Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of multiple myeloma and other plasma cell neoplasms. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Diagnosis.
• Cellular classification.
• Staging.
• Treatment options for different types of disorders.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

Note: Estimated new cases and deaths from multiple myeloma in the United States in 2008:^[1]

• New cases: 19,920.
• Deaths: 10,690.

Multiple myeloma is a systemic malignancy of plasma cells that is highly treatable but rarely curable. It is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. The median survival in the prechemotherapy era was about 7 months. After the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 to 30 months and a 10-year survival of 3%. Even further improvements in prognosis have occurred because of the introduction of newer therapies such as pulse corticosteroids, thalidomide, bortezomib, and autologous and allogeneic stem cell transplantation. The disease is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M protein) in the serum and/or urine, along with various clinical parameters, such as the hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy since almost all patients, except for rare patients with solitary bone tumors or extramedullary plasmacytomas, have generalized disease. Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.^[2]

The initial approach to the patient is to establish the diagnosis by:

1. Detection of an M protein in the serum or urine.
2. Detection of greater than10% of plasma cells on a bone marrow examination.
3. Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays.
4. Presence of soft tissue plasmacytomas.

References

Cellular Classification

Diseases associated with a monoclonal (or myeloma) protein (M protein) included in this presentation are:

1. Asymptomatic plasma cell neoplasia with minimal evidence of disease aside from the presence of an M protein (monoclonal gammopathy of undetermined significance [MGUS]).^[1] (Usually IgG kappa or gamma, IgA kappa or gamma.)
2. Symptomatic plasma cell neoplasia. (Usually IgG kappa or gamma, IgA kappa or gamma.)
   1. Primarily affecting bones:
      1. Multiple myeloma (94%).
      2. Solitary plasmacytoma (3%).
   2. Extramedullary plasmacytoma (3%).

      These usually occur in the nasopharynx, tonsils, or paranasal sinuses.^[2]

3. Macroglobulinemia.

   Patients often have lymphadenopathy and hepatosplenomegaly; less than 5% of patients have lytic bone lesions. (Usually IgM kappa or gamma.)

   1. Asymptomatic.
   2. Symptomatic.^[3]

   This entity is called lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

References

Stage Information

Multiple Myeloma

Stage I multiple myeloma

Stage I multiple myeloma means all of the following:

1. Hemoglobin greater than 10 g/dL.
2. Normal serum calcium.
3. Normal bone structure.
4. Low monoclonal (or myeloma) protein (M protein) production as shown by:
   1. IgG less than 5.0 g/dL.
   2. IgA less than 3.0 g/dL.
   3. Urinary kappa or gamma less than 4 g/24 hours.

Estimated myeloma cell mass: less than 0.6 trillion (10¹²)/m² (low burden).

The following subclassification of stages is used:

1. Creatinine less than 2.0 mg/dL.
2. Creatinine greater than or equal to 2.0 mg/dL.

Impaired renal function worsens prognosis regardless of stage.

Stage II multiple myeloma

Stage II multiple myeloma means multiple myeloma that fits in neither stage I nor stage III.

Estimated myeloma cell mass: 0.6 to 1.2 trillion (10¹²)/m² (intermediate burden).

The following subclassification of stages is used:

1. Creatinine less than 2.0 mg/dL.
2. Creatinine greater than or equal to 2.0 mg/dL.

Impaired renal function worsens prognosis regardless of stage.

Stage III multiple myeloma

Stage III multiple myeloma means one or more of the following:

1. Hemoglobin less than 8.5 g/dL.
2. Serum calcium greater than 12.0 mg/dL.
3. More than three lytic bone lesions.
4. High M protein production as shown by:
   1. IgG greater than 7.0 g/dL.
   2. IgA greater than 5.0 g/dL.
   3. Urinary kappa or gamma greater than 12.0 g/24 hours.

Estimated myeloma cell mass: greater than 1.2 trillion (10¹²)/m² (high burden).

The following subclassification of stages is used:

1. Creatinine less than 2.0 mg/dL.
2. Creatinine greater than or equal to 2.0 mg/dL.

Serum beta-2-microglobulin has been shown to be a reliable marker for prognosis.^[1] Since the great majority of symptomatic myeloma patients are classified as stage III by the Durie/Salmon criteria, this staging system has not proven to be very useful for identifying the patients with intermediate and poor prognosis. The International Myeloma Working Group studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.^[2] A new International Staging System was derived as follows, and most new clinical trials will use this staging system:

Stage I multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin greater than or equal to 3.5 (median survival of 62 months).

