- Purpose of This PDQ Summary
- General Information
- Cellular Classification
- Stage Information
- Treatment Option Overview
- Multiple Myeloma
- Isolated Plasmacytoma of Bone
- Extramedullary Plasmacytoma
- Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)
- Monoclonal Gammopathy of Undetermined Significance
- Refractory Plasma Cell Neoplasm
- Get More Information From NCI
- Changes to This Summary (12 / 11 / 2009)
- More Information
Multiple Myeloma and Other Plasma Cell Neoplasms Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER
Multiple Myeloma and Other Plasma Cell Neoplasms Treatment
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:
- Cellular classification.
- 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.
Note: Estimated new cases and deaths from multiple myeloma in the United States in 2009:
- New cases: 20,580.
- Deaths: 10,580.
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 months 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, with median survivals of 45 months to 60 months.[2,3,4] 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.
The initial approach to the patient is to evaluate the following parameters:
|1.||Detection of an M protein in the serum or urine.|
|2.||Detection of greater than 10% 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.|
|5.||Serum albumin and beta-2-microglobulin levels.|
|6.||Detection of free kappa and lambda serum immunoglobulin light chain.|
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]). (Usually IgG kappa or lambda, IgA kappa or lambda.)|
|2.||Symptomatic plasma cell neoplasia. (Usually IgG kappa or gamma, IgA kappa or gamma.)
Patients often have lymphadenopathy and hepatosplenomegaly; less than 5% of patients have lytic bone lesions. (Usually IgM kappa or gamma.)
This entity is called lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. (Refer to the PDQ summary on Adult Non Hodgkin Lymphoma Treatment for more information.)
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. An International Staging System was derived as follows:
STAGE I MULTIPLE MYELOMA: Beta-2-microglobulin less than 3.5 and albumin greater than or equal to 3.5 (median survival of 62 mo).
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 mo).
STAGE III MULTIPLE MYELOMA: Beta-2-microglobulin greater than or equal to 5.5 (median survival of 29 mo).
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.[2,3] 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).[2,3,4,5,6] Whether choice of therapy based on FISH analysis can influence outcome must await further prospective trials.
Newer clinical investigations are stratifying patients with multiple myeloma into a so-called standard-risk group, which accounts for 75% of patients, with a median survival of 3 to 6 years, and a high-risk group, which has a median survival of less than 3 years.[2,3,4,5,6,7] This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation. Bone marrow samples are sent for cytogenetic and FISH analysis.
Standard risk is defined as any one of the following cytogenetic findings:
- No adverse FISH or cytogenetics.
- t (11;14) by FISH.
- t (6;14) by FISH.
These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and they present with lytic bone lesions.
High risk is defined as any one of the following cytogenetic findings:
- del 17p by FISH.
- t (4;14) by FISH.
- t (14;16) by FISH.
- Cytogenetic del 13.
These patients often have disease that expresses IgA lambda monoclonal gammopathies and less often have skeletal-related complications.
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.
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 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. 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. (Refer to the PDQ summary on Fatigue for more information.) 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 kappa 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). Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[20,21,22]
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. (Refer to the PDQ summary on Hypercalcemia for more information.) Response criteria have been developed for patients on clinical trials.
Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[1,2][Level of evidence: 1iiA] A randomized prospective study of 100 patients with immunoglobulin amyloidosis light chain (AL) compared melphalan plus high-dose dexamethasone with high-dose melphalan plus autologous stem-cell rescue. After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 mo vs. 22.2 mo; P = .04).[Level of evidence: 1iiA] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.[3,4,5,6] A randomized trial confirming the benefit of autologous transplantation is not anticipated. As is true for all plasma cell dyscrasias, anecdotal responses for amyloidosis have been reported, as in the Southwest Oncology Group's (SWOG-9628) trial, for dexamethasone alone and in combination with thalidomide and cyclophosphamide or lenalidomide.[8,9,10,11] An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.
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.
