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Home > Health Library > Plasma Cell Neoplasms (Including Multiple Myeloma) 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.
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 2020:
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 may need to be treated immediately.[6,7]
Patients with an 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 are often 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 determine which patients are stable, asymptomatic, and do not require treatment, and which patients have progressive symptomatic myeloma who may need to be treated immediately.[6,7,22]
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.[2,23,24,25] 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 do not need to be treated. Patients with MGUS and risk factors for disease progression, however, must be followed carefully because they are more likely to develop myeloma (most commonly), amyloidosis, lymphoplasmacytic lymphoma, or chronic lymphocytic leukemia and may then require therapy.[25,26,27]
Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[28,29,30] The annual risk of progression of MGUS to a lymphoid or plasma cell malignancy ranges from 0.5% to 1.0% in population-based cohorts.[31,32] This risk ranges from 2% to more than 20% in higher-risk patients.
Risk factors that predict disease progression include the following:
A Swedish cohort study confirmed that an abnormal serum FLC ratio and a high level of serum monoclonal protein are high-risk factors. The study described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (i.e., if a patient has an IgG kappa M protein, the IgM and IgA would be below normal levels with immunoparesis). Incorporation of gene-expression profiles to better assess risk is under clinical evaluation.
Monoclonal gammopathies that cause organ damage, particularly to the kidney, heart, or peripheral nerves, require immediate therapy with the same strategies applied for the conventional plasma-cell dyscrasias. A monoclonal gammopathy causing renal dysfunction—by direct antibody deposition or amyloidosis—is referred to as monoclonal gammopathy of renal significance. Rising serum creatinine, dropping glomerular filtration rates, and increasing urinary–albumin excretion are all parameters that may signify renal damage and are assessed prospectively for high-risk MGUS patients. Although the N-terminal pro-brain natriuretic peptide is a very sensitive marker for amyloid involvement in the heart, the low specificity must be noted. These extra tests are included with the M-protein level, FLC levels, and FLC ratio when following patients with MGUS.
In a retrospective review of 6,399 patients with newly diagnosed multiple myeloma, 44 patients were found to have a biclonal IgG or IgA MGUS. The overall response rate of the myeloma clone to induction therapy was 93%, compared with 64% for the separate-clone MGUS (P = .001).[Level of evidence: 3iiiDiv] Many MGUS plasma cell clones were unresponsive to available myeloma therapy; this result highlights the need to lower expectations for response in situations in which an MGUS may require therapy because of end-organ damage.
Isolated Plasmacytoma of Bone
The patient has an isolated plasmacytoma of the bone if the following are found:
MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine and pelvis 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.[46,47,48,49] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[20,50]
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:
Accurate diagnosis of amyloidosis requires histologic evidence of amyloid deposits and characterization of the amyloidogenic protein using immunoelectron microscopy. In one series of 745 consecutive patients, 20% of patients with nonamyloid light chain amyloidosis (usually transthyretin) had an innocent monoclonal gammopathy, indicating the significant risk of misdiagnosis.
Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum FLC are poor prognostic factors.[52,53] Proposed staging systems for primary systemic amyloidosis based on these serum levels require independent and prospective confirmation.[52,54] An increase in levels of serum FLC over many years can precede the clinical diagnosis of amyloid light chain amyloidosis. Amyloidosis associated with an IgM monoclonal gammopathy is a rare, but distinct, clinical entity with more frequent neuropathy and adenopathy and less cardiac involvement.
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare paraneoplastic condition associated with a plasma cell dyscrasia of early or late stage. The acronym describes a constellation of findings often marked by polyneuropathy, organomegaly (usually splenomegaly), endocrinopathy, monoclonal plasma cell dyscrasia, and skin changes. Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman's histology) may be identified. Anecdotal reports suggest remissions using myeloma-directed therapy.[58,59,60,61]
No generally accepted staging system exists for monoclonal gammopathy of undetermined significance, 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 because 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 (IMWG) studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy. The IMWG evaluated 4,445 patients to create a Revised International Staging System (R-ISS) incorporating lactate dehydrogenase levels and interphase fluorescence in situ hybridization (I-FISH) results.
An International Staging System (ISS) was derived and is shown below in Table 2.
Genetic factors and risk groups
Newer clinical investigations are stratifying patients with multiple myeloma into so-called good-risk, intermediate-risk, and high-risk groups, based on genetic aberrations detected by I-FISH.[3,4,5] (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 otherwise favorable prognosis of hyperploidy is trumped by coexistent adverse cytogenetics.
