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.
For more information, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in B-Cell Non-Hodgkin Lymphoma Treatment.
Estimated new cases and deaths from multiple myeloma in the United States in 2024:[1]
Plasma Cell Neoplasm | M Protein Type | Pathology | Clinical Presentation |
---|---|---|---|
Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance. | |||
MGUS | IgG kappa or lambda; or IgA kappa or lambda | <10% plasma cells in bone marrow | Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein) [2] |
Isolated plasmacytoma of bone | IgG kappa or lambda; or IgA kappa or gamma | Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site | Asymptomatic or symptomatic |
Extramedullary plasmacytoma | IgG kappa or lambda; or IgA kappa or gamma | Solitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses [3] | Asymptomatic or symptomatic |
Multiple myeloma | IgG kappa or lambda; or IgA kappa or gamma | Often, multiple lesions of bone | Symptomatic |
Idiotypic myeloma cells can be found in the blood of patients with myeloma 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.[6-8]
Patients with an M protein in the serum and/or urine are evaluated by some of the following criteria:
In most patients with myeloma, 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 patients with myeloma.
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.
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.[2,23-25] 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. However, patients with MGUS and risk factors for disease progression must be followed carefully because they are more likely to develop myeloma (most commonly), amyloidosis, lymphoplasmacytic lymphoma, or chronic lymphocytic leukemia. These patients may then require therapy.[25-27]
Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[28-30] 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.[32] 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.[34]
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.[35] A monoclonal gammopathy causing renal dysfunction—by direct antibody deposition or amyloidosis—is referred to as monoclonal gammopathy of renal significance.[36] 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.[37]
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).[38][Level of evidence C3] 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.
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.[43]
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 biological therapies and better salvage options, with median survivals now exceeding 10 years.[47] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[21,48] Racial disparities because of socioeconomic factors, genetics, differences in risk factor exposure, and structural racism are under evaluation.[49]
Multiple myeloma is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. For more information, see the sections on Isolated Plasmacytoma of Bone and Extramedullary Plasmacytoma.
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.[50] Clinical symptoms and signs include the following:
Accurate diagnosis of amyloidosis requires histological evidence of amyloid deposits and characterization of the amyloidogenic protein using immunoelectron microscopy.[51] 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.[51]
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.[55] Amyloidosis associated with an IgM monoclonal gammopathy is a rare, but distinct, clinical entity with more frequent neuropathy and adenopathy and less cardiac involvement.[56]
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.[57] Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman histology) may be identified. Anecdotal reports suggest remissions have been achieved using myeloma-directed therapy.[58-62]
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.[1]
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.
The International Myeloma Working Group (IMWG) studied 11,171 patients, 2,901 of whom received high-dose therapy and 8,270 of whom received only standard-dose therapy.[2] 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.[3]
An International Staging System (ISS) was derived and is shown below in Table 2.[2]
Stage | Criteria | Median Survival (mo) |
---|---|---|
I-FISH = interphase fluorescence in situ hybridization; LDH = lactate dehydrogenase; R-ISS = Revised International Staging System. | ||
I | Beta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL | Not reached |
II | Not R-ISS I or III | 83 |
III | Beta-2-microglobulin ≥5.5 mg/L and either high LDH or high-risk chromosomal abnormalities by I-FISH (defined as presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)) | 43 |
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.[4-6] (See Table 3 below.) This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[4] Bone marrow samples are sent for cytogenetic and FISH analysis.[6] Plasma cell leukemia (>2%–5% circulating plasma cells) has a particularly poor prognosis.[7-13] The otherwise favorable prognosis of hyperploidy is trumped by coexistent adverse cytogenetics.[14]
Risk Group | Cytogenetic Findings | Disease Characteristics | Median Survival (y) | |
---|---|---|---|---|
FISH = fluorescence in situ hybridization; Ig = immunoglobulin. | ||||
