National Cancer Institute


Expert-reviewed information summary about the treatment of plasma cell neoplasms (including multiple myeloma).

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.

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).

Plasma Cell Neoplasms Treatment

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment

General Information About Plasma Cell Neoplasms

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 2017:

  • New cases: 30,280.
  • Deaths: 12,590.

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. 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.

Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated by some of the following criteria:

  • Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin (Ig) assays; however, specific Ig quantification always overestimates the M protein because normal Ig are included in the result. For this reason, the preference is often that baseline and follow-up measurements of the M protein be done by the same method. Quantitative serum-free light chains (FLC) may be helpful to follow response if an M protein is not apparent.
  • Measure and follow the amount of M-protein light chains excreted in the urine over 24 hours. Measure the total amount of protein excreted over 24 hours and multiply this value by the percentage of urine protein that is M protein, as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
  • Identify the heavy and light chain of the M protein by immunofixation electrophoresis.
  • Measure the hemoglobin, leukocyte, platelet, and differential counts.
  • Determine the percentage of marrow plasma cells. Be aware that marrow plasma-cell distribution may vary in different sites. Bone marrow is often sent for cytogenetics and fluorescence hybridization testing for genetic markers of high-risk disease. (Refer to the Genetic Factors and Risk Group section of this summary for more information.)
  • Measure serum-free kappa and lambda light chain. This is especially useful in cases of oligosecretory plasma-cell dyscrasia or for following cases of light-chain amyloidosis. The FLC ratio of over 100 can predict a greater than 70% progression within 2 years in patients with smoldering myeloma.
  • If clinically warranted, take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
  • Evaluate renal function with serum creatinine and a creatinine clearance.
  • Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light-chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin.

    In most myeloma patients, the glomeruli function normally 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.

  • Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity.
  • Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones.
  • Obtain a spinal magnetic resonance imaging (MRI) scan (or spinal computed tomography [CT] or positron emission tomography-CT scan depending on availability) if the skeletal survey is negative.
  • If amyloidosis is suspected, perform a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.
  • Measure serum albumin and beta-2-microglobulin as independent prognostic factors.
  • The presence of circulating myeloma cells is considered a poor prognostic factor. Primary plasma cell leukemia has a particularly poor prognosis.

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.

As mentioned before, the major challenge is to separate the stable, asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.

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. 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.

Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS. 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. This risk ranges from 2% to more than 20% in higher-risk patients.

Risk factors that predict disease progression include the following:

  • An abnormal serum-FLC ratio.
  • Non-IgG class MGUS.
  • A high serum-M protein level (≥15 g/L).

A Swedish cohort study confirmed the higher-risk factors of abnormal serum-FLC ratio and the high serum–monoclonal protein level. They described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (if a patient has an IgG kappa M-protein, the IgM and IgA would be below normal levels with ). Incorporation of gene-expression profiles to better assess risk is also 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.

Isolated Plasmacytoma of Bone

The patient has an isolated plasmacytoma of the bone if the following are found:

  • A solitary lytic lesion of plasma cells on skeletal survey in an otherwise asymptomatic patient.
  • A bone marrow examination from an uninvolved site contains less than 10% plasma cells. The absence of plasma cells on flow cytometry of the bone marrow suggests a low (<10%) risk of recurrence after radiation therapy of the isolated bone plasmacytoma.

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.

Extramedullary Plasmacytoma

A patient has extramedullary plasmacytoma if the following are found:

  • Isolated plasma-cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses.
  • Negative findings on skeletal x-rays and bone marrow biopsy.

Multiple Myeloma

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.

Prognosis

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. Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.

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:

  • Fatigue.
  • Purpura.
  • Enlarged tongue.
  • Diarrhea.
  • Edema.
  • Lower-extremity paresthesias.

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 non-amyloid light chain amyloidosis (usually transthyretin) had an 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. A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation. An increase in levels of serum-FLC over many years can precede the clinical diagnosis of amyloid light-chain (AL) amyloidosis.

POEMS Syndrome

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.

Stage Information About Plasma Cell Neoplasms

No generally accepted staging system exists for monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of bone, or extramedullary plasmacytoma. Of the plasma cell neoplasms, a staging system exists only for multiple myeloma.

Multiple Myeloma

Multiple myeloma is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M protein) in the serum and/or urine, along with various clinical parameters, such as hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. Impaired renal function worsens prognosis regardless of stage.