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. Quantitative serum-free light chains may be helpful to follow response if an M protein is not apparent.|
|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.||Measure serum free kappa and lambda light chain. This is especially useful in cases of oligosecretory plasma cell dyscrasia or following cases of light chain amyloidosis.|
|7.||Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.|
|8.||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.|
|9.||Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins, and serum viscosity.|
|10.||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.[5,6] 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.|
|11.||Perform MRI if a paraspinal mass is detected or if symptoms suggest spinal cord or nerve root compression.|
|12.||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.|
|13.||Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[8,9]|
|14.||A high plasma cell labeling index (=3%) and the presence of circulating myeloma cells are considered poor prognostic factors.|
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.[11,12]
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. 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.[11,12,14,15]
Current therapy for patients with symptomatic myeloma can be divided into categories of induction therapies, consolidation therapies (which are less applicable for the very elderly), maintenance therapies, and supportive care (such as bisphosphonates). (For more information on supportive care therapies such as bisphosphonates, refer to the Pain summary.) The choice of induction therapy is unclear at the present time; however, the current basic categories include the use of steroids, thalidomide, and lenalidomide, as seen in the text below. Several questions are raised when therapy is being chosen for a patient with symptomatic myeloma at first presentation:
- IS THE PATIENT ELIGIBLE FOR A CLINICAL TRIAL? The sequence and combinations of new and older therapies can only be determined by prospective clinical trials.
- IS AUTOLOGOUS STEM CELL TRANSPLANTATION A POSSIBLE CONSOLIDATION OPTION FOR THIS PATIENT? If so, alkylating agents should be avoided during induction therapy to avoid compromise of stem cell collection and to lessen leukemogenic risk.
- DOES THE PATIENT HAVE COMORBIDITIES? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications would influence the choice of induction therapies as well as the choice of whether to consider consolidation therapies.
Multiple therapeutic agents are available for induction therapy, either alone or in combinations  and include:
- Steroids (dexamethasone, prednisone).
- Alkylating agents (melphalan, cyclophosphamide).
- Other cytotoxic drugs (vincristine, doxorubicin, liposomal doxorubicin).
Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity. Current trials are listed in the section on Combination therapy. Until results become available, outside the context of a clinical trial, clinicians may choose induction therapy based on the following considerations:
|1.||In patients younger than age 70, alkylators are avoided up front to avoid stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting if transplantation is considered for consolidation.|
|2.||Bortezomib or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[18,19] (See sections on Lenalidomide and Bortezomib.)|
|3.||The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration. Bortezomib is given in frequent intravenous doses and can have significant neuropathic toxicities.[19,20,21] Lenalidomide is given orally and has increased risk for deep venous thrombosis, requiring additional prophylactic medication.[14,18] Bortezomib is preferred for patients with renal impairment.|
|4.||Patients with a standard risk, as defined in the section on Stage Information, might receive induction therapy alone followed by careful observation after best response. Patients with a high risk might receive induction therapy until best response, followed by consolidation therapy with allogeneic or autologous stem cell transplantations.|
These considerations require validation by ongoing clinical trials and participation in these studies is the preferred choice when possible.
Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days in the same schedule as administered with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen. Response rates of 60% to 70% in previously untreated patients appeared as high as those in patients treated with VAD.[24,25][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 mo).[Level of evidence: 1iiA] The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (For more information on gastrointestinal symptoms, refer to the Gastrointestinal Complications summary.)
There has never been a randomized trial comparing single-agent oral dexamethasone at a traditional high dose (40 mg a day for 4 days, repeated after 4 days off) versus a lower dose (40 mg or less weekly). This issue of dexamethasone dose has been evaluated in two prospective randomized trials, one in the context of melphalan from the National Cancer Institute of Canada (CAN-NCIC-MY7), and the other in the context of lenalidomide from the Eastern Cooperative Oncology Group (ECOG-E4A03) and published only in abstract form.[18,27] High-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but with no difference in efficacy compared to standard dose steroids. The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone (refer to the Lenalidomide section of this summary for more information). Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.