Good risk | Has any of the following cytogenetic findings: | These patients most often have disease that expresses IgG kappa monoclonal gammopathies, and lytic bone lesions. | 10–12 [15] | |
No adverse FISH or cytogenetics | ||||
Hyperdiploidy | ||||
t(11;14) by FISH | ||||
t(6;14) by FISH | ||||
Intermediate risk | Has one of the following formerly deleterious criteria that have been abrogated by standard triplet or quadruplet regimens:[16] | These patients often have IgA lambda monoclonal gammopathies and less bone disease. | 5–10 | |
t(4;14) | ||||
t(14;16) | ||||
High risk | Has any of the following cytogenetic findings: | These patients have disease that expresses IgA lambda monoclonal gammopathies (often) and skeletal-related complications (less often). | <5 for high-risk; <3 for ultra-high risk [15] | |
del 17p by FISH | ||||
t(14;16) by FISH | ||||
t(4;14) | ||||
t(14;20) | ||||
del 13 | ||||
Biallelic del TP53 (ultra-high risk) | ||||
1q gain (3 copies), 1 q amp (4 copies, ultra-high risk), monoallelic del (1p32),[17] biallelic del (1p32)[17] | ||||
Plasma cell leukemia |
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.[1-3] 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.[1,4,5] Increasing anemia is the most reliable indicator of progression.[5] The following criteria represent the new definition for smoldering myeloma:[3]
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.[6] The trial randomly assigned 125 patients to receive lenalidomide plus dexamethasone or observation.
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.[3] These criteria include the following:
Response criteria have been developed for patients on clinical trials by the IMWG.[9] 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 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 near complete response patients are incorporated into the VGPR group by the IMWG. Patients who achieve a complete response 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 complete response if their free kappa/lambda light–chain levels and ratio return to reference ranges. The clinical utility of these various categories must be validated in clinical trials.
Therapy options for patients with symptomatic myeloma can be divided into the following categories:
Treatment depends on assessing the extent of systemic damage from the amyloidosis and the underlying plasma cell dyscrasia.[1,2] 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.[3]
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 patients treated with all the same regimens active in multiple myeloma.[4-12] Lower doses of lenalidomide or pomalidomide must be used in patients with renal dysfunction.[13] Patients with amyloidosis respond to treatment with daratumumab, with or without other active agents. Daratumumab is usually combined with other agents used for myeloma.[14-20] Rapid responses to induction therapy may result in improvement of renal or cardiac function.[21,22]
Evidence (chemotherapy):
Daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone is considered a standard regimen for previously untreated patients who are eligible to receive this regimen.
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.[24] 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).[24][Level of evidence A1] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.[24-29] Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplant (SCT); the 5-year OS rate was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplant.[30][Level of evidence C1] Similarly, in a retrospective review of 672 consecutive patients with amyloidosis who underwent autologous SCT 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.[31][Level of evidence C2] A randomized trial confirming the benefit of autologous transplant is not anticipated.[3,32]
An anecdotal series describes full-intensity and reduced-intensity allogeneic SCT.[33]
The monoclonal antibody CAEL-101 binds to immunoglobulin-associated amyloid in an effort to promote phagocytosis and clearance of the amyloid deposits.
This treatment is not approved by the U.S. Food and Drug Administration and is under clinical evaluation.[34][Level of evidence C3]
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 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 observed to detect increases in monoclonal (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 M 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.[1]
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.[3-6] Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.[2]
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.
For more information, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in B-Cell Non-Hodgkin Lymphoma Treatment.
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.[1]
Most patients will eventually develop disseminated disease and require chemotherapy. Almost 50% of patients 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.[5] Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.[2,4]
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 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.[1-4]
About 25% of patients have serum and/or urine M protein; this frequently disappears after adequate radiation.
Extramedullary plasmacytoma is a highly curable disease. Progression-free survival rates range from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).[1,2,5]
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.