The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy since almost all patients, except for rare patients with solitary bone tumors or extramedullary plasmacytomas, have generalized disease.

International staging system

The International Myeloma Working Group (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 (LDH) levels and interphase fluorescence 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. (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.

Treatment Option Overview for Plasma Cell Neoplasms

The major challenge in treating plasma cell neoplasms is to separate the stable, asymptomatic group of patients who do not require immediate treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately. 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. Increasing anemia is the most reliable indicator of progression. The following criteria represent the new definition for smoldering myeloma:

  • Serum monoclonal protein immunoglobulin (Ig) G or IgA of at least 30 g/L or urinary monoclonal protein of at least 500 mg per 24 hours.
  • Clonal bone marrow plasma cells 10% to 60% (>60% represents overt myeloma).
  • Absence of amyloidosis or myeloma-defining events as follows:
    • Hypercalcemia greater than 1 mg/dl higher than normal.
    • Creatinine greater than 2 mg/dl or creatinine clearance less than 40 ml/min.
    • Anemia with hemoglobin less than 10.0 g/dl.
    • Bone lesions (one or more) on skeletal radiography, computed tomography (CT) or positron emission tomography (PET)-CT.
    • Clonal plasma cell percentage in marrow at 60% or more.
    • Involved: uninvolved serum-free light chain (FLC) ratio at 100 or more.
    • More than one focal lesion of at least 5 mm on magnetic resonance imaging (MRI) of the spine.

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.

  • With a median follow-up of 75 months, lenalidomide plus dexamethasone provided benefit in time to progression compared with observation, with a median time not reached (95% confidence interval [CI], 47 months to not reached) compared with 23 months (95% CI, 16‒31 months) (hazard ratio, 0.24; 95% CI, 0.14‒0.41).[]
  • There was no difference in overall survival (OS) at a median follow-up of 75 months.
  • At the beginning of this trial, some of the patients had what would now be considered overt myeloma, based on the updated criteria listed above. This may influence the interpretation of the study because overt myeloma patients might be responsible for some of the benefits seen with therapy.

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:

  • Amyloidosis.
  • Hypercalcemia greater than 1 mg/dl higher than normal.
  • Creatinine greater than 2 mg/dl or creatinine clearance less than 40 ml/min. Myeloma can cause renal dysfunction via hypercalcemia, amyloidosis, or light chain deposition disease.
  • Anemia with hemoglobin less than 10.0 g/dl.
  • Bone lesions (one or more) on skeletal radiography, whole-body MRI or spine and pelvis MRI, or PET-CT scans.
  • Clonal plasma cell percentage in marrow at 60% or more.
  • Involved: uninvolved serum-FLC ratio at 100 or more.
  • More than one focal lesion of at least 5 mm on skeletal bone survey, or if negative, total-body MRI, or MRI of the spine and pelvis, or PET-CT scan.

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 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 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. Whether these response definitions will translate into clinically meaningful endpoints, such as OS, remains to be seen.

Current therapy for patients with symptomatic myeloma can be divided into the following categories:

  • Induction therapies.
  • Consolidation therapies, which are less applicable for the very elderly.
  • Maintenance therapies.
  • Supportive care, such as bisphosphonates. (Refer to the Pharmacologic Therapies for Pain Control section in the PDQ summary on Cancer Pain for more information.)

Treatment for Amyloidosis Associated With Plasma Cell Neoplasms

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 (NT-proBNP) 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:

Chemotherapy

As is true for all plasma cell dyscrasias, responses have been reported for all the same regimens active in multiple myeloma.

Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[]

Stem cell rescue

A randomized, prospective study of 100 patients with immunoglobulin light-chain amyloidosis compared melphalan plus high-dose dexamethasone with high-dose melphalan plus autologous stem cell rescue. After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 months vs. 22.2 months; = .04).[] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction. Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplantation; the 5-year OS was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplantation.[] A randomized trial confirming the benefit of autologous transplantation is not anticipated.

An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with primary systemic amyloidosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Treatment for Monoclonal Gammopathy of Undetermined Significance

Treatment Options for Monoclonal Gammopathy of Undetermined Significance (MGUS)

Treatment options for MGUS include the following:

Watchful waiting

Multiple myeloma, other plasma cell dyscrasia, or lymphoma will develop in 12% of patients by 10 years, 25% by 20 years, and 30% by 25 years.

All patients with MGUS 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. 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. Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with monoclonal gammopathy of undetermined significance. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Treatment for Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Refer to the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.

