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There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.
For more information, see the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in Non-Hodgkin Lymphoma Treatment.
Incidence and Mortality
Estimated new cases and deaths from multiple myeloma in the United States in 2023:[
Clinical Presentation and Evaluation
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)[ |
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[ |
Asymptomatic or symptomatic |
Multiple myeloma | IgG kappa or lambda; or IgA kappa or gamma | Often, multiple lesions of bone | Symptomatic |
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.[
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 an M protein in the serum and/or urine are evaluated by some of the following criteria:
In most myeloma patients, the glomeruli function normally allows only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light-chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
These initial studies are often compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse.
The major challenge is to determine which patients are stable, asymptomatic, and do not require treatment, and which patients have progressive symptomatic myeloma who may need to be treated immediately.[
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.[
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.[
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.[
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.[
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).[
Isolated Plasmacytoma of Bone
The patient has an isolated plasmacytoma of the bone if the following are found:
MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine and pelvis may identify other bony lesions.[
Extramedullary Plasmacytoma
A patient has extramedullary plasmacytoma if the following are found:
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 biological therapies and better salvage options, with median survivals now exceeding 10 years.[
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.
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.[
Accurate diagnosis of amyloidosis requires histological evidence of amyloid deposits and characterization of the amyloidogenic protein using immunoelectron microscopy.[
Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum FLC are poor prognostic factors.[
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.[
References:
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
Multiple myeloma is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M protein) in the serum and/or urine, along with various clinical parameters, such as hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. Impaired renal function worsens prognosis regardless of stage.[
The stage of the disease at presentation is a strong determinant of survival, but it has little influence on the choice of therapy because almost all patients, except for rare patients with solitary bone tumors or extramedullary plasmacytomas, have generalized disease.
International staging system
The International Myeloma Working Group (IMWG) studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.[
An International Staging System (ISS) was derived and is shown below in Table 2.[
Stage | Criteria | Median Survival (mo) |
---|---|---|
I-FISH = interphase fluorescencein 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 |
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.[
Risk Group | Cytogenetic Findings | Disease Characteristics | Median Survival (y) |
---|---|---|---|
FISH = fluorescencein situ hybridization; Ig = immunoglobulin. | |||
Good risk | Has any of the following cytogenetic findings: (1) no adverse FISH or cytogenetics, (2) hyperdiploidy, (3) t(11;14) by FISH, or (4) t(6;14) by FISH. | These patients most often have (1) disease that expresses IgG kappa monoclonal gammopathies and (2) lytic bone lesions. | 8–10 |
Intermediate risk | t(4;14) by FISH | These patients often have IgA lambda monoclonal gammopathies and less bone disease. | 5 |
High risk | Has any of the following cytogenetic findings: (1) del 17p by FISH, (2) t(14;16) by FISH, (3) t(4;14), (4) t(14;20), (5) cytogenetic del 13, (6) nonhyperdiploidy without adverse cytogenetic findings, (7) 1q gain, or (8) plasma cell leukemia. | These patients have (1) disease that expresses IgA lambda monoclonal gammopathies (often) and (2) skeletal-related complications (less often). | <2 |
References:
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.[
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.[
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.[
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.[
Response criteria have been developed for patients on clinical trials by the IMWG.[
Current therapy for patients with symptomatic myeloma can be divided into the following categories:
References:
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.[
Treatment options for amyloidosis associated with plasma cell neoplasms include the following:
Induction therapy
As is true for all plasma cell dyscrasias, responses have been reported for patients treated with all the same regimens active in multiple myeloma.[
Evidence (chemotherapy):
A daratumumab combination with bortezomib, cyclophosphamide, and dexamethasone is considered a standard regimen for previously untreated patients who are fit enough to receive this regimen.
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.[
An anecdotal series describes full-intensity and reduced-intensity allogeneic SCT.[
Monoclonal antibody targeting of amyloid deposits
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.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Treatment Options for 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% of patients by 20 years, and 30% of patients by 25 years.
All patients with MGUS are generally kept under observation to detect increases in M protein levels and development of a plasma cell dyscrasia. Higher levels of initial M protein levels may correlate with increased risk of progression to multiple myeloma.[
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.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
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 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.[
Chemotherapy
Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% of them will do so within 2 years of diagnosis.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
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 after adequate radiation.
Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
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.