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 disease complications.[6]
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 monitored using a watchful waiting approach.[7] 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.[8]
Newly diagnosed patients who require therapy fall into two categories: (1) patients in good or well-controlled health (previously referred to as the fit, transplant-eligible patient) or (2) the less-fit patient with significant comorbidities or advanced age (previously referred to as not transplant eligible). Comorbidities and performance status are important determinants to help decide about fitness of patients at all ages, especially those between the ages of 70 years and 80 years. Nomograms exist for geriatric patients to define life expectancy independent of the myeloma diagnosis.[9] Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies. These factors are also important when considering consolidation therapies, such as chimeric antigen receptor T-cell therapy, bispecific antibody therapy, and autologous stem cell transplant (SCT) consolidation. Most patients also receive a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications.[10,11]
The International Myeloma Working Group has issued guidance for the diagnosis and management of patients with renal impairment.[12]
Patients in good or well-controlled health may receive induction chemotherapy with a four-drug (quadruplet) or three-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used regimens include:
After 4 to 8 months of therapy, responding patients may undergo autologous SCT consolidation.[16,21] The previously mandated autologous SCT consolidation has been questioned because a large, randomized, prospective trial failed to demonstrate an overall survival (OS) benefit.[22] Maintenance therapy is then implemented until the time of relapse.[23-25] At relapse, subsequent therapies are given sequentially by using previously successful drugs (if the interval of time since previous exposure is >1 year) or newer drugs not previously tried.
The less-fit patient may receive induction chemotherapy with a triplet or quadruplet regimen (as described for the patient in good or well-controlled health, but with dosage adjustments) including the CD38-directed monoclonal antibodies daratumumab or isatuximab, or with a doublet regimen including daratumumab or isatuximab, which might be better tolerated.[26] Therapy is continued until maximal response and then maintenance therapy is given until relapse.[27] At relapse, subsequent therapies are given sequentially (as described for the patient in good or well-controlled health).
Patients with newly diagnosed or relapsing myeloma can be identified as having standard-risk or high-risk disease. This determination is made 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.[28] Plasma cell leukemia at presentation, or as a leukemic evolution of refractory myeloma, is a particularly high-risk, poor-prognosis entity.[29-33] Plasma cell leukemia with an ultra-high poor prognosis is defined by the presence of more than 2% circulating tumor plasma cells by flow cytometry.[34] 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.[35-37] Beyond induction therapy, high-risk disease can lead to more aggressive strategies, such as tandem transplant or consideration of allogeneic SCT. More intensive maintenance therapies may also be given for high-risk disease; instead of using lenalidomide alone, lenalidomide plus bortezomib has been chosen based on prior trials using thalidomide.[38] 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 are needed to establish improved outcomes with these newer approaches for high-risk patients.
The assessment of measurable residual disease (MRD) is mandatory for the assessment of efficacy in clinical trials.[39-42] Does MRD testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing selection or duration of therapy? Achievement of MRD negativity after induction therapy (with or without consolidation therapy) is associated with improved progression-free survival (PFS) and improved OS.[43-52] While MRD negativity may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy. Similarly, there are no data to suggest that sustained MRD negativity can allow deintensification or discontinuation of maintenance therapy.[53,54]
Patients with myeloma who are symptomatic or require therapy because of progression or adverse laboratory findings require induction therapy. Ideally, induction therapy should reduce tumor burden, provide symptomatic relief, and prevent further end-organ damage.
Two randomized prospective trials have evaluated the D-VRd regimen for induction therapy in fit patients in good or well-controlled health.
A more intensive regimen of induction therapy, consolidation therapy, and maintenance therapy was investigated in patients with high-risk cytogenetic abnormalities.