Treatment for Isolated Plasmacytoma of Bone

Treatment Options for Isolated Plasmacytoma of Bone

Treatment options for isolated plasmacytoma of bone include the following:

Radiation therapy

About 25% of patients have a serum and/or urine M protein; generally this disappears following adequate radiation therapy to the lytic lesion.

The survival rate of patients with isolated plasmacytoma of bone treated with radiation therapy to the lesion is greater than 50% at 10 years, which is much better than the survival rate of patients with disseminated multiple myeloma.

Chemotherapy

Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% of them will do so within 2 years of diagnosis. 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. 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.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with isolated plasmacytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Treatment for Extramedullary Plasmacytoma

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.

About 25% of patients have serum and/or urine M protein; this frequently disappears following adequate radiation.

Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with extramedullary plasmacytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Treatment for Multiple Myeloma

Initial Evaluation

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.

Therapeutic Overview

Despite the introduction of many new therapeutic agents over the past two decades, there is still no confirmed curative approach. Major controversies have resulted regarding the framework for both future trials and current therapeutic recommendations. Unresolved questions in multiple myeloma include the following:

Several questions are raised when therapy is chosen for a patient with symptomatic myeloma at first presentation:

In summary, clinicians utilize a clinical trial or one of the following strategies for a newly diagnosed patient with multiple myeloma:

There are regional geographic variations to the approaches listed. Clinical trials and future discoveries may help to explicate the best therapeutic strategy. Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved OS. 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.

Induction Therapy

Induction therapy agents

Multiple therapeutic agents are available for induction therapy, either alone or in combinations. These include the following:

  • Steroids (e.g., dexamethasone and prednisone).
  • Immunomodulatory drugs (IMiDs).
    • Lenalidomide.
    • Pomalidomide.
    • Thalidomide.
  • Proteasome inhibitors.
    • Bortezomib.
    • Carfilzomib.
    • Ixazomib.
  • Monoclonal antibodies.
    • Daratumumab (monoclonal antibody targeting CD38).
    • Elotuzumab (monoclonal antibody targeting SLAMF7).
  • Alkylating agents (e.g., melphalan and cyclophosphamide).
  • Other cytotoxic drugs (e.g., vincristine, doxorubicin, and liposomal doxorubicin).
  • Histone-deacetylase inhibitors.

Clinical trials are needed to establish the regimens with the best efficacy and least long-term toxicity. (Refer to the Combination therapy section of this summary for a list of current clinical trials.)

Guidelines for choosing induction therapy

Until results become available, outside the context of a clinical trial, clinicians may choose induction therapy based on the following guidelines:

These guidelines require validation by ongoing clinical trials; participation in clinical trials is the preferred choice, when possible.

Corticosteroids

Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days, which is the same schedule used with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen. Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[]

Evidence (corticosteroids):

A prospective trial randomly assigned 488 patients older than 65 years to receive dexamethasone alone, melphalan plus dexamethasone, dexamethasone plus interferon-alpha, and melphalan plus prednisone (MP).

  • With a median follow-up of 7.1 years, no difference was observed in OS (median survival times were 32 months–40 months).[]
  • The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (Refer to the PDQ summary on Gastrointestinal Complications for more information on gastrointestinal symptoms.)

There has never been a randomized trial comparing single-agent oral dexamethasone at a traditional high dose (40 mg qd for 4 days, repeated after 4 days off) with a lower dose (≤40 mg weekly). This issue of dexamethasone dose has been evaluated in two of the following prospective, randomized trials:

  • In the context of melphalan, as evaluated in a National Cancer Institute of Canada trial ( [NCT00002678]).
    • Compared with standard-dose steroids, high-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but there was no difference in efficacy.
  • In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial ( [NCT00098475]).
    • The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone. (Refer to the Lenalidomide section of this summary for more information.)

On the basis of these trials, almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents: 40 mg dexamethasone (oral [PO] or intravenous [IV]) weekly in younger patients or fit older patients or 20 mg dexamethasone (PO or IV) in less-fit older patients.

IMiDs (immunomodulatory drugs)

Lenalidomide

Evidence (lenalidomide):

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT. A randomized, prospective trial of 342 previously untreated patients receiving lenalidomide-containing regimens compared aspirin (100 mg/qd) with enoxaparin (40 mg/qd); the 2% incidence of venous thromboembolic events was similar for both interventions. Empirically, the greater the number of risk factors for DVT, the more intense the recommendation for prophylactic anticoagulation. (Refer to the Thalidomide section of this summary for more information about risk factors.)