Stage II multiple myeloma: Beta-2-microglobulin less than 3.5 and albumin less than 3.5 or beta-2-microglobulin 3.5 to less than 5.5 (median survival of 44 months).

Stage III multiple myeloma: Beta-2-microglobulin greater than or equal to 5.5 (median survival of 29 months).

Impaired renal function worsens prognosis regardless of stage. Genetic aberrations detected by interphase fluorescence in situ hybridization (FISH) may define prognostic groups in retrospective and prospective analyses.^[3][4] Short survival and shorter duration of response to therapy have been reported with t(4;14)(p16;q32), t(14;16)(q32;q23), cytogenetic deletion of 13q-14, and deletion of 17p13 (p53 locus).^{[3][4][5][6][7]} Whether choice of therapy based on FISH analysis can influence outcome must await further prospective trials.

Isolated Plasmacytoma of Bone

If a solitary lytic lesion of plasma cells is found on skeletal survey in an otherwise asymptomatic patient, and a bone marrow examination from an uninvolved site contains less than 5% to 10% plasma cells, the patient has an isolated plasmacytoma of bone.^[8][9][10] About 25% of patients have a serum and/or urine M protein; this should disappear following adequate radiation of the lytic lesion. When clinically indicated, magnetic resonance imaging may reveal unsuspected bony lesions that were undetected on standard radiographs.

Extramedullary Plasmacytoma

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, should have skeletal x-rays and bone marrow biopsy.^[11][12][13] If these tests are negative, the patient has extramedullary plasmacytoma. About 25% of patients have serum and/or urine M protein; this should disappear following adequate radiation.

Macroglobulinemia

Macroglobulinemia is a proliferation of plasmacytoid lymphocytes secreting an IgM M protein. Patients often have lymphadenopathy and hepatosplenomegaly, but bony lesions are uncommon. No generally accepted staging system exists.

The term macroglobulinemia describes an increase in the serum concentration of a monoclonal IgM.^[14] Most patients are asymptomatic and do not require treatment. The most common symptoms and signs are fatigue, manifestations of hyperviscosity (e.g., headache, epistaxis, and visual disturbances), and neurologic abnormalities. Serum or plasma viscosity (relative to water) measures the risk of symptoms. The normal viscosity level is 1.7 to 2.1; symptoms may rarely appear between 3.0 and 4.0 but more commonly appear above 4.0. Emergent therapy (i.e., plasmapheresis and chemotherapy) is usually required above a viscosity level of 4.0. Lymphadenopathy and splenomegaly are found in about 33% of patients. The increased intravascular concentration of high molecular weight IgM leads to an expansion of the plasma volume, a dilutional anemia, and in extreme cases, congestive heart failure. Sludging of the blood can be seen in conjunctival and retinal veins with dilatation and segmentation of vessels (i.e., a link of sausage appearance), retinal hemorrhages, and papilledema. Similar problems with the circulation of blood in the central nervous system can cause ataxia, nystagmus, vertigo, confusion, and disturbances of consciousness.

The various disorders associated with the appearance of a monoclonal IgM include:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS). Patients are asymptomatic, the M protein is stable, and no lymphadenopathy, splenomegaly, or bony lesions are present.
2. Waldenström Macroglobulinemia (WM). This entity is called lymphoplasmacytic lymphoma in the World Health Organization/Revised European-American Lymphoma classification system. Patients are symptomatic, have lymphoplasmacytic marrow infiltration, and a rising serum IgM concentration, and may have lymphadenopathy or splenomegaly. Rarely, patients with WM have lytic bone lesions. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
3. Absolute lymphocyte count exceeding 5,000 cells/mm³. The patient may be classified as having chronic lymphocytic leukemia (CLL) if the lymphocytes are of the small, well-differentiated variety. CLL must be differentiated from the lymphoplasmacytosis that may occur as a peripheral blood manifestation of WM. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
4. Chronic cold agglutinin disease. Patients have a high cold agglutinin titer and no morphologic evidence of neoplasia. These patients often have a hemolytic anemia that is aggravated by cold exposure. The IgM has κ light chains in more than 90% of these types of patients.

