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There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.
(Refer to the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Incidence and Mortality
Estimated new cases and deaths from multiple myeloma in the United States in 2013:
Clinical Presentation and Evaluation
Evaluation of patients with monoclonal (or myeloma) protein (M protein)
Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[4,5] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.
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.[6,7]
Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated by some of the following criteria:
In most myeloma patients, the glomeruli function normally allows 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.
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.
As mentioned before, 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.[6,7]
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and have fewer than 10% of plasma cells in the bone marrow.[2,17,18,19] Patients with smoldering myeloma have similar characteristics but may have more than 10% of plasma cells in the bone marrow.
These types of patients are asymptomatic and should not be treated. They must, however, be followed carefully since about 1% to 2% of MGUS patients per year will progress to develop myeloma (most commonly), amyloidosis, lymphoma, or chronic lymphocytic leukemia and may then require therapy.[19,20,21]
Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[22,23,24]
Risk factors that predict disease progression include the following:
Isolated Plasmacytoma of Bone
The patient has an isolated plasmacytoma of the bone if the following are found:
When clinically indicated, MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine may identify other bony lesions.
A patient has extramedullary plasmacytoma if the following are found:
Multiple myeloma is a systemic malignancy of plasma cells that typically involves multiple sites within the bone marrow and secretes all or part of a monoclonal antibody.
Multiple myeloma is highly treatable but rarely curable. 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 rate of 3%. Even further improvements in prognosis have occurred because of the introduction of newer therapies such as pulse corticosteroids, thalidomide, lenalidomide, bortezomib, and autologous and allogeneic stem cell transplantation, with median survivals now exceeding 45 to 60 months.[33,34,35,36] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[16,37]
Multiple myeloma is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. (Refer to the Isolated Plasmacytoma of Bone and Extramedullary Plasmacytoma sections of this summary for more information.)
Amyloidosis Associated With Plasma Cell Neoplasms
Multiple myeloma and other plasma cell neoplasms may cause a condition called amyloidosis. Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Clinical symptoms and signs include the following:
Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum-free light chains are poor prognostic factors.[38,39] A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.
No generally accepted staging system exists for monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of bone, or extramedullary plasmacytoma. Of the plasma cell neoplasms, a staging system exists only for multiple myeloma.
Multiple myeloma 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 hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. Impaired renal function worsens prognosis regardless of stage.
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.
International staging system
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 and is shown below in Table 2.
Genetic factors and risk groups
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] The question of whether the choice of therapy based on FISH analysis can influence outcome must await further study in prospective trials.
Newer clinical investigations are stratifying patients with multiple myeloma into so-called good-risk, intermediate-risk, and high-risk groups.[2,3,4,5,6,7,8] (See Table 3 below.) 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. Plasma cell leukemia has a particularly poor prognosis.
The major challenge in treating plasma cell neoplasms is to separate the stable, asymptomatic group of patients who do not require immediate treatment from patients with progressive, symptomatic myeloma who should be treated immediately.[1,2] Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma.
Asymptomatic Plasma Cell Neoplasms
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.[1,3,4] Increasing anemia is the most reliable indicator of progression.
Symptomatic Plasma Cell Neoplasms
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.
Current therapy for patients with symptomatic myeloma can be divided into the following categories:
Treatment Options for Amyloidosis Associated With Plasma Cell Neoplasms
Treatment options for amyloidosis associated with plasma cell neoplasms include the following:
As is true for all plasma cell dyscrasias, responses have been reported for all the same regimens active in multiple myeloma.[1,2,3,4,5,6,7,8,9]
Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[10,11][Level of evidence: 1iiA]
Stem cell rescue
A randomized, prospective study of 100 patients with immunoglobulin light-chain amyloidosis 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 months vs. 22.2 months; 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.[12,13,14,15,16,17] A randomized trial confirming the benefit of autologous transplantation is not anticipated.
An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with primary systemic amyloidosis. 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.
Treatment Options for Monoclonal Gammopathy of Undetermined Significance (MGUS)
Treatment options for MGUS include the following:
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.