A meta-analysis of 3,254 individual 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; = .029). This risk was confined to the combination of lenalidomide and melphalan (HR, 4.86; 95% CI, 2.79–8.46, = .0001) but was not higher for lenalidomide with either cyclophosphamide or dexamethasone.

A retrospective review of almost 4,000 relapsed or refractory patients who received lenalidomide in 11 clinical trials suggested an increased incidence of nonmelanoma skin cancers. As a result of predominant renal clearance, lenalidomide doses need to be reduced in the setting of impaired renal function (creatinine clearance, 30–50: 10 mg qd; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis). Uncontrolled trials, including , have added clarithromycin (500 mg bid) to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach.

Pomalidomide

Evidence (pomalidomide):

Pomalidomide was approved for patients who relapse after two previous regimens, which must have included bortezomib and lenalidomide. Although some myelosuppression and increased risk of thromboembolic events are noted as with lenalidomide and thalidomide, very little peripheral neuropathy is noted in comparison with the other agents.

Thalidomide

Evidence (thalidomide):

Eleven randomized, prospective studies involving more than 4,600 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.

  • All of the trials reported improved response rates with the introduction of thalidomide and no hematopoietic damage, allowing adequate stem cell collection when applicable or allowing combinations with other myelosuppressive agents.
  • A meta-analysis of 1,685 patients from six of the randomized trials confirmed that thalidomide added to MP improves the median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; = .004).[]

As previously described in the section on corticosteroids, high-dose dexamethasone can complicate interpretation of clinical trials by worsening cardiopulmonary toxicity and deaths, especially in the context of thalidomide or lenalidomide, both of which are thrombogenic agents.

Factors that have been implicated to worsen the risk of DVT include the use of high-dose dexamethasone, concomitant erythropoietic growth factors, and concomitant doxorubicin, liposomal doxorubicin, or alkylating agents.

Personal cardiovascular risk factors can also influence the rate of DVT. Various clinical trials have included different DVT prophylaxis measures, including aspirin (81 mg–100 mg qd), warfarin, or low molecular-weight heparin. In a randomized, prospective trial, 667 previously untreated patients who received thalidomide-containing regimens were randomly assigned to aspirin (100 mg/qd), warfarin (1.25 mg/qd) or enoxaparin (40 mg/qd). The rate of serious thromboembolic events, acute cardiovascular events, or sudden death was 6.5% and similar for all three interventions.

Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.

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 PO qd), significant sedation, constipation, and neuropathy may be avoided. Prophylaxis to avoid thrombosis with aspirin, warfarin, or low molecular–weight heparin is required; the choice of therapy depends on pre-existing risk factors.

Proteasome inhibitors

Bortezomib

Evidence (bortezomib):

  • A prospective, randomized trial (the trial [NCT00111319]) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation (SCT) because of age (one-third of patients >75 years) compared bortezomib combined with melphalan and prednisone with melphalan and prednisone alone.
    • With a median follow-up of 60 months, the median OS favored the bortezomib arm (56.4 vs. 43.1 months, < .001).[]
  • A prospective, randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone.
    • With a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR, 0.77; = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[]
    • Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.
  • A prospective, randomized trial () of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.
  • With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 months vs. 6.5 months, < .001) and in OS (82% vs. 75%, = .05).[]

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment. In several retrospective, nonrandomized comparisons, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (2%–8% vs. 13%–28%) with no loss of efficacy compared with standard biweekly administration.

In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11). After a median follow-up of 1 year, grade 3 to 4 neurologic toxicity was reduced from 16% to 6% ( = .026) using the subcutaneous route, with no perceived loss of efficacy in terms of response. However, this study was not powered for noninferiority of response. New clinical trials are employing these changes of weekly treatment and subcutaneous route to improve the safety profile of bortezomib-containing regimens. In this trial, the bisphosphonates were continued until the time of relapse.

More than 6 months after completion of bortezomib induction therapy, bortezomib can be applied again with a 40% overall response rate, according to one anecdotal phase II trial.[]

Carfilzomib

Evidence (carfilzomib):

Ixazomib

Evidence (ixazomib):

Monoclonal antibodies

Daratumumab

Daratumumab is a monoclonal antibody targeting CD38 that is now FDA approved for use as a single agent or in combination therapy after failure of the previous regimen.

Evidence (daratumumab):

Elotuzumab

Elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7) that is now FDA approved for use in combination therapy after failure of one previous regimen.