In 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.[60] Bortezomib is given subcutaneously, which helps to avoid the neuropathies that were much more severe with intravenous (IV) administration.[61-63] Bortezomib is also preferred for patients with renal impairment.[64] 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.[65,66] Because lenalidomide is metabolized erratically in patients with renal failure, clinicians may choose the CyBorD regimen,[19,20] but this selection is empiric and not based on randomized trial results. 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 who receive lenalidomide (or other similar immunomodulating agents such as pomalidomide or thalidomide). Lower doses of lenalidomide must be used for patients with renal dysfunction.[67]
Triplet or quadruplet therapies such as VRd and CyBorD with daratumumab or isatuximab can be used in patients in with adequate fitness and minimal comorbidities. 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 as described in the section for fit patients.[15,26] Therapeutic options have changed with the advent of daratumumab and isatuximab, the CD38-directed monoclonal antibodies.
Immunologic reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).
Evidence (autologous bone marrow or peripheral SCT):
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 hematopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hematopoietic 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:
Evidence (single autologous bone marrow or peripheral SCT):
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.[25,84-86,97] The role of autologous SCT has changed, from a mandated standard consolidation for those patients healthy enough to undergo it toward a therapeutic option, like any other, that offers approximately 2 years of increased PFS on average with defined toxicities. Incorporating, eliminating, delaying, or even replacing autologous SCT in the future (perhaps with chimeric antigen receptor T cells or bispecific antibodies) will be the subject of ongoing and upcoming clinical trials. Subgroups of patients may have a particular benefit from autologous SCT. Patients with a t(11;14) translocation may show differential benefit, as found in a retrospective review of 3,538 total patients in a dataset from the Center of International Blood and Marrow Transplant Research.[98] One meta-analysis of only four randomized clinical trials suggested an OS benefit for up-front autologous SCT in patients with high-risk cytogenetics.[96]
Another approach to high-dose therapy has been the use of two sequential infusions of high-dose therapy with stem cell support (tandem transplants).[99-103]
Evidence (tandem autologous bone marrow or peripheral SCT):
A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[112] 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.
Evidence (allogeneic bone marrow or peripheral SCT):
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.[113]
Favorable prognostic features included the following:
Myeloablative allogeneic SCT 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.[113-115] In one anecdotal series of 60 patients who underwent allogeneic SCT, six of the patients relapsed between 6 and 12 years, suggesting that late relapses still occur with this type of consolidation.[116]
The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[115] Since the introduction of lenalidomide and bortezomib, a trial exploring donor versus no donor comparison of autologous SCT versus autologous SCT and nonmyeloablative allogeneic SCT in 260 untreated patients showed no difference in PFS or OS.[117][Level of evidence C1] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[108,118][Level of evidence C1]
Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with those of patients receiving a reduced-intensity autologous SCT 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 autologous SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[110,111][Level of evidence A1] Anecdotal long-term survivals have been reported for patients with therapy-related MDS, AML, acute lymphoblastic leukemia, or chronic myelomonocytic leukemia treated with allogeneic SCT.[119]
After relapsing more than 24 months after autologous SCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage autologous SCT or oral weekly cyclophosphamide.[120] With a median follow-up of 52 months, the median OS was superior for salvage autologous SCT: 67 months (95% CI, 55–not estimable) versus 52 months (42–60) (HR, 0.56; 0.35–0.90; P = .017).[120,121][Level of evidence A1]
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.[122][Level of evidence C3]
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.[123] Most clinical trials employ one or both.[124,125] Maintenance trials with glucocorticosteroids [126,127] and with interferon [128] showed very minor improvements in remission duration and survival but with toxicities that outweighed the benefits. The efficacy and tolerability of thalidomide, lenalidomide, bortezomib, and ixazomib in the induction and relapse settings has made these agents attractive options in maintenance trials.[123]
Evidence (maintenance therapy [lenalidomide, ixazomib, daratumumab alone or in combination]):