Nine randomized prospective studies (including E-E1A00 and HOVON 50) involving more than 3,500 patients have been published in final or preliminary abstract form examining the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[28,29,30,31,32,33,34,35,36] All of the trials reported improved response rates with the introduction of thalidomide and no hematopoietic damage, allowing adequate stem cell collection when applicable or allowing combinations with other myelosuppressive agents. Only three of the nine randomized studies reported a survival advantage using thalidomide. In both trials, the patients older than 65 years at the 2-year follow-ups showed 44-month to 56-month median overall survival (OS) for melphalan plus prednisone plus thalidomide (MPT) versus 28-month to 30-month median OS for melphalan plus prednisone (MP) (P < .03 in all three studies).[33,37][Level of evidence: 1iiA] A possible explanation is that these two trials used a lower dose of thalidomide than the other studies (100 mg vs. 200 mg or higher), a lower dose of steroids (60 mg of prednisone vs. high-dose dexamethasone), and involved the use of alkylating agents. As previously described in the section on corticosteroids, high-dose dexamethasone can complicate interpretation of clinical trials by worsening cardiopulmonary toxicity and deaths, especially in the context of thalidomide or lenalidomide, both of which are thrombogenic agents.
Factors that have been implicated to worsen the risk of deep venous thrombosis (DVT) include:
- High-dose dexamethasone.
- Concomitant erythropoietic growth factors.
- Concomitant use of doxorubicin, liposomal doxorubicin, or alkylating agents.
Personal cardiovascular risk factors can also influence the rate of DVT. Various clinical trials have included different DVT prophylaxis measures, including aspirin (81 mg–100 mg a day), warfarin, or low-molecular-weight heparin, but the validity of these measures has not been studied prospectively in a randomized study.[33,34,39,40,41,42,43] Prospective electrophysiologic monitoring provides no clear benefit versus clinical evaluation for the development of clinically significant neuropathy while on thalidomide.
A prospective randomized study of 351 relapsed patients compared lenalidomide, an analogue of thalidomide, plus high-dose dexamethasone to high-dose dexamethasone plus placebo. The lenalidomide combination showed a significantly higher time-to-tumor-progression (11.3 mo vs. 4.7 mo, P < .001) with a 16-month median follow-up, and median OS had not been reached, versus 20.6 months in the placebo group (hazard ratio [HR] = 0.66, 95% confidence interval, 0.45–0.96, P = .03).[Level of evidence: 1iiDiii][Level of evidence: 1iA] The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%). Similarly, another randomized prospective trial NCT00179647 of 353 previously treated patients favors the lenalidomide plus high-dose dexamethasone arm versus dexamethasone plus placebo; at a median follow-up of 26 months, the median time-to-progression was 11.1 months versus 4.7 months (P < .001) and the median OS was 29.6 versus 20.2 months (P < .001).[Level of evidence: 1iA] A prospective randomized study (ECOG-E4A03) 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 a median follow-up of 25 months, this trial showed improved OS for patients in the low-dose dexamethasone arm (87% vs. 75% at 2 years, P = .006), despite no difference in progression-free survival.[Level of evidence: 1iiA] The extra deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity and faster progression with subsequent therapies. DVTs were also more frequent in the high-dose arm (25% vs. 9%). OS favored the low-dose arm with a 2-year survival of 87% (low-dose) versus 75% (high-dose) (P = .006.)[Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone. Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide, but both have the same tendency for DVT.[18,44,45] DVT prophylaxis with 81 mg of aspirin has been proposed, but randomized clinical trials have not confirmed any benefit for this recommendation.
A prospective randomized trial (VISTA) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation because of age (one third of patients >75 years) compared bortezomib combined with melphalan and prednisone versus melphalan and prednisone alone. With a median follow-up of 26 months, the OS favored the bortezomib arm in the 3-year OS rates (72% vs. 59%, P = .03).[Level of evidence: 1iiA]
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; with a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR = 0.77, P = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[Level of evidence: 1iiA] Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[21,46,47,48]
A prospective randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone. With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 mo vs. 6.5 mo, P < .001) and in OS (82% vs. 75%, P = .05).[Level of evidence: 1iiA]
Patients with unfavorable molecular cytogenetics did not show any difference in progression-free or OS compared with patients with more favorable risk factors when bortezomib was incorporated with induction therapy. The benefit from bortezomib appears to be maintained across risk groups.[50,51,52,53][Level of evidence: 3iiiD]
Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.