Monoclonal Gammopathy of Undetermined Significance

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma, and with less than 10% of plasma cells in the bone marrow.^[14][15][16] These types of patients are asymptomatic and should not be treated. They must, however, be followed carefully since about 1% to 2% per year will progress to develop one of the symptomatic B-cell neoplasms and may then require therapy.^[17][18] Risk factors predicting progression include an abnormal serum-free light chain ratio, non-IgG class MGUS, and a high serum M protein level (≥15 g/L).^[19]

Treatment Option Overview

Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma. Asymptomatic patients with multiple myeloma who have no lytic bone lesions and normal renal function may be initially observed safely outside the context of a clinical trial.^[1][2][3] Treatment should be given to patients with symptomatic advanced disease. Treatment should be directed at reducing the tumor cell burden and reversing any complications of disease, such as renal failure, infection, hyperviscosity, or hypercalcemia with appropriate medical management. Response criteria have been developed for patients on clinical trials.^[4]

References

Multiple Myeloma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.^[1][2] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.

Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated as follows:

1. Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin assays; however, specific immunoglobulin quantification always overestimates the M protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M protein should be done by the same method.^[3]
2. Measure and follow the amount of M protein light chains excreted in the urine per 24 hours. Measure the total amount of protein excreted per 24 hours and multiply this value by the percentage of urine protein that is M protein as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
3. Identify the heavy- and light-chain of the M protein by immunofixation electrophoresis.
4. Measure the hemoglobin, leukocyte, platelet, and differential counts.
5. Determine the percentage of marrow plasma cells. Be aware that marrow plasma cell distribution may vary in different sites.
6. Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
7. Evaluate renal function with serum creatinine and a creatinine clearance. Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin. In most myeloma patients, the glomeruli function normally allowing only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
8. Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins, and serum viscosity.
9. Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones. Whole-body, low-dose, nonenhanced multidetector computed tomography (CT) and magnetic resonance imaging (MRI) are being evaluated as measures for therapy response monitoring.^[4][5] MRI of the spine or long bones is more sensitive in detecting lytic lesions, but any prognostic or therapeutic value for this information remains to be determined.^[5]
10. Perform MRI if a paraspinal mass is detected or if symptoms suggest spinal cord or nerve root compression.
11. If amyloidosis is suspected, do a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.^[6]
12. Measure serum albumin and beta-2-microglobulin as independent prognostic factors.^[7][8]
13. A high plasma cell labeling index (≥3%) and the presence of circulating myeloma cells are considered poor prognostic factors.^[9]

These initial studies should be compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse. The major challenge is to separate the stable asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who should be treated immediately.^[10][11]

Patients with MGUS have an M protein in the serum and/or urine and less than 10% plasma cells in the marrow but no other signs or symptoms of disease. The patients with smoldering myeloma have similar characteristics but may have greater than 10% of marrow plasma cells. Since 1% to 2% of MGUS patients per year will progress to develop myeloma (most commonly), amyloidosis, a lymphoma, or chronic lymphocytic leukemia, these types of patients must be followed carefully.^[12] Treatment is delayed until the disease progresses to the stage that symptoms or signs appear. Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions, or have improved survival if chemotherapy is started early while they are still asymptomatic as opposed to waiting for progression before treatment is initiated.^{[10][11][13][14]}

Treatment options for patients with symptomatic myeloma range from pulse dexamethasone with or without thalidomide, conventional chemotherapy to high-dose chemotherapy, and peripheral stem cell or allogeneic bone marrow transplantation. Treatment choice is determined largely by the age and general health of the patient and should be finely attuned to the preferences of patients and their families.

Conventional chemotherapy using alkylators prolongs the survival of patients with symptomatic myeloma to a median of 40 to 46 months for patients with stage I disease, 35 to 40 months for patients with stage II disease, and 24 to 30 months for patients with stage III disease. At this time, most patients begin with nonalkylator therapy to avoid exposing the tumor to these types of drugs prior to autologous or allogeneic stem cell transplantation therapy, which involves high doses of the drugs. The two most common induction regimens are high-dose pulse dexamethasone with or without thalidomide ^[15][16][17] or VAD (vincristine plus doxorubicin plus dexamethasone).^[18][19] At this time, there are five active strategies for multiple myeloma:

1. High-dose corticosteroids.
2. Antiangiogenic agents:
   • Thalidomide.
   • Lenalidomide.
3. Proteasome inhibitor:
   • Bortezomib.
4. Conventional-dose chemotherapy.
5. Autologous or allogeneic peripheral stem cell transplantation:
   • High-dose chemotherapy: autologous bone marrow or peripheral stem cell transplantation.
   • High-dose chemotherapy: allogeneic bone marrow or peripheral stem cell transplantation.