All the trials and meta-analyses of lenalidomide maintenance showed a significant improvement in PFS, while OS was improved in one trial and one meta-analysis, both after autologous SCT. All of these trials showed an increase in myelodysplasia or acute leukemia from 3% to 7% for lenalidomide, 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 used either continuously or with 1 week off every month. Genetic profiling may identify groups of patients who benefit from lenalidomide maintenance. Among 556 patients in the Myeloma XI trial (NCT01554852), those with del(1p), del(17p), and t(4;14) had a median PFS of 57.3 months with lenalidomide maintenance and 10.9 months with observation.[137] For patients unable to receive lenalidomide maintenance, ixazomib is a reasonable alternative. The combination of daratumumab plus lenalidomide is being evaluated in the GRIFFIN trial.[14] Although maintenance therapy with carfilzomib, lenalidomide, and dexamethasone resulted in improved PFS when compared with lenalidomide alone, the preliminary toxicity and efficacy results must mature before implementing this regimen.[136]
Evidence (proteasome inhibitor maintenance therapy):
Summary: After autologous SCT, 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.[140,141] 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.[142,143]
Myeloma bone disease is a consequence of increased osteoclastic activity and agents that inhibit osteoclasts are an important component of myeloma therapy.[11] The bisphosphonates pamidronate and zoledronate are used most often, via IV infusion, but the RANKL monoclonal antibody inhibitor denosumab, given subcutaneously, is also effective, especially when renal dysfunction precludes the use of bisphosphonates.[10,11]
Evidence (zoledronate):
Evidence (pamidronate):
Evidence (denosumab):
Unlike bisphosphonates, the reversible mechanism of action for denosumab may result in rebound fractures if it is discontinued, although this theoretical concern for patients with myeloma may be mitigated by continuous maintenance therapy.[157]
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.
Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.[159]
Bisphosphonates are useful for slowing or reversing the osteopenia that is common in patients with myeloma.[154]
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.
Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplant (SCT), and maintenance therapy. During initial therapy, some patients respond poorly or their disease progresses. The general strategy is to give new therapies sequentially as required. In fit patients, reinduction therapy with response may be consolidated with an autologous SCT 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 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. Other patients with primary refractory myeloma and progressive disease require a change in therapy. For more information, see the Treatment of Multiple Myeloma section.
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 given 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.[3]
Evidence (daratumumab):
In every prospective randomized trial to date, adding daratumumab to other active myeloma combination therapies showed improved responses and PFS when compared with the combination therapies alone.
Elotuzumab is a monoclonal antibody directed at SLAMF7 (signaling lymphocytic activation molecule F7).
Evidence (elotuzumab):
Isatuximab is a monoclonal antibody directed against CD38.
Evidence (isatuximab):
There are no data comparing isatuximab with daratumumab, both of which target CD38. There are no data proving that isatuximab has efficacy in patients with disease that is resistant to daratumumab.
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 intravenous (IV) route because it causes significantly less neuropathy and no loss of responsiveness.[17-19] Bortezomib is metabolized and cleared by the liver, and it appears to be active and well tolerated in patients with renal impairment.[20,21] More than 6 months after completion of bortezomib induction therapy, bortezomib can be given again with a 40% overall response rate, according to a meta-analysis of 23 phase II studies.[22][Level of evidence C3]
Evidence (bortezomib):
Carfilzomib is a second-generation proteasome inhibitor that is given by 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.[26]
Evidence (carfilzomib):
Ixazomib is a second-generation proteasome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.
Evidence (ixazomib):
CAR T-cell therapy is a cellular therapy for refractory and/or multiply relapsed myeloma. This therapy consists of autologous anti-BCMA transduced T cells. This therapy has shown a 50% to 65% complete remission rate and a median PFS of 18 to 20 months in patients from highly selected nonrandomized series.[37-39][Level of evidence C3] Based on the durable responses in these nonrandomized series, the U.S. Food and Drug Administration (FDA) approved the BCMA-directed CAR T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) for patients with relapsed or refractory disease. A review of the management of moderate-to-severe immune-related adverse events suggests immediate use of corticosteroids and supportive hospital care.[40] Other molecular targets and expanded clinical approaches are being investigated.[41][Level of evidence C3]
Evidence (cilta-cel):
Based on this trial, the FDA approved cilta-cel for patients with (1) relapsed or refractory myeloma after at least one line of therapy including a proteosome inhibitor (such as bortezomib) and an immunomodulatory agent (such as lenalidomide) AND (2) lenalidomide-refractory disease.