Indolent myeloma
Newly diagnosed patients with indolent disease, historically referred to as smoldering myeloma, can be followed on a watchful waiting approach.[
Symptomatic myeloma
Newly diagnosed patients who require therapy fall into two categories: 1) the younger fit patient who is transplant-eligible or 2) the older more unfit patient with comorbidities who is not transplant eligible. Patients younger than 65 years are usually considered younger and fit, while patients older than 75 years are usually not transplant eligible. Comorbidities and performance status are important determinants at all ages, especially between the ages of 65 years and 75 years, to help decide about transplant eligibility. Nomograms exist for geriatric patients to define life expectancy independent of the myeloma diagnosis.[
The International Myeloma Working Group has issued guidance for the diagnosis and management of patients with renal impairment.[
Younger fit patients (transplant eligible)
The younger fit patient will receive induction chemotherapy with a 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.[
Older unfit patients (not transplant eligible)
The older less-fit patient will receive induction chemotherapy with a triplet regimen (as described for the younger fit patient) plus the CD38-directed monoclonal antibody, daratumumab, or with a doublet regimen and daratumumab, which might be better tolerated.[
High risk versus standard risk
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.[
Unresolved questions regarding therapy for multiple myeloma include the following:
Induction Therapy
Myeloma patients who are symptomatic or require therapy because of progression or adverse laboratory findings will require induction therapy. Ideally, induction therapy should reduce tumor burden, provide symptomatic relief, and prevent further end-organ damage.
Younger fit patients (transplant eligible)
Two randomized prospective trials have established three-drug regimens (triplets) for induction therapy in younger fit transplant-eligible patients).
The U.S. Intergroup and French Inter-Groupe Francophone du Myélome (IFM) study chose VRd as the induction therapy for their prospective randomized trial of 700 patients aged 65 years or younger, which investigated autologous SCT consolidation after three cycles of VRd compared with time to relapse.[
The phase II GRIFFIN trial (NCT02874742) has changed the standard of care for younger, fit, transplant-eligible patients in the absence of fully published comparative data. The trial enrolled 207 patients with newly diagnosed transplant-eligible multiple myeloma. Patients were randomly assigned to receive induction therapy with either D-VRd or VRd. Patients then received autologous SCT, two more cycles of the induction regimen, and 2 years of maintenance therapy with DR (daratumumab and lenalidomide) or lenalidomide alone depending on the original randomization. With a median follow-up of 22.1 months at the clinical cutoff, the percentage of patients with a stringent complete response was 62.6% in the D-VRd group and 45.4% in the VRd group (odds ratio [OR], 1.98; 95% CI, 1.12–3.49; P = .0177).[
In younger transplant-eligible patients, alkylators such as melphalan are avoided upfront to prevent stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting.[
Older unfit patients (not transplant eligible)
Triplet therapies such as VRd and CyBorD can be used in patients in whom fitness is adequate and concurrent morbidities are minimal. When triplets are deemed too difficult, doublets with Vd (bortezomib plus dexamethasone) or Rd (lenalidomide plus dexamethasone) can be used, or even a triplet such as VMP as described in the section for younger fit patients.[
Immunologic reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (not U.S. Food and Drug Administration‒approved).
Consolidation Chemotherapy
Autologous bone marrow or peripheral stem cell transplantation
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 hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy.
Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:
Single autologous bone marrow or peripheral stem cell transplantation
Evidence (single autologous bone marrow or peripheral 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.[
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 SCT):
A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[
Allogeneic bone marrow or peripheral stem cell transplantation
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.[
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.[
The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[
Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to 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.[
Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation
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.[
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.[
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.[
Maintenance therapy (lenalidomide, ixazomib, daratumumab alone or in combination)
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 utilized either continuously or with 1 week off every month. 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.[
Proteasome inhibitor maintenance therapy
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.[
Management and Prevention of Myeloma Bone Disease
Myeloma bone disease is a consequence of increased osteoclastic activity and agents that inhibit osteoclasts are an important component of myeloma therapy.[
Zoledronate (bisphosphonate)
Evidence (zoledronate):
Pamidronate (bisphosphonate)
Evidence (pamidronate):
Denosumab (RANKL inhibitor)
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 myeloma patients may be mitigated by continuous maintenance therapy.[
Radiation therapy for bone lesions
Lytic lesions of the spine generally require radiation if any of the following are true:
Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy.
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
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.