The major challenge in treating plasma cell neoplasms is separating the stable asymptomatic group of patients who do not require immediate treatment from patients with progressive symptomatic myeloma who may need to be treated immediately.[1,2,3] Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma.
Asymptomatic Plasma Cell Neoplasms (Smoldering Multiple 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.[1,4,5] Increasing anemia is the most reliable indicator of progression. The following criteria represent the new definition for smoldering myeloma:
A prospective randomized clinical trial investigated the role of immediate therapy for patients with smoldering multiple myeloma by specifying high-risk patients with both 10% or more marrow plasma cells and a serum monoclonal (or myeloma) protein (M protein) of at least 3 g/dL. The trial randomly assigned 125 patients to receive lenalidomide plus dexamethasone or observation.
Symptomatic Plasma Cell Neoplasms
Patients with symptomatic advanced disease require treatment.
Treatment most often is 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. The International Myeloma Working Group (IMWG) has published new criteria for identifying patients with active myeloma who require therapy. These criteria include the following:
Response criteria have been developed for patients on clinical trials by the IMWG. A very good partial response (VGPR) is defined as a reduction of 90% or more in the serum monoclonal protein and a 24-hour urine monoclonal protein of less than 100 mg. Although not incorporated in the IMWG criteria, many trials report near complete response (nCR) when patients have less than 5% bone marrow plasma cells and unmeasurable serum monoclonal proteins but still have positive serum and/or urine immunofixation. Note that these nCR patients are incorporated into the VGPR group by the IMWG. Patients who achieve a CR by IMWG criteria (with a negative immunofixation along with the clear marrow and unmeasurable serum monoclonal proteins) are often said to have attained a stringent CR if they also normalize their free kappa/lambda light–chain levels and ratio. The clinical utility of these various categories must be validated in 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 depends on assessing the extent of systemic damage from the amyloidosis and the underlying plasma cell dyscrasia. A rising and elevated level of N-terminal pro brain natriuretic peptide may predict impending cardiac failure in the setting of cardiac amyloidosis, and early treatment should be considered for these patients.
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.[2,3,4,5,6,7]
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 overall survival (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.[8,9,10,11,12,13] Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplantation (ASCT); the 5-year OS was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplantation.[Level of evidence: 3iiiA] Similarly, in a retrospective review of 672 consecutive patients with amyloidosis who underwent ASCT over 20 years, the treatment-related mortality declined to 2.4% between 2010 and 2016 in comparison with 8.6% between 2003 and 2009, and 14.5% between 1996 and 2002.[Level of evidence: 3iiiD] A randomized trial confirming the benefit of autologous transplantation is not anticipated.[1,16]
An anecdotal series describes full-intensity and reduced-intensity allogeneic SCT.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment Options for 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% of patients by 20 years, and 30% of patients by 25 years.
All patients with MGUS are generally 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.
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; generally, this disappears after 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 with a negative flow cytometry on bone marrow examination for plasma cell infiltration are also unlikely to relapse. Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.[2,4]
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, may need to have skeletal x-rays and bone marrow biopsy (both of which are most often 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 frequently disappears after 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]
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, previous therapy, and the presence of complications of the disease.
Despite the introduction of many new therapeutic agents over the past two decades, there is still no confirmed curative approach.
Newly diagnosed patients with indolent disease, historically referred to as smoldering myeloma, can be followed on a watchful waiting approach. These patients are typically asymptomatic and free of lytic bone lesions, renal dysfunction, hypercalcemia, or significant anemia. Serial measurements of paraprotein parameters can help to confirm stable disease over months or years.
Newly diagnosed patients who require therapy fall into two categories: 1) the younger fit patient who is transplant-eligible or 2) the older more unfit patient with comorbidities who is not transplant eligible. Patients younger than 65 years are usually considered younger and fit, while patients older than 75 years are usually not transplant eligible. Comorbidities and performance status are important determinants at all ages, especially between the ages of 65 years and 75 years, to help decide about transplant eligibility. Nomograms exist for geriatric patients to define life expectancy independent of the myeloma diagnosis. Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as autologous stem cell transplantation (ASCT) consolidation. Most patients also receive medication with a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications.[9,10]
The International Myeloma Working Group has issued guidance for the diagnosis and management of patients with renal impairment.
Younger fit patients (transplant eligible)
The younger fit patient will receive induction chemotherapy with a triple-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used triplets include:
After 4 to 8 months of therapy, responding patients usually undergo ASCT consolidation.[13,17] After recovery from the ASCT, maintenance therapy is then implemented until the time of relapse.[18,19,20] At relapse, subsequent therapies are applied sequentially by using previously successful drugs (if the interval of time since previous exposure is >1 year) or newer drugs not previously tried.