Evidence (elotuzumab):

Conventional-dose chemotherapy

Evidence (conventional-dose chemotherapy):

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[]

  • No randomized studies support the widespread use of this regimen in untreated patients.
  • This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia.
  • Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low CR rate.
  • An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[]

Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results. The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.

Combinations, such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[]

A meta-analysis of studies comparing MP with drug combinations concluded that both forms of treatment were equally effective.[] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median OS, 17 months) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone or VAD.[]

Histone deacetylase inhibitors

Evidence (panobinostat):

Panobinostat is a potent pan-deacetylase inhibitor that combines with proteosome inhibition to block removal of overproduced, misfolded proteins from the myeloma cell, which impairs myeloma cell survival.

Combination therapy

Evidence (combination therapy):

Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials is the preferred approach, when feasible. The combination regimens in these trials represent the most successful from numerous phase II reports during the last several years.

  • Bortezomib, lenalidomide, and dexamethasone (VRd) versus lenalidomide and dexamethasone (Rd). In a prospective, randomized trial in 474 newly diagnosed patients with myeloma, VRd was compared with Rd.[]
    • With a median follow-up of 55 months, the VRd group had superior PFS (median PFS, 43 months vs. 30 months; HR, 0.71; 95% CI, 0.58–0.95; = .013) and superior OS (median OS, 75 months vs. 64 months; HR, 0.79; 95% CI, 0.52–0.97; = .025).
  • (NCT00507442) trial: Bortezomib + lenalidomide + dexamethasone versus bortezomib + cyclophosphamide + dexamethasone versus bortezomib + lenalidomide + cyclophosphamide + dexamethasone.
  • U.S. Intergroup/Intergroupe Francais du Myélome trial (IFM): Lenalidomide + bortezomib + dexamethasone for three cycles; responders are then randomly assigned to five more cycles of lenalidomide + bortezomib + dexamethasone or high-dose melphalan + stem cell transplantation.

Options for combination regimens:

Consolidation Chemotherapy

Autologous bone marrow or peripheral stem cell transplantation

Evidence (autologous bone marrow or peripheral stem cell transplantation):

The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy.

Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:

  • The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.
  • Chemotherapy patients can now be treated as outpatients.
  • Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.
  • Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.
  • Upon review of eight updated trials encompassing more than 3,100 patients, at 10 years' follow-up, there was a 10% to 35% event-free survival (EFS) rate and a 20% to 50% OS rate. New monoclonal gammopathies of an isotype (heavy and/or light chain) distinct from the original clone can emerge in long-term follow-up.

Single autologous bone marrow or peripheral stem cell transplantation

Evidence (single autologous bone marrow or peripheral stem cell transplantation):

While some prospective, randomized trials showed improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[] other trials have not shown any survival advantage.[]

Two meta-analyses of almost 3,000 patients showed no survival advantage.[]

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. The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.

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).

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 following the infusion of donor lymphocytes.

Favorable prognostic features included the following:

  • Low tumor burden.
  • Responsive disease before transplant.
  • Application of transplantation after first-line therapy.

Myeloablative allogeneic stem cell transplantation has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality. 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.[] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[] Given the lack of evidence so far that the high-risk patients benefit from allogeneic stem cell transplantation in this era of novel new agents, it remains debatable whether ASCT should be offered in the first-line setting outside the context of a clinical trial.

Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity allogeneic 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 allogeneic SCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[]

Maintenance Therapy

Myeloma patients who respond to treatment show a progressive fall in the M protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. No clinical trial has directly compared a consolidation approach with a maintenance approach to assess which is better in prolonging remission and, ultimately, survival. Most clinical trials employ one or both. Maintenance trials with glucocorticosteroids 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

After ASCT, three randomized, prospective trials showed benefit in median EFS or PFS (40–43 months vs. 21–27 months), one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; = .03).[] For elderly patients not eligible for transplantation, a randomized, prospective trial of lenalidomide maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide showed a 66% reduction in the rate of progression (HR, 0.34; < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[] All three trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.

Bortezomib maintenance therapy

For 178 elderly, untreated patients with an induction combination regimen including bortezomib, maintenance using bortezomib plus thalidomide versus bortezomib plus prednisone was not significantly different in PFS or OS, but both resulted in median PFS of 32 to 39 months and a 5-year OS over 50%.[]

In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance using bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.