All patients with MGUS should be kept under observation to detect increases in M protein levels and development of a plasma cell dyscrasia. Higher levels of initial M protein levels may correlate with increased risk of progression to multiple myeloma.[1,2] 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.
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.[3,4,5,6] Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
Refer to the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.
Treatment Options for Isolated Plasmacytoma of Bone
Treatment options for isolated plasmacytoma of bone include the following:
About 25% of patients have a serum and/or urine M protein; this should disappear following adequate radiation therapy to the lytic lesion.
The survival rate of patients with isolated plasmacytoma of bone treated with radiation therapy to the lesion is greater than 50% at 10 years, which is much better than the survival rate of patients with disseminated multiple myeloma.
Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% of them will do so within 2 years of diagnosis.[2,3] 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]
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
Treatment Options for Extramedullary Plasmacytoma
Treatment options for extramedullary plasmacytoma include the following:
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 M protein in serum and urine.[1,2,3,4]
About 25% of patients have serum and/or urine M protein; this should disappear following adequate radiation.
Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).[1,2,5]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extramedullary plasmacytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The initial approach to the patient is to evaluate the following parameters:
Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.
The choice of induction therapy is unclear at the present time; however, the current basic categories include the use of steroids, thalidomide, lenalidomide, bortezomib, and alkylating agents, often in combination.
Several questions are raised when therapy is being chosen for a patient with symptomatic myeloma at first presentation, including the following:
Induction therapy agents
Multiple therapeutic agents are available for induction therapy, either alone or in combinations. These include the following:
Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity. (Refer to the Combination therapy section of this summary for a list of current clinical trials.)
Guidelines for choosing induction therapy
Until results become available, outside the context of a clinical trial, clinicians may choose induction therapy based on the following guidelines:
These guidelines require validation by ongoing clinical trials; participation in clinical trials 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, which is the same schedule used with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen. Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[13,14][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 (MP).
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) with a lower dose (≤40 mg weekly). This issue of dexamethasone dose has been evaluated in two of the following prospective, randomized trials:
Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.
IMiDs (immunomodulatory drugs)
Eleven randomized prospective studies involving more than 4,600 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[17,18,19,20,21,22,23,24,25,26]
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 DVT include the use of high-dose dexamethasone, concomitant erythropoietic growth factors, and concomitant doxorubicin, liposomal doxorubicin, or alkylating agents.[28,29]
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.[21,29,30] In a randomized, prospective trial, 667 previously untreated patients who received thalidomide-containing regimens were randomly assigned to aspirin (100 mg/day), warfarin (1.25 mg/day) or enoxaparin (40 mg/day). The rate of serious thromboembolic events, acute cardiovascular events, or sudden death was 6.5% and similar for all three interventions.
Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.
Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[6,33,34,35] A randomized, prospective trial of 342 previously untreated patients receiving lenalidomide-containing regimens compared aspirin (100 mg/day) with enoxaparin (40 mg/day); the 2% incidence of venous thromboembolic events was similar for both interventions. Empirically, the greater the number of risk factors for DVT, the more intense the recommendation for prophylactic anticoagulation. (Refer to the Thalidomide section of this summary for more information about risk factors.)
A retrospective review of almost 4,000 relapsed or refractory patients who received lenalidomide in 11 clinical trials suggested an increased incidence of nonmelanoma skin cancers. As a result of predominant renal clearance, lenalidomide doses need to be reduced in the setting of impaired renal function (creatinine clearance, 30–50: 10 mg per day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis). Uncontrolled trials, including NCT00151203, have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach.
Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[10,51] In several retrospective, nonrandomized comparisons, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (2%–8% vs. 13%–28%) with no loss of efficacy compared with standard biweekly administration.[52,53]
In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11). After a median follow-up of 1 year, grade 3 to 4 neurologic toxicity was reduced from 16% to 6% (P = .026) using the subcutaneous route, with no perceived loss of efficacy in terms of response. However, this study was not powered for noninferiority of response. New clinical trials are employing these changes of weekly treatment and subcutaneous route to improve the safety profile of bortezomib-containing regimens. In this trial, the bisphosphonates were continued until the time of relapse.
