Friday, August 9, 2019

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version

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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 2019:[1]
  • New cases: 32,110.
  • Deaths: 12,960.

Clinical Presentation and Evaluation

Table 1. Clinical Presentation of Plasma Cell Neoplasms
Plasma Cell NeoplasmM Protein TypePathologyClinical Presentation
Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.
MGUSIgG kappa or lambda; or IgA kappa or lambda<10% plasma cells in bone marrowAsymptomatic, with minimal evidence of disease (aside from the presence of an M protein) [2]
Isolated plasmacytoma of boneIgG kappa or lambda; or IgA kappa or gammaSolitary lesion of bone; <10% plasma cells in marrow of uninvolved siteAsymptomatic or symptomatic
Extramedullary plasmacytomaIgG kappa or lambda; or IgA kappa or gammaSolitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses [3]Asymptomatic or symptomatic
Multiple myelomaIgG kappa or lambda; or IgA kappa or gammaOften, multiple lesions of boneSymptomatic

Evaluation of patients with monoclonal (or myeloma) protein (M protein)

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[4,5] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.
The major challenge is to separate the stable asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[6,7]
Patients with an M protein in the serum and/or urine are evaluated by some of the following criteria:
  • 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.[8] Quantitative serum free light chains (FLC) may be helpful to follow response when 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 in situ 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 chains. This is especially useful in cases of oligosecretory plasma-cell dyscrasia or for following cases of light-chain amyloidosis.[9] The FLC ratio of over 100 can predict a greater than 70% progression within 2 years in patients with smoldering myeloma.[10]
  • If clinically warranted, obtain 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 (PET)–CT scan depending on availability) if the skeletal survey is negative.[11-13] At diagnosis, whole-body PET scan or MRI of the total spine and pelvis appears to be equally efficacious in the detection of bone lesions.[14]
  • 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.[15]
  • Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[16,17]
  • The presence of circulating myeloma cells is considered a poor prognostic factor.[18] Primary plasma cell leukemia has a particularly poor prognosis.[19,20]
These initial studies are often compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse.
The major challenge is to determine which patients are stable, asymptomatic, and do not require treatment, and which patients have progressive symptomatic myeloma who may need to be treated immediately.[6,7,21]

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and have fewer than 10% of plasma cells in the bone marrow.[2,22-24] 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.[24-26]
Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[27-29] 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.[30,31] 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.[30,32]
  • Non-IgG class MGUS.
  • A high level of serum M protein (≥1.5 g/L).[30,32]
A Swedish cohort study confirmed that an abnormal serum FLC ratio and high level of serum monoclonal protein are high-risk factors.[31] The study described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (i.e., if a patient has an IgG kappa M protein, the IgM and IgA would be below normal levels with immunoparesis). Incorporation of gene-expression profiles to better assess risk is under clinical evaluation.[33]
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.[34] 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.[35]
In a retrospective review of 6,399 newly diagnosed patients with 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).[36][Level of evidence: 3iiiDiv] Many MGUS plasma cell clones were unresponsive to available myeloma therapy; this result highlights the need to lower expectations for response in situations in which an MGUS may require therapy due to end-organ damage.

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.[37-39] 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.[40]
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.[41]

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.[42-44]

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.[45-48] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[19,49]
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 Boneand 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.[50] In one series of 745 consecutive patients, 20% of patients with nonamyloid light chain amyloidosis (usually transthyretin) had an innocent monoclonal gammopathy, indicating the significant risk of misdiagnosis.[50]
Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum FLC are poor prognostic factors.[51,52] A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.[51] An increase in levels of serum FLC over many years can precede the clinical diagnosis of amyloid light chain amyloidosis.[53]

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.[54] Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman's histology) may be identified. Anecdotal reports suggest remissions using myeloma-directed therapy.[55-58]
References
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  37. Ozsahin M, Tsang RW, Poortmans P, et al.: Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys 64 (1): 210-7, 2006. [PUBMED Abstract]
  38. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000. [PUBMED Abstract]
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  41. Liebross RH, Ha CS, Cox JD, et al.: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 41 (5): 1063-7, 1998. [PUBMED Abstract]
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  45. Kumar SK, Rajkumar SV, Dispenzieri A, et al.: Improved survival in multiple myeloma and the impact of novel therapies. Blood 111 (5): 2516-20, 2008. [PUBMED Abstract]
  46. Ludwig H, Durie BG, Bolejack V, et al.: Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood 111 (8): 4039-47, 2008. [PUBMED Abstract]
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  48. Palumbo A, Anderson K: Multiple myeloma. N Engl J Med 364 (11): 1046-60, 2011. [PUBMED Abstract]
  49. Bladé J, Fernández de Larrea C, Rosiñol L, et al.: Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 29 (28): 3805-12, 2011. [PUBMED Abstract]
  50. Fernández de Larrea C, Verga L, Morbini P, et al.: A practical approach to the diagnosis of systemic amyloidoses. Blood 125 (14): 2239-44, 2015. [PUBMED Abstract]
  51. Kumar S, Dispenzieri A, Lacy MQ, et al.: Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 30 (9): 989-95, 2012. [PUBMED Abstract]
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Stage Information About Plasma Cell Neoplasms

