactic treatment of impending fractures and the treatment of pathologic fractures may involve bracing. In general, bracing is not effective for the long bones, though it may be effective for treating spinal involvement without neurologic compromise.

Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or joint surface is involved, resection of the diseased bone and reconstruction with a total joint or, more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe destruction of the diaphysis may require reconstruction with combinations of methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.

Consultations

Patients with MM have significant systemic comorbidities. These include potentially severe hematologic, infectious, and metabolic diseases. The orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in conjunction with the radiation oncologists and the medical oncologists.

Activity

In general, patients with activity-related pain in either the femur or tibia should be given a walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the target bone. Prophylactic treatment of an impending fracture is usually easier than reconstruction of a pathologic fracture. Therefore, one should have a low threshold for initiating protected weight bearing.

MEDICATION

Section 7 of 9  

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

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Corticosteroids

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

Drug Category: Immunomodulatory agents

These regulate key factors of the immune system.

Drug Category: Antineoplastic agents

These inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 9  

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

Further Outpatient Care

• The following laboratory results are helpful in the follow-up care of patients with MM:
• • CBC count, chemical profile 7 (especially BUN and creatinine levels), serum calcium level, and serum uric acid level, and SPEP findings
  • M-component level in the serum and/or urine (This is an indicator of tumor burden; a reduction with chemotherapy is used as a sign of a treatment response.)
  • Serum level of beta-2-microglobin (B2M) (An elevated level indicates a large malignant cell mass, renal impairment, or both.)
  • Serum LDH level (A high level is predictive of an aggressive lymphomalike course.)

Complications

• Renal failure and insufficiency are seen in 25% of patients with MM:
• • Myeloma kidney syndrome with multiple etiologies
  • Amyloidosis with light chains
  • Nephrocalcinosis due to hypercalcemia
• Anemia, neutropenia, or thrombocytopenia is due to bone marrow infiltration of plasma cells.
• Bacterial infection is the leading cause of death in patients with myeloma. The highest risk is in the first 2-3 months of chemotherapy.
• Radiculopathy and/or cord compression may occur due to skeletal destruction and nerve compression.
• Bone disease may result:
• • Severe bone pain, pathologic fracture due to lytic lesions
  • Increased bone resorption leading to hypercalcemia
  • Spinal cord compression
• Purpura, retinal hemorrhage, papilledema, coronary ischemia, seizures, and confusion are due to hyperviscosity syndrome.
• Thrombosis and Raynaud phenomenon due to cryoglobulinemia may be present.
• Hypercalcemia may involve polyuria and polydipsia, muscle cramps, constipation, and a change in the patient's mental status.

Prognosis

• MM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years.
• • The tumor burden and proliferation rate are the 2 key indicators for the prognosis in patients with MM.
  • B2M is an expression of tumor burden and is correlated with the Durie and Salmon staging system for assigning a prognosis.
• Poor prognostic factors include the following:
• • Tumor mass
  • Hypercalcemia
  • Bence Jones proteinemia
  • Renal failure
• The prognosis by treatment is as follows:
• • Conventional therapy: Overall survival is approximately 3 years, and event-free survival is less than 2 years.
  • High-dose chemotherapy with stem-cell transplantation: The overall survival rate is greater than 50% at 5 years.
  • Serum amyloid P retention: More than 50% of patients have a median survival of approximately 11 months.
  • Serum amyloid P retention: Median survival is 24 months.

Patient Education

• What is MM, and how does it affect the body? MM is a cancer of bone marrow. People with myeloma have uncontrolled growth of plasma cells and have large numbers of plasma cells in their bone marrow. Plasma cells produce enzymes that stimulate the growth of osteoclast, which destroys bone (bone resorption). Plasma cells secrete proteins called antibodies, which can potentially be dangerous and cause thickening of the blood (stroke-induced condition).
• What are the causes of myeloma? The etiology is unknown. Fertilizers and insecticides may cause MM. Myeloma usually occurs in people older than 55 years, it occurs more commonly in African Americans than in whites, and it occurs slightly more frequently in men than in women.
• What is the treatment for myeloma? Myeloma is life threatening, but treatment helps patients to live better and longer. Remission can last months to decades. The 2 medicines most often used are prednisone (a steroid) and melphalan.
• What are the adverse effects of medicine? Like most cancer treatments, myeloma treatments generally involved the use of strong drugs to destroy malignant cells; however, these can have adverse effects. Patients undergo blood tests once a month while taking these medicines. Patients will probably lose their hair and have skin rashes, cough, fever, bleeding, and possibly other adverse effects.
• What are some of the complications of MM? Pain and/or fractures may result when myeloma leads to destruction of bone. Orthopaedic surgeons have developed improved techniques to treat these pathologic fractures and also to prevent them from occurring. Radiation therapy and newer medications (bisphosphonates) may also be used to effectively treat bone disease.
• Where can additional information be found? For information on MM, visit the International Myeloma Foundation (IMF) or call the IMF at 1-800-452-CURE.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Myeloma.

REFERENCES

Section 9 of 9

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

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Article Last Updated: Apr 13, 2005