Evidence (ide-cel):
Based on this trial, the FDA approved ide-cel for patients with (1) relapsed or refractory myeloma after at least two lines of therapy AND (2) lenalidomide-refractory disease.
Bispecific antibodies target both CD3, which is on the surface of T cells, and either BCMA or GPRC5D (G protein–coupled receptor family C group 5 member D), both of which concentrate on the surface of myeloma cells.[44,45]
Teclistamab is a T-cell-redirecting bispecific antibody.
Evidence (teclistamab):
Talquetamab is a T-cell-redirecting bispecific antibody that targets GPRC5D, a receptor highly expressed on plasma cells, along with CD3.
Evidence (talquetamab):
Elranatamab is a T-cell directing bispecific antibody targeting BCMA and CD3.
Evidence (elranatamab):
Summary: Patients with myeloma who have received one to four prior lines of therapy, are refractory to proteosome inhibitors and immunomodulatory agents, and are also experiencing a slow relapse are often referred for CAR T-cell therapy. This is because delays in production of the CAR T-cell agent are less problematic, and because time receiving therapy is fixed and short-term, allowing a long duration therapy-free time after a response.[45] Patients who experience a quick relapse may benefit from an "off-the-shelf" bispecific antibody that results in similar response rates and durability of response, but this approach comes with the downside of required continual therapy.[45] The choice of bispecific antibody cannot be made based on any clinical evidence because of the lack of comparative trials. In heavily pretreated patients, bispecific antibodies impair humoral immunity, but this can be ameliorated using IV or subcutaneous immunoglobulin and antimicrobial prophylaxis.[45] Current logic supports using products with different targets sequentially.
Pomalidomide is a third-generation immunomodulatory agent. Pomalidomide is associated with 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.
Evidence (pomalidomide):
Lenalidomide is a second-generation immunomodulatory agent. Lenalidomide is associated with increased incidence of thromboembolic events, as noted with pomalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), myelosuppression (more than pomalidomide), and neuropathy (less than thalidomide, but more than pomalidomide).[53-57]
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).[58] 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.[58] 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.[59]
As a result of predominant renal clearance, lenalidomide doses need to be reduced for patients with 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).[60] Uncontrolled trials have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone, with reports of increased response rates.[61] Controlled studies are required to establish the value of this approach.
Evidence (lenalidomide):
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).[64,65] 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.[66] By using 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 preexisting risk factors.[57]
Evidence (thalidomide):
Belantamab mafodotin is an antibody-drug conjugate composed of an anti-BCMA monoclonal antibody attached to monomethyl auristatin, which inhibits microtubule formation. In 2020, the FDA approved this antibody-drug conjugate for patients with relapsed or refractory myeloma, but this approval was withdrawn in 2023 based on findings from a prospective randomized trial in 325 patients with relapsed or refractory myeloma: this trial compared belantamab mafodotin with pomalidomide plus dexamethasone and showed no significant difference in median PFS.[68][Level of evidence B1] Since then, the results of several European clinical trials may revive interest in seeking FDA approval in the United States.
Evidence (belantamab mafodotin):
Summary: The use of BCMA-targeted therapy in the second- or third-line of therapy appears better than the usual standard of care. FDA approval may occur after review of these European trials. The use of belantamab mafodotin may affect the subsequent efficacy of other BCMA-directed therapies which have already been approved by the FDA, including the CAR T-cell therapies, cilta-cel and ide-cel, and the bispecific BCMA T-cell enhancers, teclistamab and elranatamab. Clinical trials must establish the correct sequencing of BCMA-directed therapies. In the meantime, belantamab mafodotin has not been approved by the FDA.