References:
Treatment Options for Relapsed or Refractory Multiple Myeloma
Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplantation (SCT), and maintenance therapy. During initial therapy, some patients respond poorly or their disease progresses. The general strategy is to apply new therapies sequentially as required. In younger fit patients, reinduction therapy with response may be consolidated with an 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 enjoy a survival prognosis that is as good as that for responding patients.[
For patients who respond to their initial therapy, the myeloma growth rate, as measured by the monoclonal (or myeloma) protein-doubling time, increases progressively with each subsequent relapse, and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally, the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed.
Combinations of drugs or single agents may be administered sequentially as required. The goal is to avoid symptoms and adverse consequences of relapsing disease; however, the onset of therapy may be delayed because of slow disease progression and good performance status.
Treatment options for relapsed or refractory multiple myeloma include the following:
Monoclonal antibodies
Daratumumab
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.[
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
Elotuzumab is a monoclonal antibody directed at SLAMF7 (signaling lymphocytic activation molecule F7).
Evidence (elotuzumab):
Isatuximab
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.
Proteasome inhibitors
Bortezomib
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.[
Evidence (bortezomib):
Carfilzomib
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.[
Evidence (carfilzomib):
Ixazomib
Ixazomib is a second-generation proteasome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.
Evidence (ixazomib):
Immunomodulatory agents
Pomalidomide
Pomalidomide is a third-generation immunomodulatory agent that shows some myelosuppression and an increased incidence of thromboembolic events, as noted with lenalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), but very little peripheral neuropathy compared with other agents.
Evidence (pomalidomide):
Lenalidomide
Lenalidomide is a second-generation immunomodulatory agent that shows increased incidence of thromboembolic events as noted with pomalidomide and thalidomide (requiring thromboprophylaxis with aspirin at least), increased incidence of myelosuppression (more than pomalidomide), and an increased incidence of neuropathy (less than thalidomide, but more than pomalidomide).[
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).[
As a result of predominant renal clearance, lenalidomide doses need to be reduced in the setting of impaired renal function (creatinine clearance, 30–50: 10 mg every day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis).[
Evidence (lenalidomide):
Thalidomide
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).[
Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses.[
Evidence (thalidomide):
Chemotherapy (cytotoxic agents)
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.
CAR T cells
A cellular therapy for refractory and/or multiply relapsed myeloma has been introduced, consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor (CAR T-cell therapy), after myeloablative chemotherapy and autologous SCT. This therapy has shown a 50% to 65% complete remission rate and a median PFS of 18 to 20 months in patients from a highly selected nonrandomized series.[
Selinexor
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.[
Venetoclax
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):
BCMA-directed therapy
The B-cell maturation antigen (BCMA), which is expressed on myeloma cells, has been targeted in CAR T-cell therapy and also using antibody-drug conjugates and bispecific antibody-based molecules.[
Belantamab mafodotin, an anti-BCMA antibody conjugated to the drug mafodotin, resulted in a 32% response rate in 198 heavily pretreated patients.[
Two phase I trials of a bispecific antibody targeting BCMA and T cells included 166 patients who were heavily pretreated. Overall, 68% to 70% of patients responded to the therapy, resulting in a T-cell–mediated lysis.[
Corticosteroids
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 younger patients or fit older patients, or 20 mg (oral or IV) in less-fit older patients.
T-cell-redirecting bispecific antibodies
T-cell-redirecting bispecific antibodies target both CD3, which is on the surface of T cells, and BCMA (B-cell maturation antigen), which is on the surface of myeloma cells.[
Evidence (teclistamab):
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
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.
General Information About Plasma Cell Neoplasms
Updated statistics with estimated new cases and deaths for 2023 (cited American Cancer Society as reference 1).
Added Vaxman et al. as reference 8.
Added Garcés et al. as reference 20.
Revised text to state that improvements in multiple myeloma prognosis have occurred because of the introduction of newer biological therapies and better salvage options, with median survivals now exceeding 10 years (cited Joseph et al. as reference 48).
Treatment of Amyloidosis Associated With Plasma Cell Neoplasms
Added Palladini et al. as reference 2.
Revised text to include induction therapy as a treatment option for amyloidosis.
Added Lentzsch et al. and Mikhael et al. as references 11 and 12, respectively. Added text to state that rapid responses to induction therapy may result in improvement of renal or cardiac function (cited Basset et al. as reference 20).
Treatment of Multiple Myeloma
Added Vaxman et al. as reference 8.