Evidence (conventional-dose chemotherapy):
The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[58,59,60,61][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.[64,65,66]
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.[67,68,69,70][Level of evidence: 1iiA]
A meta-analysis of studies comparing MP 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 OS, 17 months) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone or VAD.[Level of evidence: 1iiA]
Evidence (combination therapy):
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.
Options for combination regimens:
High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation
Evidence (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.
Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:
Single autologous bone marrow or peripheral stem cell transplantation
Evidence (single autologous bone marrow or peripheral stem cell transplantation):
While some prospective randomized trials, such as the U.S. Intergroup trial (SWOG-9321 [NCT00602641]), showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[86,87,88][Level of evidence: 1iiA] other trials have not shown any survival advantage.[89,90,91,92][Level of evidence: 1iiA]
Two meta-analyses of almost 3,000 patients showed no survival advantage.[93,94][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.[86,87,88,95] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[96,97]
Tandem autologous bone marrow or peripheral stem cell transplantation
Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[98,99,100,101,102]
Evidence (tandem autologous bone marrow or peripheral stem cell transplantation):
A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants. None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.
High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation
Evidence (high-dose chemotherapy: allogeneic bone marrow or peripheral stem cell transplantation):
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.
Favorable prognostic features included the following:
Myeloablative allogeneic stem cell transplantation has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[111,112,113]
The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse. Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of autologous stem cell transplantation (SCT) versus autologous SCT and nonmyeloablative allogeneic (SCT) in 260 untreated patients showed no difference in PFS or OS.[Level of evidence: 3iiiA] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[106,115][Level of evidence: 3iiiA] Given the lack of evidence so far that the high-risk patients benefit from allogeneic stem cell transplantation in this era of novel new agents, it remains debatable whether allogeneic stem cell transplantation should be offered in the first-line setting outside the context of a clinical trial.[113,116]
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. No clinical trial has directly compared a consolidation approach with a maintenance approach to assess which is better in prolonging remission and, ultimately, survival. Most clinical trials employ one or both. Maintenance trials with glucocorticosteroids [16,118] and with interferon  showed very minor improvements in remission duration and survival but with toxicities that outweighed the benefits. The efficacy and tolerability of thalidomide, lenalidomide, and bortezomib in the induction and relapse settings has made these agents attractive options in maintenance trials.
Thalidomide maintenance therapy
After ASCT, six randomized, prospective trials showed benefit in PFS for maintenance thalidomide (30–36 months vs. 20–26 months), but only three showed benefit in OS (11–19 months in median OS).[18,25,120,121,122,123] No survival benefit could be consistently seen for thalidomide maintenance after induction chemotherapy alone; interpretation of some trials was confounded by thalidomide use during induction.[19,122,124,125,126,127,128] Several trials suggested particularly poor outcomes using thalidomide for patients with poor-risk cytogenetics.[25,122] The lowest active dose for thalidomide is 50 mg daily with a duration of at least 1 year.
Lenalidomide maintenance therapy
After ASCT, two randomized, prospective trials showed benefit in median EFS (40–43 months vs. 23–27 months),[129,130] one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; P = .03).[Level of evidence: 1iiA] For elderly patients not eligible for transplantation, a randomized, prospective trial of lenalidomide maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide showed a 66% reduction in the rate of progression (HR, 0.34; P < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[Level of evidence: 1iiDi] All three trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.
Bortezomib maintenance therapy
For 178 elderly, untreated patients with an induction combination regimen including bortezomib, maintenance using bortezomib plus thalidomide versus bortezomib plus prednisone was not significantly different in PFS or OS, but both resulted in median PFS of 32 to 39 months and a 5-year OS over 50%.[Level of evidence: 1iiDiv]
In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance using bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.
With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01) and 5-year OS was 59% versus 46% (P = .04).[Level of evidence: 1iiA] Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.
Management of lytic bone lesions with bisphosphonates
Evidence (bisphosphonate therapy):
Radiation therapy for bone lesions
Lytic lesions of the spine should be radiated if any of the following are true:
Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (Refer to the PDQ summary on Pain for more information on back 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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
There are two main types of refractory myeloma patients:
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. (Refer to the Treatment for Multiple Myeloma section of this summary for more information.)
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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
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.