Older unfit patients (not transplant eligible)
The older less-fit patient will receive induction chemotherapy with a triplet (as described for the younger fit patient) plus the monoclonal antibody to CD38, daratumumab, or with a doublet and daratumumab, which might be better tolerated. Therapy is continued until maximal response and then maintenance therapy is applied until relapse. At relapse, subsequent therapies are applied sequentially (as described for the younger fit patient).
High risk versus standard risk
Newly diagnosed patients and relapsing patients can be allocated to standard-risk versus high-risk disease on the basis of cytogenetics, genetic aberrations detected by fluorescence in situ hybridization, and possibly the genetic expression profile analyses that are in the process of standardization. Higher-risk patients are candidates for clinical trials employing newer agents upfront or for use of newer combination therapies currently used for relapsed disease at the discretion of the clinician. Beyond induction therapy, high-risk disease can lead to more aggressive strategies, such as tandem transplantation or consideration of allogeneic SCT. More intensive maintenance therapies may also be applied for high-risk disease; instead of using lenalidomide alone, lenalidomide plus bortezomib has been chosen based on prior trials using thalidomide. These more aggressive strategies have been implemented because of poor responsiveness to standard regimens and the worse prognosis of high-risk patients. Ultimately, randomized prospective trials will be needed to establish improved outcomes with these newer approaches for high-risk patients.
Unresolved questions regarding therapy for multiple myeloma include the following:
Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved overall survival (OS).[27,28,29] While this interim marker may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy.
Myeloma patients who are symptomatic or require therapy because of progression or adverse laboratory findings will require induction therapy. Ideally, induction therapy should reduce tumor burden, provide symptomatic relief, and prevent further end-organ damage.
Two randomized prospective trials have established three-drug regimens (triplets) for induction therapy in younger fit transplant-eligible patients).
The U.S. Intergroup and French Inter-Groupe Francophone du Myélome (IFM) study chose VRd as the induction therapy for their prospective randomized trial of 700 patients aged 65 years or younger, which investigated ASCT consolidation after three cycles of VRd compared with time to relapse. In the United States, VRd has become the standard regimen that is compared to newer combinations for induction therapy. Because lenalidomide is metabolized erratically in the setting of renal failure, clinicians often choose the CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone),[15,16] but this selection is empiric and not based on randomized trial results.
In younger transplant-eligible patients, alkylators such as melphalan are avoided upfront to prevent stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting. Bortezomib is given subcutaneously, which helps to avoid the neuropathies that were much more severe with intravenous administration.[32,33,34] Bortezomib is also preferred in the setting of renal impairment. Patients on a bortezomib-containing regimen need prophylaxis for herpes zoster (usually with valacyclovir or acyclovir). Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT) or pulmonary embolism, requiring additional prophylactic medication.[7,36] For patients without extra risk factors for DVT, aspirin (81 mg daily) suffices, but stronger anticoagulants should be considered for patients with multiple risk factors in the presence of lenalidomide (or other similar immunomodulating agents such as pomalidomide or thalidomide).
Triplet therapies such as VRd and CyBorD can be used in patients in whom fitness is adequate and concurrent morbidities are minimal. When triplets are deemed too difficult, doublets with VD (bortezomib plus dexamethasone) or RD (lenalidomide plus dexamethasone) can be used, or even a triplet such as VMP (bortezomib, melphalan, and prednisone) as described in the section for younger fit patients.[12,21] The advent of daratumumab, the monoclonal antibody directed at CD38, has changed the options since this biologic therapy has been studied with the aforementioned doublets and triplets in both phase II and phase III trials.
Immunologic reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (not U.S. Food and Drug Administration‒approved).
Autologous bone marrow or peripheral stem cell transplantation
Evidence (autologous bone marrow or peripheral stem cell transplantation):
The failure of conventional therapy to cure myeloma 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):
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.[20,47,48,49,58] The role of ASCT has also been questioned with the advent of novel induction therapies with high rates of complete remission.[59,60] However, ASCT consolidation remains the standard approach for younger fit patients with no contraindications to the procedure.
Tandem autologous bone marrow or peripheral stem cell transplantation followed by autologous or allogeneic 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).[62,63,64,65,66]
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.
Allogeneic bone marrow or peripheral stem cell transplantation
Evidence (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 after the infusion of donor lymphocytes.
Favorable prognostic features included the following:
Myeloablative ASCT 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.[76,77,78] In one anecdotal series of 60 patients who underwent ASCT, six of the patients relapsed between 6 and 12 years, suggesting that late relapses still occur with this type of consolidation.