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.[1] The IMWG evaluated 4,445 patients to create a Revised International Staging System (R-ISS) incorporating lactate dehydrogenase levels and interphase fluorescence in situhybridization (I-FISH) results.[2]
An International Staging System (ISS) was derived and is shown below in Table 2.[1]
Table 2. The International Staging System (ISS) for Multiple Myeloma
StageCriteriaMedian Survival (mo)
I-FISH = interphase fluorescence in situ hybridization; LDH = lactate dehydrogenase; mo = month; R-ISS = Revised International Staging System.
IBeta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dLNot reached
IINot R-ISS I or III83
IIIBeta-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.[3-5] (See Table 3 below.) This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[3] Bone marrow samples are sent for cytogenetic and FISH analysis.[5] Plasma cell leukemia has a particularly poor prognosis.[6] The otherwise favorable prognosis of hyperploidy is trumped by coexistent adverse cytogenetics.[7]
Table 3. Risk Groups for Multiple Myeloma
Risk GroupCytogenetic FindingsDisease CharacteristicsMedian Survival (y)
FISH = fluorescence in situ hybridization; Ig = immunoglobulin.
Good riskHas 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 riskt(4;14) by FISHThese patients often have IgA lambda monoclonal gammopathies and less bone disease.5
High riskHas 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
  1. Greipp PR, San Miguel J, Durie BG, et al.: International staging system for multiple myeloma. J Clin Oncol 23 (15): 3412-20, 2005. [PUBMED Abstract]
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  3. Kumar SK, Mikhael JR, Buadi FK, et al.: Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 84 (12): 1095-110, 2009. [PUBMED Abstract]
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  5. Sonneveld P, Avet-Loiseau H, Lonial S, et al.: Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood 127 (24): 2955-62, 2016. [PUBMED Abstract]
  6. Ramsingh G, Mehan P, Luo J, et al.: Primary plasma cell leukemia: a Surveillance, Epidemiology, and End Results database analysis between 1973 and 2004. Cancer 115 (24): 5734-9, 2009. [PUBMED Abstract]
  7. Pawlyn C, Melchor L, Murison A, et al.: Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood 125 (5): 831-40, 2015. [PUBMED Abstract]

Treatment Option Overview for Plasma Cell Neoplasms

The major challenge in treating plasma cell neoplasms is separating the stable asymptomatic group of patients who do not require immediate treatment from patients with progressive symptomatic myeloma who may need to be treated immediately.[1-3] Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma.

Asymptomatic Plasma Cell Neoplasms (Smoldering Multiple Myeloma)

Asymptomatic patients with multiple myeloma who have no lytic bone lesions and normal renal function may be initially observed safely outside the context of a clinical trial.[1,4,5] Increasing anemia is the most reliable indicator of progression.[5] The following criteria represent the new definition for smoldering myeloma:[3]
  • 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.[6] 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).[6][Level of evidence: 1iiDiii]
  • 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.[3] 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.[7]
  • 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.[8]
  • 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.[9] A very good partial response (VGPR) is defined as a reduction of 90% or more in the serum monoclonal protein and a 24-hour urine monoclonal protein of less than 100 mg. Although not incorporated in the IMWG criteria, many trials report near complete response (nCR)when patients have less than 5% bone marrow plasma cells and unmeasurable serum monoclonal proteins but still have positive serum and/or urine immunofixation. Note that these nCR patients are incorporated into the VGPR group by the IMWG. Patients who achieve a CR by IMWG criteria (with a negative immunofixation along with the clear marrow and unmeasurable serum monoclonal proteins) are often said to have attained a stringent CR if they also normalize their free kappa/lambda light–chain levels and ratio. The clinical utility of these various categories must be validated in clinical trials. 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.)
References
  1. He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003. [PUBMED Abstract]
  2. Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 356 (25): 2582-90, 2007. [PUBMED Abstract]
  3. 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]
  4. Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000. [PUBMED Abstract]
  5. Bladé J, Dimopoulos M, Rosiñol L, et al.: Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 28 (4): 690-7, 2010. [PUBMED Abstract]
  6. Mateos MV, Hernández MT, Giraldo P, et al.: Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol 17 (8): 1127-36, 2016. [PUBMED Abstract]
  7. Sayed RH, Wechalekar AD, Gilbertson JA, et al.: Natural history and outcome of light chain deposition disease. Blood 126 (26): 2805-10, 2015. [PUBMED Abstract]
  8. Dimopoulos MA, Hillengass J, Usmani S, et al.: Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol 33 (6): 657-64, 2015. [PUBMED Abstract]
  9. Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006. [PUBMED Abstract]

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 may predict impending cardiac failure in the setting of cardiac amyloidosis, and early treatment should be considered for these patients.[1]
Treatment options for amyloidosis associated with plasma cell neoplasms include the following:
  1. Chemotherapy, immunomodulatory (IMiDs) agents, and proteasome inhibitors.
  2. Stem cell rescue.

Chemotherapy

As is true for all plasma cell dyscrasias, responses have been reported for all the same regimens active in multiple myeloma.[2-10]

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.[11] After a median follow-up of 3 years, median overall survival (OS) favored the nontransplant arm (56.9 months vs. 22.2 months;P = .04).[11][Level of evidence: 1iiA] The 24% transplant-related mortality in this series and others reflects the difficulties involved with high-dose chemotherapy in older patients with organ dysfunction.[11-16] Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplantation (ASCT); the 5-year OS was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplantation.[17][Level of evidence: 3iiiA] Similarly, in a retrospective review of 672 consecutive patients with amyloidosis who underwent ASCT over 20 years, the treatment-related mortality declined to 2.4% between 2010 and 2016 in comparison with 8.6% between 2003 and 2009, and 14.5% between 1996 and 2002.[18][Level of evidence: 3iiiD] A randomized trial confirming the benefit of autologous transplantation is not anticipated.[1,19]
An anecdotal series describes full-intensity and reduced-intensity allogeneic SCT.[20]

