eMedicine Specialties > Orthopedic Surgery > Neoplasms

Myeloma

Seema S Rizvi, MD, Associate Medical Director, Lutheran Care Center
Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center

Updated: May 29, 2009

Introduction

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.^1,2

The American Cancer Society estimates that about 20,580 new cases of multiple myeloma (11,680 in men and 8,900 in women) will be diagnosed during 2009. In the United States, the lifetime risk of getting multiple myeloma is 1 in 161 (0.62%).³

About 10,580 Americans (5,640 men and 4,940 women) are expected to have died of multiple myeloma in 2008.³

The 5-year relative survival rate for multiple myeloma is around 35%. Survival is higher in younger people and lower in the elderly.^3,4,5  

Pathophysiology

The malignant cells of multiple myeloma (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 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/orcordcompression 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

The American Cancer Society estimates that in the United States, 20,580 new cases of multiple myeloma will be diagnosed during 2009, with 11,680 cases occurring in men and 8,900 in women. The lifetime risk of getting multiple myeloma is 1 in 161 (0.62%).³

International

The incidence is 4 cases per 100,000 population per year. Multiple myeloma 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.

• About 10,580 Americans (5,640 men and 4,940 women) are expected to die of multiple myeloma in 2008.³
• The 5-year relative survival rate for multiple myeloma is around 35%. Survival is higher in younger people and lower in the elderly.³
• Bacterial infection is the leading cause of death in patients with myeloma.³

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

The American Cancer Society estimates that in the United States, 20,580 new cases of multiple myeloma will be diagnosed during 2009, with 11,680 cases in men and 8,900 in women.³

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

History

• The diagnosis is incidental in 30% of cases. Multiple myeloma (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 precise etiology of multiple myeloma (MM) has not yet been 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).
• Some studies have shown that abnormalities of certain oncogenes, such as c-myc, are associated with development early in the course of plasma cell tumors and that abnormalities of oncogenes such as N-ras and K-ra are associated with development after bone marrow relapse. Abnormalities of tumor suppressor genes, such as p53, have been shown to be associated with spread to other organs.³

Differential Diagnoses

Malignant Lymphoma
Metastatic Carcinoma

Other Problems to Be Considered

MGUS
Smoldering MM
Primary amyloidosis
Heavy chain disease
Plasma cell leukemia

Workup

Laboratory Studies

• The complete blood count (CBC) 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, and 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 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 multiple myeloma 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.
• Multiple myeloma (MM) is characterized by an increased number of bone marrow plasma cells.
• Plasma cells show 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

Staging

The Durie and Salmon classification of multiple myeloma (MM) is based on 3 stages and additional subclassifications.

• In stage I, the MM cell mass is less than 0.6 cells X 10¹² m², 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 is 0.6-1.2 cells per 10¹² m². The other values fit neither those of stage I nor those of stage III.
• In stage III, the MM cell mass is greater than 1.2 cells per 10¹² m², 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

Medical Care

Although multiple myeloma (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.^{6,7,8,9,10,11,12}

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.^13,14,15

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 used 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), and immunotherapy with bortezomib.

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

In a Mayo Clinic study, nearly one third of patients with advanced MMs in whom current standard chemotherapy or stem cell transplantation failed were shown to respond to thalidomide for a median duration of nearly 1 year.¹⁶ 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.^17,18

Allotransplants

Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens (mini-allotransplantation) may hold promise for more widely exploiting this feature.^19,20

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 multiple myeloma 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 the 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

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

Corticosteroids

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

Prednisone (Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dosing

Adult

2 mg/kg PO qd

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Immunomodulatory agents

These regulate key factors of the immune system.

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

Dosing

Adult

200 mg PO qd; increase to maximum 800 mg/d

Pediatric

Not established

Interactions

May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine; due to teratogenic effects, women must use 2 additional methods of contraception or abstain from intercourse

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Perform pregnancy test within 24 h before therapy (weekly during first month, then monthly tests in women with regular menstrual cycles or q2wk in those with irregular cycles); bradycardia may occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must enter STEPS program established by manufacturer

Interferon alfa-2b (Intron A)

Recombinant DNA product. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may be important.