The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[54,55,56,57][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.[58,59]Level of evidence: 3iiiDiv]
Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results. The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[60,61,62]
Combinations such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[63,64,65,66][Level of evidence: 1iiA] A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.[Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median 17 mo) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone (VBMCP) or VAD.
Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials should be the preferred approach, when feasible. The combination regimens in these trials represent the most successful from numerous phase II reports during the last several years:
- ECOG-E1A05: bortezomib + dexamethasone versus lenalidomide + bortezomib + dexamethasone.
- SWOG-SO777: lenalidomide + dexamethasone versus lenalidomide + bortezomib + dexamethasone.
- EVOLUTION trial: bortezomib + lenalidomide + dexamethasone versus bortezomib + cyclophosphamide + dexamethasone versus bortezomib + lenalidomide + cyclophosphamide + dexamethasone.
- US Intergroup/IFM trial: lenalidomide + bortezomib + dexamethasone for three cycles, then responders randomized to five more cycles versus high-dose melphalan + stem cell transplantation.
OPTIONS FOR COMBINATION REGIMENS:
|1.||Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[50,68]|
|2.||Lenalidomide + dexamethasone (as demonstrated in SWOG-SO777).[18,44,45]|
|3.||Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-SO777, EVOLUTION trial, and US Intergroup/IFM trial).[50,68,69]|
|4.||Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[70,71]|
|5.||Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).|
|6.||Lenalidomide + cyclophosphamide + dexamethasone.|
|7.||Bortezomib + melphalan + prednisone.|
|8.||Bortezomib + liposomal doxorubicin.|
|9.||Melphalan + prednisone + thalidomide.[30,37]|
|10.||Melphalan + prednisone.[30,37]|
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. 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. Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.[75,76,77]
Single autologous bone marrow or peripheral stem cell transplantation
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,[13,78,79][Level of evidence: 1iiA] other trials have not shown any survival advantage.[80,81,82,83][Level of evidence: 1iiA] Two meta-analyses of almost 3,000 patients showed no survival advantage.[84,85][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.[13,78,79,86]
Tandem autologous bone marrow or stem cell transplantation
A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single versus tandem autologous hematopoietic cell transplantation; there was no difference in OS (HR = .94; 95% CI, 0.77–1.14) or in event-free survival (HR = .86; 95% CI, 0.70–1.05).[Level of evidence: 1A]
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. 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).[Level of evidence: 1iiA]
Three different groups have compared two tandem autologous transplants versus one autologous transplant followed by a reduced-intensity conditioning allograft from an HLA-identical sibling; the results have been discordant for survival in these nonrandomized trials. One study showed a survival advantage for the two tandem autologous transplants, one study showed a survival advantage for the autologous followed by allograft arm, and one study showed no difference in OS.[93,94,95,96][Level of evidence: 3iiiA] (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).[Level of evidence: 3iiA]
A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous stem cell transplant followed by 6 months of maintenance therapy with thalidomide. With a median follow-up of 33 months, the thalidomide maintenance arm showed a benefit in PFS (85% vs. 57% at 3 years, P = .02) and OS (85% vs. 65% at 3 years, P = .04).[Level of evidence: 1iiA]
Interferon maintenance after stem cell transplantation
Maintenance therapy with interferon showed a benefit in progression-free survival (PFS) (46 vs. 27 mo, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[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.[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.[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.[101,102,103,104] 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.[104,105] 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.[106,107,108] Such strategies aim to maintain efficacy (so called graft-versus-tumor-effective) while reducing transplant-related mortality.[109,110]
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, it was observed that maintenance therapy with MP prolonged the initial remission duration (31 mo) compared to no maintenance treatment (23 mo). 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  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.[112,113,114,115] 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). Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.