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
  1. Merlini G, Wechalekar AD, Palladini G: Systemic light chain amyloidosis: an update for treating physicians. Blood 121 (26): 5124-30, 2013. [PUBMED Abstract]
  2. Dispenzieri A, Lacy MQ, Zeldenrust SR, et al.: The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 109 (2): 465-70, 2007. [PUBMED Abstract]
  3. Kastritis E, Wechalekar AD, Dimopoulos MA, et al.: Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 28 (6): 1031-7, 2010. [PUBMED Abstract]
  4. Moreau P, Jaccard A, Benboubker L, et al.: Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood 116 (23): 4777-82, 2010. [PUBMED Abstract]
  5. Reece DE, Hegenbart U, Sanchorawala V, et al.: Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood 124 (16): 2498-506, 2014. [PUBMED Abstract]
  6. Kumar SK, Hayman SR, Buadi FK, et al.: Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood 119 (21): 4860-7, 2012. [PUBMED Abstract]
  7. Venner CP, Lane T, Foard D, et al.: Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood 119 (19): 4387-90, 2012. [PUBMED Abstract]
  8. Wechalekar AD, Schonland SO, Kastritis E, et al.: A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 121 (17): 3420-7, 2013. [PUBMED Abstract]
  9. Sanchorawala V, Shelton AC, Lo S, et al.: Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood 128 (8): 1059-62, 2016. [PUBMED Abstract]
  10. Palladini G, Milani P, Foli A, et al.: Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies. Blood 131 (5): 525-532, 2018. [PUBMED Abstract]
  11. Jaccard A, Moreau P, Leblond V, et al.: High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 357 (11): 1083-93, 2007. [PUBMED Abstract]
  12. Dispenzieri A, Kyle RA, Lacy MQ, et al.: Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood 103 (10): 3960-3, 2004. [PUBMED Abstract]
  13. Skinner M, Sanchorawala V, Seldin DC, et al.: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 140 (2): 85-93, 2004. [PUBMED Abstract]
  14. Leung N, Leung TR, Cha SS, et al.: Excessive fluid accumulation during stem cell mobilization: a novel prognostic factor of first-year survival after stem cell transplantation in AL amyloidosis patients. Blood 106 (10): 3353-7, 2005. [PUBMED Abstract]
  15. Madan S, Kumar SK, Dispenzieri A, et al.: High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood 119 (5): 1117-22, 2012. [PUBMED Abstract]
  16. Cibeira MT, Sanchorawala V, Seldin DC, et al.: Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 118 (16): 4346-52, 2011. [PUBMED Abstract]
  17. D'Souza A, Dispenzieri A, Wirk B, et al.: Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study. J Clin Oncol 33 (32): 3741-9, 2015. [PUBMED Abstract]
  18. Sidiqi MH, Aljama MA, Buadi FK, et al.: Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time. J Clin Oncol 36 (13): 1323-1329, 2018. [PUBMED Abstract]
  19. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.
  20. Schönland SO, Lokhorst H, Buzyn A, et al.: Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light-chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation. Blood 107 (6): 2578-84, 2006. [PUBMED Abstract]

Treatment for Monoclonal Gammopathy of Undetermined Significance (MGUS)

Treatment Options for MGUS

Treatment options for MGUS include the following:
  1. Watchful waiting.

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.[1,2] In a large retrospective report, the risk of progression at 20 years was 14% for an initial monoclonal protein level of 0.5 g/dL or less, 25% for a level of 1.5 g/dL, 41% for a level of 2.0 g/dL, 49% for a level of 2.5 g/dL, and 64% for a level of 3.0 g/dL.[1]
Treatment is delayed until the disease progresses to the stage that symptoms or signs appear.
Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions, or have improved survival if chemotherapy is started early while they are still asymptomatic as opposed to waiting for progression before treatment is initiated.[3-6] Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.[2]

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
  1. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346 (8): 564-9, 2002. [PUBMED Abstract]
  2. Bird J, Behrens J, Westin J, et al.: UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 147 (1): 22-42, 2009. [PUBMED Abstract]
  3. Bladé J, Dimopoulos M, Rosiñol L, et al.: Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 28 (4): 690-7, 2010. [PUBMED Abstract]
  4. He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003. [PUBMED Abstract]
  5. Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000. [PUBMED Abstract]
  6. Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 356 (25): 2582-90, 2007. [PUBMED Abstract]

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:
  1. Radiation therapy to the lesion.
  2. Chemotherapy (if the monoclonal [or myeloma] protein [M protein] increases and other evidence of symptomatic multiple myeloma occurs).

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.[1]

Chemotherapy

Most patients will eventually develop disseminated disease and require chemotherapy; almost 50% of them will do so within 2 years of diagnosis.[2,3] However, patients with serum paraprotein or Bence Jones protein, who have complete disappearance of these proteins after radiation therapy, may be expected to remain free of disease for prolonged periods.[2,4] Patients with a negative flow cytometry on bone marrow examination for plasma cell infiltration are also unlikely to relapse.[5] Patients who progress to multiple myeloma tend to have good responses to chemotherapy with a median survival of 63 months after progression.[2,4]

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
  1. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001. [PUBMED Abstract]
  2. Liebross RH, Ha CS, Cox JD, et al.: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 41 (5): 1063-7, 1998. [PUBMED Abstract]
  3. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000. [PUBMED Abstract]
  4. Dimopoulos MA, Goldstein J, Fuller L, et al.: Curability of solitary bone plasmacytoma. J Clin Oncol 10 (4): 587-90, 1992. [PUBMED Abstract]
  5. Paiva B, Chandia M, Vidriales MB, et al.: Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma. Blood 124 (8): 1300-3, 2014. [PUBMED Abstract]

Treatment for Extramedullary Plasmacytoma

Treatment Options for Extramedullary Plasmacytoma

Treatment options for extramedullary plasmacytoma include the following:
  1. Radiation therapy to the isolated lesion with fields that cover the regional lymph nodes, if possible.[1,2]
  2. In some cases, surgical resection may be considered, but it is usually followed by radiation therapy.[2]
  3. If the monoclonal (or myeloma) protein (M protein) persists or reappears, the patient may need further radiation therapy. In some patients, the plasmacytoma may shrink, but not disappear, and the M protein persists. Close follow-up is generally warranted for these patients. Surgery often is performed if the plasmacytoma is in a site where it can be removed easily (e.g., in the tonsil); the M protein may disappear from the blood or urine. In other cases, persistence or an increasing M protein may herald progression to multiple myeloma.
  4. Chemotherapy is required if the disease progresses and causes symptoms.
Patients with isolated plasma cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses, may need to have skeletal x-rays and bone marrow biopsy (both of which are most often negative) and evaluation for M protein in serum and urine.[1-4]
About 25% of patients have serum and/or urine M protein; this frequently disappears after adequate radiation.
Extramedullary plasmacytoma is a highly curable disease with progression-free survival ranging from 70% to 87% at 10 to 14 years after treatment with radiation therapy (with or without previous resection).[1,2,5]