Typical regimens include:

1. High-dose dexamethasone.^[15]
2. Oral thalidomide alone or in combination with dexamethasone.^{[16][17][20][21][22][23]}
3. Oral lenalidomide in combination with low-dose dexamethasone ().^[24]
4. The proteasome inhibitor bortezomib, alone or in combination with dexamethasone.^[25]
5. Melphalan and prednisone (MP) alone or in combination with thalidomide, lenalidomide, or bortezomib.^{[26][27][28][29][30]}
6. Autologous or allogeneic stem cell transplantation.^{[12][31][32][33][34][35][36]}
7. Cyclophosphamide plus prednisone.^[37]
8. VAD.^[18][19][38]
9. VBMCP (the M2 protocol: vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone).^[26]
10. VMCP/VBAP (vincristine plus melphalan plus cyclophosphamide plus prednisone alternating with vincristine plus carmustine plus doxorubicin plus prednisone).^[26][39]

High-Dose Corticosteroids

Dexamethasone is given at a dose of 40 mg orally for 4 consecutive days in the same schedule as given with the VAD regimen.^[15] Response rates of 60% to 70% in previously untreated patients appear as high as those in patients treated with VAD.^[15][40][Level of evidence: 3iiiDiv] A prospective trial randomly assigned 488 patients older than 65 years to receive dexamethasone alone, melphalan plus dexamethasone, dexamethasone plus interferon-alpha, and melphalan plus prednisone; with a median follow-up of 7.1 years, no difference was observed in overall survival (OS) (median survival times were 32 to 40 months).^[41][Level of evidence: 1iiA] The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints.

Thalidomide

A prospective randomized study of 207 untreated patients compared thalidomide plus dexamethasone to dexamethasone alone; the combination showed a significantly higher response rate (63% vs. 41%, P = .001), but it also showed significantly higher grade 3 or greater toxicities (45% vs. 21%, P < .001) and no advantage in OS.^[42][Level of evidence: 1iiDiv] The thalidomide-containing arm had significantly more deep venous thrombosis (DVT) (17% vs. 3%) and grade 3 or higher neuropathy (7% vs. 3%). A prospective randomized study of 668 untreated patients compared thalidomide (from time of induction to time of progression or unacceptable toxicity) versus no thalidomide in the context of two sequential high-dose melphalan-based chemotherapy cycles supported by autologous stem cell support.^[43] With a 42-month median follow-up, OS at 5 years was 65% in both groups (P = .90), but toxicity, which was manifested by severe peripheral neuropathy and DVT, was worse in the thalidomide group. A prospective randomized study of 255 untreated patients aged 60 to 85 years compared melphalan plus prednisone plus thalidomide versus melphalan plus prednisone; with a median follow-up of 16 months, the 2-year event-free survival (EFS) favored the thalidomide arm (54% vs. 27%, P = .006), but the 3-year OS was not significantly different (80% vs. 64%, P = .19).^[28][Level of evidence: 1iiA] The use of low-molecular-weight heparin in this trial lowered the rate of DVT to 3% in the thalidomide arm. The substantial toxicities and lack of any survival benefit during induction therapy thus far for the use of thalidomide raises doubts about its use during induction therapy outside of the context of a clinical trial. Prophylactic anticoagulation with aspirin, warfarin, or low-molecular-weight heparin is under clinical evaluation; recommendations must await further clinical trials.^[17][44][45] Factors that worsen the risk of DVT include high-dose dexamethasone, concomitant erythropoietic growth factors, or concomitant use of doxorubicin, liposomal doxorubicin, or alkylating agents. Prospective electrophysiologic monitoring provides no clear benefit versus clinical evaluation for the development of clinically significant neuropathy while on thalidomide.^[46] Other combinations of thalidomide, dexamethasone, and conventional chemotherapy are also under evaluation.^{[29][47][48][49][50]} The superior response rates using thalidomide with other agents must be balanced against the toxic effects seen with the combinations.