With a median follow-up of 47 months, 3-year PFS was 55% versus 33% ( < .01) and 5-year OS was 59% versus 46% ( = .04).[] Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.

Management of Lytic Bone Lesions With Bisphosphonates

Bisphosphonate therapy

Evidence (bisphosphonate 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.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Refractory Multiple Myeloma

There are two main types of refractory myeloma patients:

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

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients. When the stable nature of the disease becomes established, these types of patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy. (Refer to the Treatment for Multiple Myeloma section of this summary for more information.)

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

A cellular therapy for refractory myeloma has been introduced that consists of autologous T-cells transduced with an anti-CD19 chimeric antigen receptor (so-called CAR T-cells) after myeloablative chemotherapy and autologous stem cell transplantation, with anecdotal responses. Other molecular targets and expanded clinical approaches are being investigated.[]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with refractory multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Key References for Plasma Cell Neoplasms (Including Multiple Myeloma)

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.

  • Dimopoulos MA, Oriol A, Nahi H, et al.: Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 375 (14): 1319-1331, 2016.[PUBMED Abstract]

    Cited in:

    • Treatment for Multiple Myeloma.
  • Moreau P, Masszi T, Grzasko N, et al.: Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 374 (17): 1621-34, 2016.[PUBMED Abstract]

    Cited in:

    • Treatment for Multiple Myeloma.
  • Morgan GJ, Davies FE, Gregory WM, et al.: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376 (9757): 1989-99, 2010.[PUBMED Abstract]

    Cited in:

    • Treatment for Multiple Myeloma.
  • Palumbo A, Avet-Loiseau H, Oliva S, et al.: Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 33 (26): 2863-9, 2015.[PUBMED Abstract]

    Cited in:

    • Stage Information About Plasma Cell Neoplasms
  • Palumbo A, Chanan-Khan A, Weisel K, et al.: Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 375 (8): 754-66, 2016.[PUBMED Abstract]

    Cited in:

    • Treatment for Multiple Myeloma.
  • Rajkumar SV, Dimopoulos MA, Palumbo A, et al.: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15 (12): e538-48, 2014.[PUBMED Abstract]

    Cited in:

    • General Information About Plasma Cell Neoplasms.
    • Treatment Option Overview for Plasma Cell Neoplasms.
  • Richardson PG, Weller E, Lonial S, et al.: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116 (5): 679-86, 2010.[PUBMED Abstract]

    Cited in:

    • Treatment for Multiple Myeloma.

Changes to This Summary (08/10/2017)

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 Royer et al. as reference 19.

Stage Information About Plasma Cell Neoplasms

Revised textto state that 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 interphase fluorescence hybridization (cited Sonneveld et al. as reference 5.)

Revised cytogenetic findings for high-risk multiple myeloma in Table 3.

Treatment Option Overview for Plasma Cell Neoplasms

Added text about a prospective, randomized clinical trial that 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; at a median follow-up of 75 months, lenalidomide plus dexamethasone provided benefit in time to progression compared with observation; however, there was no difference in overall survival (OS) (cited Mateos et al. as reference 6 and ).

Treatment for Amyloidosis Associated With Plasma Cell Neoplasms

Added Sanchorawala et al. as reference 10.

Treatment for Multiple Myeloma

Added text to state that achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved OS; and that 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 (added Munshi et al. as reference 11 and Gormley et al. as reference 12).

Revised text to update 46-month follow-up data for a prospective, randomized study of 1,623 transplant-ineligible, untreated patients that compared lenalidomide and low-dose dexamethasone (when given until progression) with a 72-week induction regimen with melphalan plus prednisone plus thalidomide (cited Hulin et al. as reference 28 and ).

Extensively revised the subsection on daratumumab.

Added text to state that elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7) that is now U.S. Food and Drug Administration approved for use in combination therapy after failure of one previous regimen.

Added pomalidomide/cyclophosphamide/dexamethasone as a new combination regimen (cited Baz et al. as reference 104).

Added Gay et al. as reference 120.

Added text about a clinical trial of zoledronate given once a month compared with zoledronate given every 12 weeks that showed noninferiority for the 12-week regimen in 1,822 patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma; however, this study included only 278 myeloma patients, and evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen (cited Himelstein et al. as reference 164).

Refractory Multiple Myeloma

Added Ali et al. as reference 4.

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.

About This PDQ Summary

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment is:

  • Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

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 . Available at: https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq. Accessed . [PMID: 26389362]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

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March 17, 2017

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