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
  1. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome. Int J Radiat Oncol Biol Phys 50 (1): 113-20, 2001. [PUBMED Abstract]
  2. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999. [PUBMED Abstract]
  3. Meis JM, Butler JJ, Osborne BM, et al.: Solitary plasmacytomas of bone and extramedullary plasmacytomas. A clinicopathologic and immunohistochemical study. Cancer 59 (8): 1475-85, 1987. [PUBMED Abstract]
  4. Soesan M, Paccagnella A, Chiarion-Sileni V, et al.: Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 3 (1): 51-7, 1992. [PUBMED Abstract]
  5. Strojan P, Soba E, Lamovec J, et al.: Extramedullary plasmacytoma: clinical and histopathologic study. Int J Radiat Oncol Biol Phys 53 (3): 692-701, 2002. [PUBMED Abstract]

Treatment for Multiple Myeloma

Initial Evaluation

The initial approach to the patient is to evaluate the following parameters:
  1. Detection and quantification of a monoclonal (or myeloma) protein (M protein) in the serum or urine, and possible immunoparesis (suppression of the other uninvolved immunoglobulins).[1]
  2. Detection of more than 10% of plasma cells on a bone marrow examination, along with flow cytometry, cytogenetics, and fluorescence in situ hybridization testing.
  3. Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays, or whole-body or spinal and pelvic magnetic resonance imaging (MRI) scans, or focal bone lesions on positron emission tomography-computed tomography (CT) scan.[2,3]
  4. Presence of soft tissue plasmacytomas.
  5. Serum albumin and beta-2-microglobulin levels.
  6. Detection of free kappa and free lambda serum immunoglobulin light chain, with calculation of the serum free light chain ratio.[1,4]
  7. Presence of hypercalcemia.
  8. Detection of renal dysfunction attributable to the plasma cell dyscrasia (induced by gammopathy or amyloidosis.)
  9. Presence of anemia.
  10. Presence of circulating plasma cells.
  11. Presence of hyperviscosity. Asymptomatic patients usually respond to myeloma therapy; plasma exchange is indicated with hemorrhagic or central nervous system manifestations.[5]
Treatment selection is influenced by the age and general health of the patient, previous therapy, and the presence of complications of the disease.[6]

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.[7] These patients are typically asymptomatic and free of lytic bone lesions, renal dysfunction, hypercalcemia, or significant anemia. Serial measurements of paraprotein parameters can help to confirm stable disease over months or years.

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.[8] Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as autologous stem cell transplantation (ASCT) consolidation. Most patients also receive medication with a bisphosphonate or RANKL inhibitor to prevent skeletal-related complications.[9,10]
Younger fit patients (transplant eligible)
The younger fit patient will receive induction chemotherapy with a triple-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used triplets include:
  • VRd: lenalidomide + bortezomib + dexamethasone.[11-14]
  • CyBorD: cyclophosphamide + bortezomib + dexamethasone.[15,16] This regimen is preferred in the presence of significant renal dysfunction (creatinine clearance less than 45 cc/min). If the renal function recovers rapidly, some clinicians switch to VRd.
After 4 to 8 months of therapy, responding patients usually undergo ASCT consolidation.[14,17] After recovery from the ASCT, maintenance therapy is then implemented until the time of relapse.[18-20] At relapse, subsequent therapies are applied sequentially by using previously successful drugs (if the interval of time since previous exposure is >1 year) or newer drugs not previously tried.
Older unfit patients (not transplant eligible)
The older less-fit patient will receive induction chemotherapy with a triplet (as described for the younger fit patient) plus the monoclonal antibody to CD38, daratumumab, or with a doublet and daratumumab, which might be better tolerated.[21] Therapy is continued until maximal response and then maintenance therapy is applied until relapse.[22] At relapse, subsequent therapies are applied sequentially (as described for the younger fit patient).

High-risk versus standard-risk

Newly diagnosed patients and relapsing patients can be allocated to standard-risk versus high-risk disease on the basis of cytogenetics, genetic aberrations detected by fluorescence in situ hybridization, and possibly the genetic expression profile analyses that are in the process of standardization.[23] Higher-risk patients are candidates for clinical trials employing newer agents upfront or for use of newer combination therapies currently used for relapsed disease at the discretion of the clinician. Beyond induction therapy, high-risk disease can lead to more aggressive strategies, such as tandem transplantation or consideration of allogeneic SCT. More intensive maintenance therapies may also be applied for high-risk disease; instead of using lenalidomide alone, lenalidomide plus bortezomib has been chosen based on prior trials using thalidomide.[24] These more aggressive strategies have been implemented because of poor responsiveness to standard regimens and the worse prognosis of high-risk patients. Ultimately, randomized prospective trials will be needed to establish improved outcomes with these newer approaches for high-risk patients.
Unresolved questions regarding therapy for multiple myeloma include the following:
  1. How do we incorporate the newer agents such as daratumumab and elotuzumab upfront and create four or five drug regimens? Should these regimens be applied to all patients or just high-risk patients? Can we find a more personalized targeted approach and create a smaller drug cocktail?
  2. As newer agents, such as carfilzomib and pomalidomide, move upfront into triplets, and with the introduction of the anti-CD38 monoclonal antibody daratumumab and the monoclonal antibody targeting SLAMF7 (signal lymphocyte activating molecule F7) elotuzumab, will the stringent complete remissions equal or surpass ASCT with less long-term toxicities? Can ASCT be omitted in some patients?
  3. The assessment of minimal residual disease is mandatory for the assessment of efficacy in clinical trials.[25,26] Does this testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing selection or duration of therapy?
  4. How do we deal with the financial toxicity of all these advances?
Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved overall survival (OS).[25-28] 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