Dosing

Adult

5-10 million SC IU/m² or 3-7 times/wk

Pediatric

Not established

Interactions

Potential risk of renal failure with concurrent IL-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Contraindications

Documented hypersensitivity; patients who have anaphylactic sensitivity to mouse IgG, egg protein, or neomycin; autoimmune hepatitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Depression and suicidal ideation possible; severe or fatal GI hemorrhage infrequently reported; before therapy, determine peripheral blood hemoglobin, platelet, granulocyte, hairy cell, and bone marrow hairy cell values; monitor periodically (eg, monthly) during treatment to determine response; if no response within 6 mo, discontinue; if response occurs, continue until no further improvement observed; whether continued treatment after that time is beneficial not known

Antineoplastic agents

These inhibit cell growth and proliferation.

Vincristine (Oncovin, Vincasar PFS)

Inhibits microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at metaphase stage.

Dosing

Adult

1.4 mg/m² IV qwk

Pediatric

Not established

Interactions

Acute pulmonary reaction may occur with concurrent mitomycin-C; simultaneous administration of phenytoin and antineoplastic chemotherapy combination reduces blood levels of anticonvulsant and increases seizure activity

Contraindications

Documented hypersensitivity; patients with demyelinating form of Charcot-Marie tooth syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Acute uric acid nephropathy and severe bronchospasms reported; caution in preexisting neuromuscular disease

Doxorubicin (Adriamycin, Rubex)

Cytotoxic anthracycline antibiotic. Inhibits topoisomerase II and produces free radicals, which may cause DNA destruction. Combination of these 2 events can in turn inhibit growth of neoplastic cells. Used in combination with other chemotherapy drugs.

Dosing

Adult

40-60 mg/m² IV

Pediatric

Not established

Interactions

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity

Contraindications

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Colors urine red; periodically monitor CBC counts, hepatic function tests, and radionucleotide LVEF; may induce hyperuricemia; requires appropriate supportive and pharmacologic measures; irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

Monotherapy: 40-50 mg/kg IV in divided doses over 2-5 d; alternatively, 1-5 mg/kg/d PO

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Melphalan (Alkeran)

Inhibits mitosis by cross-linking DNA strands.

Dosing

Adult

0.25 mg/kg/d PO for 4 d on an intermittent schedule

Pediatric

Not established

Interactions

Concurrent administration with cyclosporine increases nephrotoxicity; cimetidine and H2 antagonists increase gastric pH, decreasing effects

Contraindications

Documented hypersensitivity; severe bone marrow depression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in compromised bone marrow reserve; reduce dose in renal insufficiency; pulmonary fibrosis and skin hypersensitivity reported; amenorrhea may occur; caution in previously diagnosed myelosuppression

Bortezomib (Velcade)

First proteasome inhibitors (anticancer agents) approved. Proteasome pathway is enzyme complex in all cells; degrades ubiquitinated proteins that control cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, decreasing cancer cell survival.

Dosing

Adult

1.3 mg/m² IV bolus 2 times/wk for 2 wk (days 1, 4, 8, and 11); rest for 10 d (days 12-21), then repeat cycle

Pediatric

Not established

Interactions

Substrate of CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4; may inhibit CYP450 2C19, therefore, caution with coadministration of isoenzyme 2C19 substrates (eg, barbiturates, phenytoin, valproic acid, imipramine, lansoprazole, warfarin)

Contraindications

Documented hypersensitivity to bortezomib, boron, or mannitol

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, fatigue, diarrhea, constipation, headache, decreased appetite, thrombocytopenia, anemia, fever, vomiting, and peripheral neuropathy; may cause hypotension; caution in hepatic impairment; allow at least 72 h between doses

Follow-up

Further Outpatient Care

• The following laboratory results are helpful in the follow-up care of patients with multiple myeloma:
  • CBC, chemical profile 7 (especially BUN and serum creatinine), serum calcium, and serum uric acid, 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 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 multiple myeloma²¹ :
  • 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 because of skeletal destruction and nerve compression.
• Bone disease may result in:
  • 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 cause polyuria and polydipsia, muscle cramps, constipation, and a change in the patient's mental status.