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 ASCT 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.[71,81][Level of evidence: 3iiiA] Given the lack of evidence so far that the high-risk patients benefit from allogeneic SCT in this era of novel new agents, it remains debatable whether ASCT should be offered in the first-line setting outside the context of a clinical trial.[78,82]
Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity ASCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity ASCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[73,74][Level of evidence: 1iiA]
Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation
After relapsing more than 24 months after ASCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage ASCT or oral weekly cyclophosphamide. With a median follow-up of 52 months, the median OS was superior for salvage ASCT: 67 months (95% CI, 55–not estimable) versus 52 months (42–60); HR, 0.56 (0.35–0.90, P = .017).[83,84][Level of evidence: 1iiA]
In a retrospective review of 233 patients with refractory myeloma or relapsed and refractory myeloma who underwent a salvage autologous SCT, 81% of patients achieved a partial response (PR) or better.[Level of evidence: 3iiiDiv]
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.[87,88] Maintenance trials with glucocorticosteroids [89,90] 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.
Lenalidomide maintenance therapy
Evidence (lenalidomide maintenance therapy):
All of these trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. This increased risk is mostly seen in patients with previous exposure to alkylating agents. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.
Proteasome inhibitor maintenance therapy
Evidence (proteasome inhibitor maintenance therapy):
Summary: After ASCT, patients are offered lenalidomide maintenance therapy based on the consistent PFS and occasional OS benefits previously described. But short-term and long-term toxicities, and financial toxicities, may prevent implementation.[99,100] High-risk patients, especially those with del(17p) or t(14;16), may require bortezomib maintenance (with or without lenalidomide), but this approach is not evidence-based and confirmatory clinical trials are required.[101,102]
Management and Prevention of Myeloma Bone Disease
Myeloma bone disease is a consequence of increased osteoclastic activity and agents that inhibit osteoclasts are an important component of myeloma therapy. The bisphosphonates pamidronate and zoledronate are used most often, via intravenous infusion, but the RANKL monoclonal antibody inhibitor denosumab, given subcutaneously, is also effective, especially when renal dysfunction precludes the use of bisphosphonates.[9,10]
Denosumab (RANKL inhibitor)
Unlike bisphosphonates, the reversible mechanism of action for denosumab may result in rebound fractures if it is discontinued, although this theoretical concern for myeloma patients may be mitigated by continuous maintenance therapy.
Radiation therapy for bone lesions
Lytic lesions of the spine generally require radiation 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 Cancer 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.
Treatment Options for Relapsed or Refractory Multiple Myeloma
Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplantation (ASCT), and maintenance therapy. During initial therapy, some patients respond poorly or their disease progresses. The general strategy is to apply new therapies sequentially as required. In younger fit patients, reinduction therapy with response may be consolidated with an ASCT or allogeneic SCT in some cases. Sometimes, when relapse occurs 1 year or more after initial therapy, the same drugs can be administered a second time.
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 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.)
For patients who respond to their initial therapy, the myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, 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.
Combinations of drugs or single agents may be administered sequentially as required. The goal is to avoid symptoms and adverse consequences of relapsing disease; however, the onset of therapy may be delayed because of slow disease progression and good performance status.
Treatment options for relapsed or refractory multiple myeloma include the following:
Daratumumab is a monoclonal antibody targeting CD38 that can be given on its own but is usually given in combination with other drugs. Although it is given as an infusion, the subcutaneous formulation has equivalent efficacy and fewer adverse events.
Daratumumab has also been combined with carfilzomib and dexamethasone in a phase I study of 85 patients with refractory or resistant disease.
Elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7).
Carfilzomib is a second-generation proteasome inhibitor that is given intravenously (IV) (unlike the subcutaneous route for bortezomib); most studies have employed twice-weekly administration, but once-weekly administration appears at least equally efficacious and safe.
Ixazomib is a second-generation proteasome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.
Bortezomib is the first-in-class proteasome inhibitor that is given subcutaneously on a weekly basis for 3 of every 4 weeks; the subcutaneous route is preferred to the IV route because it causes significantly less neuropathy and no loss of responsiveness.[19,20,21] Bortezomib is metabolized and cleared by the liver, and it appears to be active and well tolerated in patients with renal impairment.[22,23] More than 6 months after completion of bortezomib induction therapy, bortezomib can be given again with a 40% ORR, according to a meta-analysis of 23 phase II studies.[Level of evidence: 3iiiDiv]
Pomalidomide is a third-generation immunomodulatory agent that shows some myelosuppression and an increased incidence of thromboembolic events, as noted with lenalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), but very little peripheral neuropathy compared with other agents.