Regimens:
Evidence (chemotherapy):
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.
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.
Selinexor (evidence):
Selinexor has significant side effects, including nausea, vomiting, fatigue, diarrhea, weight loss, poor appetite, and cytopenias. A descriptive retrospective study of 437 patients enrolled in clinical trials focused on aggressive medical support for these side effects.[83]
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.
Evidence (venetoclax):
Although activating BRAF variants are rarely found in patients with newly diagnosed myeloma, these variants appear in multiple-relapsing disease. Twelve such patients with a BRAF V600E variant who received encorafenib and binimetinib had an overall response rate of 83.3%, a median PFS of 5.6 months, and an OS rate of 55% at 24 months.[86][Level of evidence C3]
Dexamethasone dosage has been evaluated in two prospective randomized trials.
On the basis of these trials, all ongoing trials and regimens use the low-dose dexamethasone schedule in combination with other therapeutic agents: 40 mg dexamethasone (oral or IV) weekly in fit patients, or 20 mg (oral or IV) in less-fit patients at higher risk for complications.
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.
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.
Cited in:
Cited in:
Cited in:
Cited in:
Cited in:
Cited in:
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.
Revised text to state that newly diagnosed patients with multiple myeloma who require therapy fall into two categories: (1) patients in good or well-controlled health or (2) the less-fit patient with significant comorbidities or advanced age. Comorbidities and performance status are important determinants at all ages, especially between the ages of 70 years and 80 years, to help decide about fitness. Also revised text to state that age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as chimeric antigen receptor (CAR) T-cell therapy, bispecific antibody therapy, and autologous stem cell transplant consolidation.
Revised text to state that the less-fit patient may receive induction chemotherapy with a triplet or quadruplet regimen, including the CD38-directed monoclonal antibodies daratumumab or isatuximab, or with a doublet regimen including daratumumab or isatuximab which might be better tolerated
Added Pasquini et al. as reference 52.
Revised text about the results of the GRIFFIN trial which randomly assigned 207 patients with newly diagnosed transplant-eligible multiple myeloma to receive induction therapy with either the D-VRd (daratumumab plus bortezomib, lenalidomide, and dexamethasone) or Vrd regimen (cited Voorhees et al. as reference 56).
Revised text to state that triplet or quadruplet therapies such as VRd and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) with daratumumab or isatuximab can be used in patients in with adequate fitness and minimal comorbidities. Therapeutic options have changed with the advent of daratumumab and isatuximab, the CD38-directed monoclonal antibodies.
Added text about the results of a prospective randomized trial in 446 patients with newly diagnosed myeloma who were ineligible for transplant which compared isatuximab plus VRd with VRd alone (cited Facon et al. as reference 71 and level of evidence B1).
Added text about the results of a prospective randomized trial in 270 patients with newly diagnosed myeloma who were transplant ineligible and aged 65 to 79 years which compared isatuximab plus VRd with isatuximab plus Rd (lenalidomide and dexamethasone) (cited Leleu et al. as reference 72 and level of evidence B3).
Treatment of Relapsed or Refractory Multiple Myeloma
Revised the list of treatment options for relapsed or refractory multiple myeloma to include ciltacabtagene autoleucel, idecabtagene vicleucel, and the BCMA-targeting antibody-drug conjugate, belantamab mafodotin.
The CAR T-cell therapy subsection was extensively revised.
Revised text to state that patients with myeloma who have received one to four prior lines of therapy, are refractory to proteosome inhibitors and immunomodulatory agents, and are also experiencing a slow relapse are often referred for CAR T-cell therapy. Also added text to state that in heavily pretreated patients, bispecific antibodies impair humoral immunity, but this can be ameliorated using intravenous or subcutaneous immunoglobulin and antimicrobial prophylaxis.
Added BCMA-targeting antibody-drug conjugates as a new subsection.
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® Cancer Information for Health Professionals pages.
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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).
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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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