Myeloma patients who are symptomatic or require therapy due to 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).
  1. In a prospective randomized trial in 474 newly diagnosed patients with myeloma, VRd (bortezomib, lenalidomide, and dexamethasone) was compared with Rd (lenalidomide and dexamethasone).[12]
    • With a median follow-up of 55 months, the VRd group had superior progression-free survival (PFS) (median PFS, 43 months vs. 30 months [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.58‒0.95; P = .013]) and superior OS (median OS, 75 months vs. 64 months [HR, 0.79; 95% CI, 0.52‒0.97; P = .025]).[12][Level of evidence: 1iiA]
  2. A prospective randomized trial of 682 patients older than 65 years compared VMP (bortezomib, melphalan, and prednisone) with melphalan and prednisone alone.[11]
    • With a median follow-up of 60 months, the median OS favored the triplet with bortezomib: 56.4 versus 43.1 months (P < .001).[11][Level of evidence: 1iiA]
The U.S. Intergroup and French Inter-Groupe Francophone du Myélome (IFM) study chose VRd as the induction therapy for their prospective randomized trial of 700 patients aged 65 years or younger, which investigated ASCT consolidation after three cycles of VRd compared with time to relapse.[14] In the United States, VRd has become the standard regimen that is compared to newer combinations for induction therapy. Because lenalidomide is metabolized erratically in the setting of renal failure, clinicians often choose the CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone),[15,16] but this selection is empiric and not based on randomized trial results.
In younger transplant-eligible patients, alkylators such as melphalan are avoided upfront to prevent stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting.[29] Bortezomib is given subcutaneously, which helps to avoid the neuropathies that were much more severe with intravenous administration.[30-32] Bortezomib is also preferred in the setting of renal impairment.[33] Patients on a bortezomib-containing regimen need prophylaxis for herpes zoster (usually with valacyclovir or acyclovir). Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT) or pulmonary embolism, requiring additional prophylactic medication.[7,34] For patients without extra risk factors for DVT, aspirin (81 mg daily) suffices, but stronger anticoagulants should be considered for patients with multiple risk factors in the presence of lenalidomide (or other similar immunomodulating agents such as pomalidomide or thalidomide).

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 (bortezomib, melphalan, and prednisone) as described in the section for younger fit patients.[11,21] The advent of daratumumab, the monoclonal antibody directed at CD38, has changed the options since this biologic therapy has been studied with the aforementioned doublets and triplets in both phase II and phase III trials.
  1. In a prospective randomized trial in 706 patients with newly diagnosed myeloma who were ineligible for transplantation, daratumumab plus VMP was compared with VMP alone.[35]
    • With a median follow-up of 16.5 months, the 18-month PFS favored the daratumumab combination 71.6% (95% CI, 65.5‒76.8) versus 50.2% (95% CI, 43.2‒56.7) (HR, 0.50; 95% CI, 0.38‒0.65; P < .001).[35][Level of evidence: 1iiDiii]
    • Patients without minimal residual disease favored daratumumab 22.3% (threshold of one tumor cell per 105 white cells) versus 6.2% in the control group (P < .001).
    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).
  2. Many other phase II and phase III trials, published in preliminary abstract form, show results similar to the trial that combined daratumumab with melphalan and prednisone, and used daratumumab with other triplets and doublets in both previously untreated and previously treated patients.[36,37] Further follow-up is required to establish OS benefits.

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 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:
  • The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[38]
  • Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.[29]
  • Younger patients in good health tolerate high-dose therapy better than older patients with a poor performance status.[39-41]
  • 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.[17][Level of evidence: 3iiiD] New monoclonal gammopathies of an isotype (heavy and/or light chain) distinct from the original clone can emerge in long-term follow-up.[42]

Single autologous bone marrow or peripheral stem cell transplantation

Evidence (single autologous bone marrow or peripheral stem cell transplantation):
  1. 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,[20,43-45][Level of evidence: 1iiA] other trials have not shown any survival advantage.[46-51][Level of evidence: 1iiA]
  2. Between 2010 and 2012, 700 newly diagnosed patients, aged 65 years or younger, were randomly assigned to receive VRd for three cycles followed by ASCT consolidation and two more cycles of VRd versus VRd alone for eight cycles, with maintenance lenalidomide given to both groups.[14] At relapse, patients on the chemotherapy-only arm were re-induced and offered transplantation if they were still responding. This trial compared ASCT at first induction with transplant at relapse.
    • With a median follow-up of 44 months, the median PFS favored early transplantation (50 months vs. 36 months; HR, 0.65; 95% CI, 0.53–0.80; P < .001), but the 4-year OS was unchanged (81% vs. 82%; HR, 1.16; 95% CI, 0.80–1.68; P = .87).[14][Level of evidence: 1iiDiii]
    • Long-term follow-up of this U.S. Intergroup and French IFM study will establish whether transplantation during induction therapy is better, the same, or worse than a strategy of delay until after first relapse.
  3. Two meta-analyses of almost 3,000 patients showed no survival advantage.[52,53][Level of evidence: 1iiA]
Even the trials suggesting improved survival showed no signs of a slowing in the relapse rate or a plateau to suggest that any of these patients had been cured.[20,43-45,54] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[55,56] However, ASCT consolidation remains the standard approach for younger fit patients with no contraindications to the procedure.

Tandem autologous bone marrow or peripheral stem cell transplantation followed by autologous or allogeneic transplantation

Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support (tandem transplants).[57-61]
Evidence (tandem autologous bone marrow or peripheral stem cell transplantation):
  1. A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplantation with tandem autologous hematopoietic cell transplantation.
    • There was no difference in OS (HR, 0.94; 95% CI, 0.77–1.14) or in EFS (HR, 0.86; 95% CI, 0.70–1.05).[62][Level of evidence: 1A]
  2. In a trial of 194 previously untreated patients aged 50 to 70 years, the patients were randomly assigned to either conventional oral melphalan and prednisone or vincristine, doxorubicin, and dexamethasone (VAD) for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m2) with stem cell support.[45]
    • With a median follow-up of more than 3 years, the double transplant group had superior EFS (37% vs. 16% at 3 years, P < .001) and OS (77% vs. 62%, P < .001).[45][Level of evidence: 1iiA]
  3. Five different groups have compared single or tandem autologous transplants with one autologous transplant followed by a reduced-intensity conditioning allograft from an HLA-identical sibling; treatment assignment was based on the presence or absence of an HLA-identical sibling. The results have been discordant for survival in these nonrandomized trials.[63-66][Level of evidence: 3iiiA]
  4. Six clinical trials compared the outcomes of patients receiving tandem autologous transplant with 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.[67,68][Level of evidence: 1iiA]
A Cochrane review of 14 controlled studies found none of the trials helpful for contemporary treatment decisions regarding single versus tandem transplants.[69] None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.