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 mo vs. 5 mo, P = .003) and OS (36 mo vs. 26 mo, P = .05) for the patients receiving the higher-dose corticosteroids.[Level of evidence: 1iiA] In a larger trial by the National Cancer Institute of Canada (CAN-NCIC-MY7) 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 = .002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).[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.[Level of evidence: 1iiA] After autologous transplantation, 129 patients were randomly assigned to indefinite prednisone versus indefinite prednisone with 12 months of thalidomide; with a median follow-up of 3 years, the thalidomide arm was favored by PFS (42% vs. 23%, P < .001) and by OS at 3 years (86% vs. 75%, P = .004).[Level of evidence: 1iiA]
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 mo of therapy, P = .015).[Level of evidence: 1iDiii] (For more information on bisphosphonate therapy, refer to the Pain summary.)
A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications.[Level of evidence: 1iDiii] However, bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients) including osteonecrosis of the jaw and avascular necrosis of the hip.[123,124] (For more information on osteonecrosis of the jaw, refer to the Oral Complications of Chemotherapy and Head/Neck Radiation summary.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.
Lytic lesions of the spine should be radiated if they are associated with an extramedullary (paraspinal) plasmacytoma, if a painful destruction of a vertebral body occurred, or if CT or MRI scans present evidence of spinal cord compression.
Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (For more information on back pain, refer to the PDQ summary on Pain.) Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated. Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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. Magnetic resonance imaging scans of the total spine may identify other bony lesions. 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. 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.|
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with isolated plasmacytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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]
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.|
|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.|
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extramedullary plasmacytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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. 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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with monoclonal gammopathy of undetermined significance. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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.[1,2] 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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with refractory multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
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Changes to This Summary (12 / 11 / 2009)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to include the additional parameters of serum albumin and beta-2-microglobulin levels and detection of free kappa and lambda serum immunoglobulin light chain, which are used in the initial evaluation of a patient (cited Dispenzieri et al. as reference 6).
Added text to include measuring serum-free kappa and lambda light chain, and stated cases in which it is particularly useful, as a step in the evaluation of patients with a monoclonal protein in the serum and/or urine (cited 2009 Dispenzieri et al. as reference 4).
Added text about multiple therapeutic agents that are available for induction therapy, either alone or in combinations (cited Palumbo et al. as reference 16).
Added text to list considerations of a clinician in choosing induction therapy and added that patients with a standard risk might receive induction therapy alone followed by careful observation after best response and patients with a high risk might receive induction therapy until best response, followed by consolidation therapy with allogeneic or autologous stem cell transplantations (cited 2007 Dispenzieri et al. as reference 23).
Added Ludwig et al. as reference 35.
Added Hulin et al. as reference 36; updated text in the Thalidomide subsection.
Added Richardson et al. as reference 48.
Added Bruno et al. as reference 90 and Rotta et al. as reference 91.
Added text to include a meta-analysis of six randomized clinical trials that compared patients with single versus tandem autologous hematopoietic cell transplantations and showed no difference in overall survival or event-free survival (cited Kumar et al. as reference 92 and level of evidence 1A).
- PDQ® - NCI's Comprehensive Cancer Database.
Full description of the NCI PDQ database.
ADDITIONAL PDQ SUMMARIES
- PDQ® Cancer Information Summaries: Adult Treatment
Treatment options for adult cancers.
- PDQ® Cancer Information Summaries: Pediatric Treatment
Treatment options for childhood cancers.
- PDQ® Cancer Information Summaries: Supportive and Palliative Care
Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
- PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
Tests or procedures that detect specific types of cancer.
- PDQ® Cancer Information Summaries: Prevention
Risk factors and methods to increase chances of preventing specific types of cancer.
- PDQ® Cancer Information Summaries: Genetics
Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
- PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
Information about complementary and alternative forms of treatment for patients with cancer.
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Date Last Modified: 2009-12-11