Lenalidomide

A prospective randomized study (MM-010) of 351 relapsed patients, published in abstract form only, compared lenalidomide, an analogue of thalidomide, plus dexamethasone to dexamethasone alone; the combination showed a significantly higher time-to-tumor-progression (13 months vs. 5 months, P < .001) with an 18-month follow-up.^[51][Level of evidence: 1iiDiii] The lenalidomide-containing arm had more DVT (8.5% vs. 4.5%).^[44][51] Survival data are not yet available for the use of lenalidomide. A prospective randomized study (E-4A03) of 445 untreated symptomatic patients, published in abstract form only, compared lenalidomide and high-dose dexamethasone (40 mg D1–4, 9–12, 17–20 every 28 days) to lenalidomide and low-dose dexamethasone (40 mg D1, 8, 15, 22 every 28 days); with only an 18-month follow-up, OS favored the low-dose arm with a 1-year survival of 96.5% (low-dose) versus 86% (high-dose), P< .001.^[24][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.

Bortezomib

A prospective randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone; OS at 1 year favored bortezomib (80% vs. 66%) (P = .003).^[52][Level of evidence: 1iiA] Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.^[53][54]

Clinical trials for previously untreated patients and for relapsing patients are under way combining bortezomib with other agents:

• Bortezomib plus dexamethasone.^[55]
• Bortezomib plus doxorubicin plus dexamethasone.^[56]
• Bortezomib plus melphalan with or without prednisone.^[30][57]
• Bortezomib plus melphalan plus prednisone plus thalidomide.^[29]

Conventional-Dose Chemotherapy

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.^{[18][19][38][58]}[Level of evidence: 3iiiDiv] No randomized studies support the widespread use of this regimen in untreated patients. This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia. Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low complete response rate. An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.^[59][60]Level of evidence: 3iiiDiv]

High-Dose Chemotherapy: Autologous Bone Marrow or Peripheral Stem Cell Transplantation

The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy. From the experience with thousands of patients treated in this way, it is possible to draw a few conclusions. The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.^[36] Chemotherapy patients can now be treated as outpatients. Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.^[66] Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.^[67][68][69]

While some prospective randomized trials such as the U.S. Intergroup trial SWOG-9321, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,^{[6] [12]}[Level of evidence: 1iiA] other trials have not shown any survival advantage.^{[70][71][72][73]}[Level of evidence: 1iiA] A meta-analysis of 575 patients with individual data showed no survival advantage.^[74][Level of evidence: 1iiA] Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.^{[6] [12]}

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).^[33][75][76] In a trial of 399 previously untreated patients younger than 60 years, the patients were randomly assigned to a single or double (tandem) autologous stem-cell transplantation.^[77] With a median follow-up of more than 6 years, the double-transplant group had a superior event-free survival (EFS) (20% vs. 10% at 7 years, P = .03) and OS (42% vs. 21% at 7 years, P = .01).^[77][Level of evidence: 1iiA] Patients with a reduction of paraprotein of greater than 90% after the first transplant (the best responders) had the least incremental benefit from the second transplant (retrospective subgroup analysis).^[77] In a trial of 321 previously untreated patients under 60 years, patients were randomly assigned to a single or tandem transplant; with a median follow-up of 55 months, the double transplant group had superior EFS (35 months vs. 23-month median, P = .001), but there was no difference in 7-year survival (43% vs. 46%, P = .90).^[78][Level of evidence: 1iiA] In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to conventional oral melphalan and prednisone versus VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m²) with stem cell support.^[79] With a median follow-up of greater than 3 years, the double transplant group had superior EFS (37% vs. 16% at 3 years, P < .001) and OS (77% vs. 62%, P < .001).^[79][Level of evidence: 1iiA] A trial of 162 consecutive newly diagnosed patients compared two tandem autologous transplants versus one autologous transplant followed by an allograft from an HLA-identical sibling (assignment was based on the presence or absence of an HLA-identical sibling); with a median follow-up of 45 months, the median OS was 54 months for the tandem autologous grafts versus 80 months for the allogeneic arm (P = .01).^[80][Level of evidence: 3iiA]