Allogeneic bone marrow or peripheral stem cell transplantation

Evidence (allogeneic bone marrow or peripheral stem cell transplantation):
Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses after the infusion of donor lymphocytes.[70]
Favorable prognostic features included the following:
  • Low tumor burden.
  • Responsive disease before transplant.
  • Application of transplantation after first-line therapy.
Myeloablative ASCT has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[70-72] 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.[73]
The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[72] 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.[74][Level of evidence: 3iiiA] This result contrasted with two older trials (before introduction of lenalidomide and bortezomib), which suggested improvement of PFS and OS with a sibling donor.[65,75][Level of evidence: 3iiiA] Given the lack of evidence so far that the high-risk patients benefit from allogeneic SCT in this era of novel new agents, it remains debatable whether ASCT should be offered in the first-line setting outside the context of a clinical trial.[72,76]
Six clinical trials compared the outcomes of patients receiving tandem autologous transplant to those of patients receiving a reduced-intensity ASCT after autologous transplant. Patients were assigned to the latter treatments based on the availability of an HLA-matched donor. Two meta-analyses of these data showed that although the complete remission rate was higher in patients undergoing reduced-intensity ASCT, OS was comparable because of an increased incidence of nonrelapse mortality with allogeneic transplant.[67,68][Level of evidence: 1iiA]

Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation

After relapsing more than 24 months after ASCT, 174 patients received reinduction therapy and were then randomly assigned to receive either high-dose melphalan and salvage ASCT or oral weekly cyclophosphamide.[77] With a median follow-up of 52 months, the median OS was superior for salvage ASCT: 67 months (95% CI, 55–not estimable) versus 52 months (42–60); HR, 0.56 (0.35–0.90, P = .017).[77][Level of evidence: 1iiA]

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.[78] Most clinical trials employ one or both.[79,80] Maintenance trials with glucocorticosteroids [81,82] and with interferon [83] 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.[78]

Lenalidomide maintenance therapy

After ASCT, three randomized, prospective trials showed benefit in median EFS or PFS (40–43 months vs. 21–27 months),[18-20] one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; P = .03).[18][Level of evidence: 1iiA] In a meta-analysis of 1,208 patients newly diagnosed after autologous SCT, with a median follow-up of 79.5 months, OS was not reached for the lenalidomide maintenance group versus 86 months for the placebo or observation group (HR, 0.75; 95% CI, 0.63‒0.90, P = .001).[84][Level of evidence: 1A] For elderly patients not eligible for transplantation, a randomized, prospective trial of lenalidomide maintenance after induction with melphalan and prednisone or melphalan, prednisone, and lenalidomide showed a 66% reduction in the rate of progression (HR, 0.34; P < .001), which translated to an EFS of 31 months versus 14 months in favor of maintenance lenalidomide.[22][Level of evidence: 1iiDi] All of these trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. This increased risk is mostly seen in patients with previous exposure to alkylating agents. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.

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%.[24][Level of evidence: 1iiDiv]
In 511 previously untreated patients not eligible for transplant and aged 65 years or older, a randomized comparison of bortezomib, melphalan, prednisone, thalidomide and subsequent maintenance using bortezomib plus thalidomide versus bortezomib, melphalan, and prednisone (with no maintenance) showed superiority of the arm with thalidomide and bortezomib during induction and maintenance.
With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01), and 5-year OS was 59% versus 46% (P = .04).[85][Level of evidence: 1iiA] Because of trial design, it is unclear whether the improved results were caused by the addition of thalidomide during the induction or by the use of maintenance therapy with bortezomib and thalidomide.
Summary: After ASCT, patients are offered lenalidomide maintenance therapy based on the OS benefits previously described. But short-term and long-term toxicities, and financial toxicities, may prevent implementation.[86,87] High-risk patients, especially those with del(17p) or t(14;16), may require bortezomib maintenance (with or without lenalidomide), but this approach is not evidence-based and confirmatory clinical trials are required.[88]

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.[10] The bisphosphonates pamidronate and zoledronate are used most often, via intravenous infusion, but the RANKL monoclonal antibody inhibitor denosumab, given subcutaneously, is also effective, especially when renal dysfunction precludes the use of bisphosphonates.[9,10]

Zoledronate (bisphosphonate)

Evidence (zoledronate):
  1. A randomized, prospective trial of 1,970 patients compared intravenous zoledronate with oral clodronate in newly diagnosed patients receiving induction chemotherapy with or without consolidation.[89] With a median follow-up of 3.7 years, zoledronate improved median OS from 44.5 months to 50.0 months (HR, 0.84; CI, 0.74–0.96; P = .0118).[89][Level of evidence: 1iiA] In this trial, both bisphosphonates were continued until time of relapse. As expected, skeletal-related events were also reduced in the zoledronate group (27% vs. 35%; P = .004).[90,91]
  2. The improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[92][Level of evidence: 1A] This meta-analysis also showed that 6 to 15 patients need treatment with bisphosphonates to prevent one skeletal-related event.
  3. A clinical trial of zoledronate given once a month compared with zoledronate given every 12 weeks showed noninferiority for the 12-week regimen in 1,822 patients with bone metastases from breast cancer, prostate cancer, or multiple myeloma.[93] However, this study included only 278 myeloma patients, and evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen. Nonetheless, this trial is used as justification for implementing a 12-week schedule at the start of therapy or as soon as maximal response has been reached.
  4. Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[94,95] (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information on osteonecrosis of the jaw.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.[96] Bisphosphonates are usually given intravenously on a monthly basis for 2 years and then extended at the same schedule or at a reduced schedule (i.e., once every 3–4 months), if there is evidence of active myeloma bone disease.[97,98] The aforementioned randomized trial,[90] which showed OS advantage, continued patients on bisphosphonates monthly until time of relapse.