Prognosis

• Multiple myeloma (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 multiple myeloma (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 osteoclasts, which destroy 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. Orthopedic 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

1. Caers J, Vande broek I, De Raeve H, Michaux L, Trullemans F, Schots R, et al. Multiple myeloma--an update on diagnosis and treatment. Eur J Haematol. Nov 2008;81(5):329-43. [Medline].

2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. Jan 2009;23(1):3-9. [Medline].

3. Detailed Guide: Multiple Myeloma What Are the Key Statistics About Multiple Myeloma?. American Cancer Society. Available at http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_multiple_myeloma_30.asp. Accessed May 28, 2009.

4. Rodon P. Management and treatment of multiple myeloma in elderly patients. Ann Long-Term Care. 2002;10:20-7.

5. Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J, et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood. Apr 15 2008;111(8):4039-47. [Medline].

6. Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med. Feb 17 1994;330(7):484-9. [Medline].

7. Anderson KC, Hamblin TJ, Traynor A. Management of multiple myeloma today. Semin Hematol. Jan 1999;36(1 suppl 3):3-8. [Medline].

8. Barlogie B, Shaughnessy J, Tricot G. Treatment of multiple myeloma. Blood. Jan 1 2004;103(1):20-32. [Medline].

9. Desikan KR, Dhodapkar MV, Munshi NC, Barlogie B. Recent advances in the treatment of multiple myeloma. Curr Opin Hematol. Jul 1999;6(4):216-21. [Medline].

10. Kanis JA, McCloskey EV. Bisphosphonates in multiple myeloma. Cancer. Jun 15 2000;88(12 suppl):3022-32. [Medline].

11. Singhal S, Mehta J, Barlogie B. Advances in the treatment of multiple myeloma. Curr Opin Hematol. Jul 1997;4(4):291-7. [Medline].

12. Lust JA, Lacy MQ, Zeldenrust SR, Dispenzieri A, Gertz MA, Witzig TE, et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc. Feb 2009;84(2):114-22. [Medline].

13. Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF. New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol. Dec 2008;9(12):1157-65. [Medline].

14. Palumbo A, Rajkumar SV. Treatment of newly diagnosed myeloma. Leukemia. Mar 2009;23(3):449-56. [Medline].

15. Bensinger WI. Role of autologous and allogeneic stem cell transplantation in myeloma. Leukemia. Mar 2009;23(3):442-8. [Medline].

16. Kumar S, Witzig TE, Rajkumar SV. Thalidomid: current role in the treatment of non-plasma cell malignancies. J Clin Oncol. Jun 15 2004;22(12):2477-88. [Medline].

17. Ludwig H, Hajek R, Tóthová E, Drach J, Adam Z, Labar B, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. Apr 9 2009;113(15):3435-42. [Medline].

18. van Rhee F, Dhodapkar M, Shaughnessy JD Jr, Anaissie E, Siegel D, Hoering A, et al. First thalidomide clinical trial in multiple myeloma: a decade. Blood. Aug 15 2008;112(4):1035-8. [Medline].

19. Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F, et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood. Apr 2 2009;113(14):3375-82. [Medline].

20. Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T, et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood. Apr 2 2009;113(14):3383-91. [Medline].

21. Blade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med. Sep 28 1998;158(17):1889-93. [Medline].

22. Abeloff MD, Armitage AS, Lichter JO, Armitage N, eds. Clinical Oncology. 2nd ed. Churchill Livingstone;. 2000: 2597-8, 2602-3.