Maintenance therapy with interferon showed a benefit in progression-free survival (PFS) (46 vs. 27 months, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.^[81][Level of evidence: 1iiA] A larger randomized trial of 805 patients showed no difference in PFS or OS with interferon applied after peripheral stem cell transplantation or conventional chemotherapy.^[82] [Level of evidence: 1iiA]

High-Dose Chemotherapy: Allogeneic Bone Marrow or Peripheral Stem Cell Transplantation

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.^[83][Level of evidence: 3iiiA] Favorable prognostic features included low tumor burden, responsive disease before transplant, and application of transplantation after first-line therapy. Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses following the infusion of donor lymphocytes.^{[34][84][85][86]} Allogeneic marrow transplants have significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma reaction makes this procedure attractive.^[34][87] Further research is required to make allogeneic transplants less dangerous and to find methods for initiating an autoimmune response to the myeloma cells. Nonmyeloablative allogeneic stem cell transplant is under development.^[88][89][90] Such strategies aim to maintain efficacy (so called graft-versus-tumor-effective) while reducing transplant-related mortality.^[91] Early reports indicate that significant graft-versus-host disease and transplant-related mortality remain challenges with this approach.^[35][89] In one phase II prospective study, high-risk patients (beta-2-microglobulin >3 mg/dl or chromosome 13 deletion) with an HLA-identical sibling donor underwent nonmyeloablative allogeneic stem cell transplantation after autologous stem cell transplantation.^[92] This approach requires further evaluation.

Maintenance Therapy

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. In a single study,^[93] it was observed that maintenance therapy with MP prolonged the initial remission duration (31 months) compared to no maintenance treatment (23 months). No effect on OS was found because the majority of patients who relapsed in the no maintenance arm responded again to MP, while those on maintenance MP did not respond to further treatment. The Canadian group ^[93] suggests that induction chemotherapy be continued as long as the M protein continues to fall; therapy can be discontinued after the M protein reaches a plateau that remains stable for 4 months.

Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration.^{[94][95][96][97]} While the impact of interferon maintenance on disease-free survival and OS has significantly varied among trials, a meta-analysis of 1,543 patients treated on 12 trials randomizing between interferon maintenance and observation indicated that interferon maintenance was associated with improved relapse-free survival (27% vs. 19% at 3 years, P < .001) and OS (12% odds reduction, P = .04).^[98] Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.^[99]

A study of 125 responding patients with first-line VAD induction who were randomly assigned to maintenance corticosteroids at 10 mg or 50 mg on alternate days showed improved PFS (14 months vs. 5 months, P = .003) and OS (36 months vs. 26 months, P = .05) for the patients receiving the higher-dose corticosteroids.^[100][Level of evidence: 1iiA] In a larger trial (NCIC-CTG-MY.7) of 585 patients treated with first-line MP, 292 patients were randomly assigned to pulse dexamethasone (40 mg a day for 4 days monthly) versus no maintenance; PFS favored the dexamethasone maintenance (2.8 vs. 2.1 years, P = .0002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).^[101][Level of evidence: 1iiDiii]

Two months after autologous transplantation, 597 patients younger than 65 years were randomly assigned to no maintenance, pamidronate, or pamidronate plus thalidomide; the thalidomide arm was favored by EFS (36% vs. 37% vs. 52%, P < .009) and OS at 4 years (77% vs. 74% vs. 87%, P < .04), while no differences were seen for skeletal events.^[102][Level of evidence: 1iiA]

Bisphosphonate Therapy

A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduces pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treated group vs. 51% in the placebo group after 21 months of therapy, P = .015).^[103][Level of evidence: 1iDiii] In addition, survival was increased (median survival was 21 months vs. 14 months) in the patients receiving pamidronate and second-line or greater chemotherapy.