General Information About Plasma Cell Neoplasms
Added text to include a list of clinical symptoms and signs of primary amyloidosis: fatigue, purpura, enlarged tongue, diarrhea, edema, and lower-extremity paresthesias.
Revised text to state that elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum-free light chains are poor prognostic factors.
Stage Information About Plasma Cell Neoplasms
Revised text to state that newer clinical investigations are stratifying patients with multiple myeloma into so-called good-risk, intermediate-risk, and high-risk groups (cited Avet-Loiseau et al. as reference 8).
Treatment for Amyloidosis Associated With Plasma Cell Neoplasms
Revised text to state that treatment options for amyloidosis associated with plasma cell neoplasms includes chemotherapy, IMiDs (immunomodulatory drugs), and proteasome inhibitors.
Added Kumar et al., Venner et al., and Wechalekar et al. as references 7, 8 and 9.
Treatment for Multiple Myeloma
Revised text to state that multiple therapeutic agents are available for induction therapy, either alone or in combinations and included: IMiDs, such as thalidomide, lenalidomide, and promalidomide; and, proteasome inhibitors, such as bortezomib and carfilzomib.
Added text to state that a retrospective review of almost 4,000 relapsed or refractory patients who received lenalidomide in 11 clinical trials suggested an increased incidence of nonmelanoma skin cancers (cited Dimopoulos et al. as reference 37). Also added that uncontrolled trials have added clarithromycin to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach (cited Rossi et al. as reference 39).
Added Pomalidomide as a new subsection.
Revised text about bortezomib-related evidence to state that with a median follow-up of 60 months, the median overall survival (OS) favored the bortezomib arm (cited San Miguel et al. as reference 43 and level of evidence 1iiA).
Added text to state that two studies compared bortezomib plus thalidomide plus dexamethasone versus thalidomide plus dexamethasone after stem cell transplantation (SCT) and showed improved progression-free survival (PFS) but no difference in OS (cited Cavo et al. and Garderet et al. as references 47 and 48, respectively and level of evidence 1iiDiii).
Added text to state that in 511 previously untreated patients not eligible for transplant and older than 65 years, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance used bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone and showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.
Added text to state that with a median follow-up of 47 months, 3-year PFS was 55% versus 33%, and 5-year OS was 59% versus 46% (cited Palumbo et al. as reference 49 and level of evidence 1iiA). Because of the trial design, it is unclear whether the improved results were caused by the addition of thalidomide during induction or by the use of maintenance therapy with bortezomib and thalidomide.
Added text to state that in 827 previously untreated patients, a randomized comparison of bortezomib plus doxorubicin plus dexamethasone followed by high-dose melphalan plus autologous SCT plus bortezomib maintenance for 2 years versus vincristine plus doxorubicin plus dexamethasone followed by the same SCT consolidation plus thalidomide maintenance showed superiority of the arm with bortezomib during induction and maintenance (cited Sonneveld et al. as reference 50 and level of evidence 1iiDiii).
Added text to state that with a median follow-up of 41 months, the median PFS was 35 months versus 28 months in favor of the bortezomib arm with no significant difference in OS.
Added Carfilzomib as a new subsection.
Added text to state that a Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants (cited Naumann-Winter et al. as reference 110). Also added that none of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.
Added text to state that since the introduction of lenalidomide and bortezomib, a trial explored donor versus no donor comparison of autologous SCT versus autologous SCT and nonmyeloablative allogeneic SCT in 260 untreated patients and showed no difference in PFS or OS (cited Lokhorst et al. as reference 114 and level of evidence 3iiiA). This result contrasted with two older trials, which suggested improvement of PFS and OS with a sibling donor (cited Giaccone et al. as reference 115 and level of evidence 3iiiA).
Added Moreau as reference 116.
Added Kagoya et al. as reference 128.
Added Bortezomib maintenance therapy as a new subsection.
Added text to state that the improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis (cited Mhaskar et al. as reference 139 and level of evidence 1A).
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about treatment of plasma cell neoplasms (including multiple myeloma). It 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.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment are:
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Levels of Evidence
Some of the reference citations in this 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.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/healthprofessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-09-24
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