Revised text to include D-VRd (daratumumab, bortezomib, lenalidomide, and dexamethasone) as a common induction regimen for younger transplant-eligible patients (cited 2020 Voorhees et al. and 2021 Voorhees et al. as references 13 and 14, respectively).
Added text to state that the previously mandated consolidation with autologous stem cell transplant (SCT) has been questioned because a large, randomized, prospective trial failed to demonstrate an overall survival (OS) benefit.
Added Royer et al., Gonsalves et al., Cazaubiel et al., and Landgren et al. as references 30 to 33, respectively.
Revised text to state that achievement of measurable residual disease (MRD) negativity after induction therapy is associated with improved progression-free survival (PFS) and, possibly, improved OS (cited San-Miguel et al., Avet-Loiseau et al., de Tute et al., and Paiva et al. as references 42 to 45, respectively). Added text to state that there are no data to suggest that sustained MRD negativity can allow deintensification or discontinuation of maintenance therapy (cited Bianchi et al. and Costa et al. as references 46 and 47, respectively).
Added text about the results of the GRIFFIN trial that enrolled 207 patients with newly diagnosed transplant-eligible multiple myeloma and randomly assigned them to receive induction therapy with either D-VRd or VRd (bortezomib, lenalidomide, and dexamethasone) (cited level of evidence B3). The preliminary results warrant consideration of this regimen for first-line therapy (cited Laubach et al. as reference 49); a Markov model using MRD status to predict PFS suggests improved quality of life and lower cost over 10 years with the use of daratumumab in the first-line setting (cited Yamamoto et al. as reference 50).
Added text to state that lower doses of lenalidomide must be used in the setting of renal dysfunction (cited Mikhael et al. as reference 58).
Added text to state that mature OS data are required to better assess the cost effectiveness of daratumumab in the first-line setting (cited Patel et al. as reference 66).
Added text to state that fit patients older than 70 years can receive autologous SCT consolidation (cited 2020 Munshi et al. as reference 71).
Added text to state that anecdotal long-term survivals have been reported for patients with therapy-related myelodysplastic syndromes, acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myelomonocytic leukemia treated with allogeneic SCT (cited Vasudevan Nampoothiri et al. as reference 105).
Treatment of Relapsed or Refractory Multiple Myeloma
Added text about the results of a prospective randomized trial of 1,304 previously treated patients who received either daratumumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone (Pd) alone (cited Dimopoulos et al. as reference 9 and level of evidence B1).
Added text about the results of a prospective randomized trial of 387 patients with relapsed or refractory disease who received Pd with or without isatuximab (cited Richardson et al. as reference 16 and level of evidence B1). Also added the results of a prospective randomized trial in which 302 patients with relapsed or refractory disease received the combination of carfilzomib and dexamethasone was given with or without isatuximab (cited 2021 Moreau et al. as reference 17 and level of evidence B1).
Added text to state that there are no data comparing isatuximab with daratumumab, and no data proving that isatuximab has efficacy in patients with disease that is resistant to daratumumab.
Revised text to state that CAR T-cell therapy has been introduced for refractory and/or multiply relapsed myeloma after myeloablative chemotherapy and autologous SCT, with a 50% to 65% complete remission rate and median PFS of 18 to 20 months in patients from a highly selected nonrandomized series (cited Wang et al., 2021 Munshi et al., and Mailankody et al. as references 67, 68, and 70, respectively, and level of evidence C3).
Added text about the results of a randomized prospective trial in which 402 patients with relapsed or refractory disease received either selinexor plus bortezomib and dexamethasone or bortezomib and dexamethasone (cited Grosicki et al. as reference 71 and level of evidence B1).
Added text to state that the U.S. Food and Drug Administration approved belantamab mafodotin for myeloma patients who had received four previous therapies. Severe corneal toxicities in 30% of patients, rarely leading to blindness, mandated ophthalmologic exams before each treatment via a risk evaluation and mitigation strategy program.
Added text to state that two phase I trials of a bispecific antibody targeting BCMA and T cells included 166 patients who were heavily pretreated. Overall, 68% to 70% of patients responded to the therapy, resulting in a T-cell–mediated lysis (added Topp et al. and D'Souza et al. as references 79 and 80, respectively, and level of evidence C3).
Added 2022 Moreau et al. as reference 82.
Key References for Plasma Cell Neoplasms (Including Multiple Myeloma)
Added Facon et al. as a key reference.
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.
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment is:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389362]
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Last Revised: 2023-04-14
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