Lenalidomide is a second-generation immunomodulatory agent that shows increased incidence of thromboembolic events as noted with pomalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), increased incidence of myelosuppression (more than pomalidomide), and an increased incidence of neuropathy (less than thalidomide, but more than pomalidomide).[30,31,32,33]
A meta-analysis of 3,254 patients from seven randomized trials showed that lenalidomide was associated with an increased risk of hematologic second primary malignancies (3.1% in patients who received lenalidomide vs. 1.4% in those who did not; HR, 3.8; 95% CI, 1.15–12.62; P = .029). This risk was confined to the combination of lenalidomide and melphalan (HR, 4.86; 95% CI, 2.79–8.46; P = .0001) but was not higher for lenalidomide with either cyclophosphamide or dexamethasone. A retrospective review of almost 4,000 patients with relapsed or refractory disease 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 every day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis). Uncontrolled trials have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone, with reports of increased response rates. Controlled studies are required to establish the value of this approach.
Thalidomide is a first-generation immunomodulatory agent that is not often used because of its sedative and constipating effects, its significant and potentially debilitating neuropathy, and its thrombogenic effect (thromboprophylaxis is required).[40,41] Very little myelosuppression is seen with this agent.
Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses. By utilizing a low dose (50 mg by mouth every day), significant sedation, constipation, and neuropathy may be avoided. Thromboprophylaxis with aspirin, warfarin, or low-molecular-weight heparin is required; the choice of therapy depends on pre-existing risk factors.
Chemotherapy (cytotoxic agents)
Chemotherapy alone has been used to obtain a clinical remission after exhausting most of the new regimens, allowing improvement in performance status that may permit subsequent use of clinical trials investigating alternative therapies.
A cellular therapy for refractory myeloma has been introduced, consisting of autologous T-cells transduced with an anti-CD19 chimeric antigen receptor (so-called CAR T-cells) after myeloablative chemotherapy and ASCT, with anecdotal responses.[53,54,55,56] Other molecular targets and expanded clinical approaches are being investigated.[Level of evidence: 3iiiDiv]
Selinexor is a selective inhibitor of nuclear export compounds that blocks exportin 1 (which activates tumor suppressor proteins), inhibits nuclear factor κB, and reduces oncoprotein mRNA translation.
Venetoclax is a selective BCL-2 inhibitor that induces apoptosis in myeloma cells, particularly in those with t(11;14) which expresses high levels of bcl2.
Histone deacetylase inhibitors
Panobinostat is a potent pan-deacetylase inhibitor that combines with proteasome inhibition to block removal of overproduced, misfolded proteins from the myeloma cell, which impairs myeloma cell survival.
Dexamethasone dosage has been evaluated in two prospective randomized trials.
On the basis of these trials, all ongoing trials and regimens utilize the low-dose dexamethasone schedule in combination with other therapeutic agents: 40 mg dexamethasone (oral or IV) weekly in younger patients or fit older patients, or 20 mg (oral or IV) in less-fit older patients.
These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of plasma cell neoplasms and multiple myeloma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for plasma cell neoplasms and multiple myeloma. Listed after each reference are the sections within this summary where the reference is cited.
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 Zamagni et al. as reference 15.
Added Lilleness et al. as reference 54.
Treatment for Multiple Myeloma
Added Rosiñol et al. as reference 14.
Added Perrot et al. as reference 29.
Added Kumar et al. as reference 61.
Added text about a prospective randomized trial of 758 patients who completed induction therapy in less than 12 months that compared autologous stem cell transplantation (ASCT) plus lenalidomide maintenance, tandem ASCT, and ASCT plus VRd (bortezomib + lenalidomide + dexamethasone) maintenance. There was no difference in 38-month progression-free survival and overall survival (OS) among these three randomized groups (cited Stadtmauer et al. as reference 68 and level of evidence 1iiA).
Added text to state that a prospective randomized trial of 460 patients with newly diagnosed multiple myeloma who had completed induction therapy and ASCT compared lenalidomide maintenance with placebo. With a median follow-up of 91 months, the median OS for the lenalidomide maintenance group was 113.8 months versus 84.1 months for the placebo group. This translated to a 5-year OS of 76% for the lenalidomide group versus 64% for the placebo group (cited Holstein et al. as reference 92 and level of evidence 1iA).
Relapsed or Refractory Multiple Myeloma
This section was renamed from Refractory or Relapsing Multiple Myeloma.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
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.
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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:
PDQ® Adult Treatment Editorial Board. PDQ Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389362]
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Last Revised: 2020-05-15
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