Amyloidosis

Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Two randomized trials showed prolonged OS with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.^[110][111][Level of evidence: 1iiA] Autologous peripheral stem cell transplantation has been proposed for eligible patients with a nonrandomized series reporting complete hematologic remissions and improvement in amyloid-induced organ damage.^[112] In a retrospective series comparing 63 patients in each group between transplantation and standard chemotherapy, the OS rates favored transplantation as follows: 89% versus 71% at 1 year, 81% versus 55% at 2 years, and 71% versus 41% at 4 years.^[113][Level of evidence: 3iiiA] The degree to which these results are influenced by patient selection factors is unclear. The 13% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.^{[112][113][114]} A randomized trial confirming the benefit of autologous transplantation is not anticipated.^[115] As is true for all plasma cell dyscrasias, anecdotal responses for amyloidosis have been reported, as in the SWOG-9628 trial, for dexamethasone alone and in combination with thalidomide and cyclophosphamide or lenalidomide.^{[116][117][118][119]} An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.^[120]

Elevated serum levels of cardiac troponins and brain natriuretic peptide are poor prognostic factors. A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.^[121]

Isolated Plasmacytoma of Bone

If a solitary lytic lesion of plasma cells is found on skeletal survey in an otherwise asymptomatic patient, and a bone marrow examination from an uninvolved site contains less than 5% of plasma cells, the patient may have an isolated plasmacytoma of bone.^[1] Magnetic resonance imaging scans of the total spine may identify other bony lesions.^[2] The survival rate of patients with isolated plasmacytoma of bone treated with radiation of the lesion is greater than 50% at 10 years, which is much better than the survival with disseminated multiple myeloma.^[3] Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% will do so within 2 years of diagnosis;^[1][2] however, patients with serum paraprotein or Bence Jones protein who have complete disappearance of these proteins after radiation therapy may be expected to remain free of disease for prolonged periods.^[2][4] Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.^[2][4]

Standard treatment options:

1. Radiation of the lesion.
2. If the monoclonal (or myeloma) protein (M protein) increases and other evidence of symptomatic multiple myeloma occurs, chemotherapy is required.

References

Extramedullary Plasmacytoma

Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, should have skeletal x-rays and bone marrow biopsy (both of which should be negative), and evaluation for a monoclonal or (myeloma) protein (M protein) in serum and urine.^[1][2][3][4]

Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years using radiation therapy (with or without previous resection).^[2][4][5]

Standard treatment options:

1. Radiation therapy to the isolated lesion with fields that cover the regional lymph nodes, if possible.^[2][4]
2. In some cases, surgical resection may be considered, but it is usually followed by radiation therapy.^[4]
3. If the monoclonal (or myeloma) protein (M protein) persists or reappears, the patient may need further radiation therapy. In some patients, the plasmacytoma may shrink, but not disappear, and the M protein persists. These types of patients should be followed closely. Surgery should be performed if the plasmacytoma is in a site where it can be removed easily, e.g., in the tonsil; the M protein may disappear from the blood or urine. In other cases, persistence or an increasing M protein may herald progression to multiple myeloma.
4. Chemotherapy is required if the disease progresses and causes symptoms.

References

Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Refer to the Waldenström macroglobulinemia section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.

Monoclonal Gammopathy of Undetermined Significance

Patients with monoclonal gammopathy of undetermined significance (MGUS) have a monoclonal (or myeloma) protein (M protein) in the serum without symptoms or findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and with less than 10% of plasma cells in the bone marrow.^{[1] [2]} Multiple myeloma, other plasma cell dyscrasia, or lymphoma will develop in 12% of patients by 10 years, 25% by 20 years, and 30% by 25 years. Unfortunately, patients who will eventually develop plasma cell malignancy or lymphoma cannot be identified on the basis of the level of M protein, peripheral blood count, type of monoclonal immunoglobulin, percentage of plasma cells in the bone marrow, or levels of normal immunoglobulins. Therefore, all patients with MGUS must be kept under observation to detect increases in M protein levels and development of one of the above malignancies; however, higher levels of initial M protein levels correlate with increased risk of progression to multiple myeloma.^[2] In a large retrospective report, the risk of progression at 20 years was 14% for an initial monoclonal protein level of 0.5 g/dL or less, 25% for a level of 1.5 g/dL, 41% for a level of 2.0 g/dL, 49% for a level of 2.5 g/dL, and 64% for a level of 3.0 g/dL.^[2]

References

Refractory Plasma Cell Neoplasm

There are two main types of refractory myeloma patients:

• Primary refractory patients who never achieve a response and progress while still on induction chemotherapy.
• Secondary refractory patients who do respond to induction chemotherapy but do not respond to treatment after relapse.

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients. Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol.^[1] When the stable nature of the disease becomes established, these types of patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy; the options appear in the previous section on Multiple Myeloma Treatment Options.

The myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, for patients who respond to their initial therapy, increases progressively with each subsequent relapse and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed.

References

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