23. Amoura Z, Papo T, Ninet J, et al. Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med. Dec 1997;103(6):514-9. [Medline].

24. Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med. Jun 5 1997;336(23):1657-64. [Medline].

25. Boccadoro M, Pileri A. Diagnosis, prognosis, and standard treatment of multiple myeloma. Hematol Oncol Clin North Am. Feb 1997;11(1):111-31. [Medline].

26. Bubley GJ, Schnipper LE. Textbook of Clinical Oncology. 1995:470-83.

27. Dalton WS, Jove R. Drug resistance in multiple myeloma: approaches to circumvention. Semin Oncol. Oct 1999;26(5 suppl 13):23-7. [Medline].

28. Dunbar CE, Nienhuis AW. Multiple myeloma. New approaches to therapy. JAMA. May 12 1993;269(18):2412-6. [Medline].

29. George ED, Sadovsky R. Multiple myeloma: recognition and management. Am Fam Physician. Apr 1 1999;59(7):1885-94. [Medline].

30. Hachulla E, Maulin L, Deveaux M. Prospective and serial study of primary amyloidosis with serum amyloid P component scintigraphy: from diagnosis to prognosis. Am J Med. Jul 1996;101(1):77-87. [Medline].

31. Kyle RA. Maintenance therapy and supportive care for patients with multiple myeloma. Semin Oncol. Oct 1999;26(5 suppl 13):35-42. [Medline].

32. Rajkumar SV, Greipp PR. Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am. Dec 1999;13(6):1295-314, xi. [Medline].

Keywords

myeloma, multiple myeloma, MM, plasma cell dyscrasia, plasma cell proliferation, hematologic cancer, plasmacytoid lymphocytes, M proteins

Contributor Information and Disclosures

Author

Seema S Rizvi, MD, Associate Medical Director, Lutheran Care Center
Seema S Rizvi, MD is a member of the following medical societies: American Academy of Family Physicians and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center
Howard A Chansky, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Miguel A Schmitz, MD, Consulting Surgeon, Department of Orthopedics, Klamath Orthopedic and Sports Medicine Clinic
Miguel A Schmitz, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Society for Sports Medicine, and Arthroscopy Association of North America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Sean P Scully, MD, PhD, Professor, Department of Orthopedics, University of Miami
Sean P Scully, MD, PhD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, International Society on Thrombosis and Haemostasis, and Society of Surgical Oncology
Disclosure: Nothing to disclose.

CME Editor

Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital
Dinesh Patel, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Association of Physicians of Indian Origin, American College of International Physicians, and American College of Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Harris Gellman, MD, Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami School of Medicine
Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society
Disclosure: Nothing to disclose.

Related eMedicine topics

Multiple Myeloma (Hematology)

Multiple Myeloma (Radiology)

Monoclonal Gammopathies of Uncertain Origin (Hematology)

Heavy Chain Disease, Gamma (Hematology)

Heavy Chain Disease, Mu (Hematology)

Light-Chain Deposition Disease (Hematology)

Waldenstrom Hypergammaglobulinemia (Hematology)

Clinical guidelines

Guidelines on the diagnosis and management of multiple myeloma 2005.

Bortezomib in multiple myeloma and lymphoma: a clinical practice guideline.

American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma.

Clinical trials

Study of MAGE-A3 and NY-ESO-1 Immunotherapy in Combo With DTPACE Chemo and Auto Transplantation in Multiple Myeloma

Dexamethasone and Chemotherapy With or Without Plasma Exchange in Patients With Newly Diagnosed Multiple Myeloma and Acute Kidney Failure

High-Dose Melphalan and a Second Stem Cell Transplant or Low-Dose Cyclophosphamide in Treating Patients With Relapsed Multiple Myeloma After Chemotherapy

Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I, Stage II, or Stage III Multiple Myeloma

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)