Pamidronate (bisphosphonate)

Evidence (pamidronate):
  1. A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduced pathologic fractures, bone pain, spinal cord compression, and the need for bone radiation therapy (38% skeletal-related events were reported in the treatment group vs. 51% in the placebo group after 21 months of therapy, P = .015).[99][Level of evidence: 1iDiii] (Refer to the Pharmacologic Therapies for Pain Control section in the PDQ summary on Cancer Pain for more information on bisphosphonate therapy.)
  2. A double-blind, randomized, controlled trial with 504 patients with newly diagnosed multiple myeloma compared 30 mg of pamidronate to 90 mg of pamidronate and found there was no difference in skeletal-related events, but there was less osteonecrosis (2 events vs. 8 events) seen in the low-dose group.[100][Level of evidence: 1iDiv]
  3. A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications (both were given for 2 years).[101][Level of evidence: 1iDiii]

Denosumab (RANKL inhibitor)

Evidence (denosumab):
  1. In a prospective randomized double-blind trial, 1,718 patients with newly diagnosed myeloma and at least one documented lytic bone lesion received either zoledronate or denosumab.[9]
    • The study met its primary endpoint of noninferiority for denosumab compared with zoledronate (HR, 0.98; 95% CI, 0.85‒1.14; P = .01 for noninferiority).[9][Level of evidence: 1iD]
    • Denosumab is significantly more expensive than the bisphosphonates, which are available in generic form.

Radiation therapy for bone lesions

Lytic lesions of the spine generally require radiation if any of the following are true:
  1. They are associated with an extramedullary (paraspinal) plasmacytoma.
  2. A painful destruction of a vertebral body occurred.
  3. CT or MRI scans present evidence of spinal cord compression.[102]
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.[103]
Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[99]

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.
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  44. Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348 (19): 1875-83, 2003. [PUBMED Abstract]
  45. Palumbo A, Bringhen S, Petrucci MT, et al.: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 104 (10): 3052-7, 2004. [PUBMED Abstract]
  46. Segeren CM, Sonneveld P, van der Holt B, et al.: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 101 (6): 2144-51, 2003. [PUBMED Abstract]
  47. Fermand JP, Katsahian S, Divine M, et al.: High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23 (36): 9227-33, 2005. [PUBMED Abstract]
  48. Bladé J, Rosiñol L, Sureda A, et al.: High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106 (12): 3755-9, 2005. [PUBMED Abstract]
  49. Barlogie B, Kyle RA, Anderson KC, et al.: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 24 (6): 929-36, 2006. [PUBMED Abstract]
  50. Cook G, Williams C, Brown JM, et al.: High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (8): 874-85, 2014. [PUBMED Abstract]
  51. Gay F, Oliva S, Petrucci MT, et al.: Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol 16 (16): 1617-29, 2015. [PUBMED Abstract]
  52. Lévy V, Katsahian S, Fermand JP, et al.: A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 84 (4): 250-60, 2005. [PUBMED Abstract]
  53. Koreth J, Cutler CS, Djulbegovic B, et al.: High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13 (2): 183-96, 2007. [PUBMED Abstract]
  54. Pineda-Roman M, Barlogie B, Anaissie E, et al.: High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients. Cancer 112 (8): 1754-64, 2008. [PUBMED Abstract]
  55. Giralt S, Stadtmauer EA, Harousseau JL, et al.: International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia 23 (10): 1904-12, 2009. [PUBMED Abstract]
  56. Harousseau JL: Hematopoietic stem cell transplantation in multiple myeloma. J Natl Compr Canc Netw 7 (9): 961-70, 2009. [PUBMED Abstract]
  57. Barlogie B, Tricot GJ, van Rhee F, et al.: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135 (2): 158-64, 2006. [PUBMED Abstract]
  58. Barlogie B, Tricot G, Rasmussen E, et al.: Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107 (7): 2633-8, 2006. [PUBMED Abstract]
  59. Barlogie B, Zangari M, Bolejack V, et al.: Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 6 (6): 469-74, 2006. [PUBMED Abstract]
  60. Bruno B, Rotta M, Patriarca F, et al.: Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 113 (14): 3375-82, 2009. [PUBMED Abstract]
  61. Rotta M, Storer BE, Sahebi F, et al.: Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 113 (14): 3383-91, 2009. [PUBMED Abstract]
  62. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al.: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101 (2): 100-6, 2009. [PUBMED Abstract]
  63. Moreau P, Garban F, Attal M, et al.: Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood 112 (9): 3914-5, 2008. [PUBMED Abstract]
  64. Bruno B, Rotta M, Patriarca F, et al.: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356 (11): 1110-20, 2007. [PUBMED Abstract]
  65. Gahrton G, Iacobelli S, Björkstrand B, et al.: Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood 121 (25): 5055-63, 2013. [PUBMED Abstract]
  66. Rosiñol L, Pérez-Simón JA, Sureda A, et al.: A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 112 (9): 3591-3, 2008. [PUBMED Abstract]
  67. Armeson KE, Hill EG, Costa LJ: Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 48 (4): 562-7, 2013. [PUBMED Abstract]
  68. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al.: Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 6: 2, 2013. [PUBMED Abstract]
  69. Naumann-Winter F, Greb A, Borchmann P, et al.: First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 10: CD004626, 2012. [PUBMED Abstract]
  70. Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27 (8): 801-7, 2001. [PUBMED Abstract]
  71. Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35 (12): 1133-40, 2005. [PUBMED Abstract]
  72. Lokhorst H, Einsele H, Vesole D, et al.: International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 28 (29): 4521-30, 2010. [PUBMED Abstract]
  73. Sahebi F, Shen Y, Thomas SH, et al.: Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study. Br J Haematol 160 (2): 199-206, 2013. [PUBMED Abstract]
  74. Lokhorst HM, van der Holt B, Cornelissen JJ, et al.: Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood 119 (26): 6219-25; quiz 6399, 2012. [PUBMED Abstract]
  75. Giaccone L, Storer B, Patriarca F, et al.: Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood 117 (24): 6721-7, 2011. [PUBMED Abstract]
  76. Moreau P: Death of frontline allo-SCT in myeloma. Blood 119 (26): 6178-9, 2012. [PUBMED Abstract]
  77. Cook G, Ashcroft AJ, Cairns DA, et al.: The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol 3 (7): e340-51, 2016. [PUBMED Abstract]
  78. Ludwig H, Durie BG, McCarthy P, et al.: IMWG consensus on maintenance therapy in multiple myeloma. Blood 119 (13): 3003-15, 2012. [PUBMED Abstract]
  79. Benboubker L, Dimopoulos MA, Dispenzieri A, et al.: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371 (10): 906-17, 2014. [PUBMED Abstract]
  80. Palumbo A, Gay F, Cavallo F, et al.: Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol 33 (30): 3459-66, 2015. [PUBMED Abstract]
  81. Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007. [PUBMED Abstract]
  82. Berenson JR, Crowley JJ, Grogan TM, et al.: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99 (9): 3163-8, 2002. [PUBMED Abstract]
  83. The Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113 (4): 1020-34, 2001. [PUBMED Abstract]
  84. McCarthy PL, Holstein SA, Petrucci MT, et al.: Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol 35 (29): 3279-3289, 2017. [PUBMED Abstract]
  85. Palumbo A, Bringhen S, Rossi D, et al.: Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients. [Abstract] Blood 120 (21): A-200, 2012.
  86. Olszewski AJ, Dusetzina SB, Eaton CB, et al.: Subsidies for Oral Chemotherapy and Use of Immunomodulatory Drugs Among Medicare Beneficiaries With Myeloma. J Clin Oncol 35 (29): 3306-3314, 2017. [PUBMED Abstract]
  87. Olszewski AJ, Dusetzina SB, Trivedi AN, et al.: Prescription Drug Coverage and Outcomes of Myeloma Therapy Among Medicare Beneficiaries. J Clin Oncol 36 (28): 2879-2886, 2018. [PUBMED Abstract]
  88. Mikhael JR: Maintenance Lenalidomide After Transplantation in Multiple Myeloma Prolongs Survival-In Most. J Clin Oncol 35 (29): 3269-3271, 2017. [PUBMED Abstract]
  89. 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]
  90. Morgan GJ, Child JA, Gregory WM, et al.: Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol 12 (8): 743-52, 2011. [PUBMED Abstract]
  91. Morgan GJ, Davies FE, Gregory WM, et al.: Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood 119 (23): 5374-83, 2012. [PUBMED Abstract]
  92. Mhaskar R, Redzepovic J, Wheatley K, et al.: Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 5: CD003188, 2012. [PUBMED Abstract]
  93. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017. [PUBMED Abstract]
  94. Badros A, Weikel D, Salama A, et al.: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24 (6): 945-52, 2006. [PUBMED Abstract]
  95. Kademani D, Koka S, Lacy MQ, et al.: Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 81 (8): 1100-3, 2006. [PUBMED Abstract]
  96. Lacy MQ, Dispenzieri A, Gertz MA, et al.: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 81 (8): 1047-53, 2006. [PUBMED Abstract]
  97. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.: Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27 (30): 5015-22, 2009. [PUBMED Abstract]
  98. Terpos E, Sezer O, Croucher PI, et al.: The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 20 (8): 1303-17, 2009. [PUBMED Abstract]
  99. Berenson JR, Lichtenstein A, Porter L, et al.: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16 (2): 593-602, 1998. [PUBMED Abstract]
  100. Gimsing P, Carlson K, Turesson I, et al.: Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 11 (10): 973-82, 2010. [PUBMED Abstract]
  101. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003. [PUBMED Abstract]
  102. Rades D, Hoskin PJ, Stalpers LJ, et al.: Short-course radiotherapy is not optimal for spinal cord compression due to myeloma. Int J Radiat Oncol Biol Phys 64 (5): 1452-7, 2006. [PUBMED Abstract]
  103. Catell D, Kogen Z, Donahue B, et al.: Multiple myeloma of an extremity: must the entire bone be treated? Int J Radiat Oncol Biol Phys 40 (1): 117-9, 1998. [PUBMED Abstract]

Refractory or Relapsing Multiple Myeloma

Relapses occur for almost all patients after induction therapy, consolidation with autologous stem cell transplantation (ASCT), and maintenance therapy. Some patients respond poorly or progress during initial therapy. The general strategy is to apply new therapies sequentially as required. In younger fit patients, reinduction therapy with response may be consolidated with an ASCT or allogeneic SCT in some cases. Sometimes, when relapse occurs one or more years after initial therapy, the same drugs can be administered a second time.
A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients.[1,2] When the stable nature of the disease becomes established, these patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy. (Refer to the Treatment for Multiple Myeloma section of this summary for more information.)
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.
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, onset of therapy may be delayed because of slow progression and good performance status. The following options are available for relapsed or refractory myeloma.

Daratumumab

Daratumumab is a monoclonal antibody targeting CD38 that can be given on its own but is usually given in combination with other drugs.
Evidence (daratumumab):
  1. In a prospective, randomized trial, 498 previously treated patients were randomly assigned to receive daratumumab plus bortezomib plus dexamethasone or bortezomib plus dexamethasone.[3]
    • With a median follow-up of 7.4 months, the median progression-free survival (PFS) was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28‒0.53; P< .001).[3][Level of evidence: 1iiDiii]
  2. In a prospective, randomized trial, 569 previously treated patients were randomly assigned to receive daratumumab plus lenalidomide plus dexamethasone or lenalidomide plus dexamethasone.[4]
    • With a median follow-up of 13.5 months, the 1-year PFS was 81.5% in the daratumumab group versus 59.0% in the control group (HR, 0.37; 95% CI, 0.27‒0.52; P < .001).[4][Level of evidence: 1iiDiii]
  3. Several phase I and phase II trials evaluated daratumumab as a single agent for relapsed or refractory multiple myeloma.[5-7]
    • With a median follow-up of 12 to 17 months, the overall response rate (ORR) was 31% and 36%, with minimal response or stable disease in about 40% of patients.[5-7][Level of evidence: 3iiiDiv]

Carfilzomib

Carfilzomib is a second generation proteosome inhibitor that is given intravenously (IV) (unlike the subcutaneous route for bortezomib); most studies have employed twice-weekly administration, but once-weekly administration appears at least equally efficacious and safe.[8]
Evidence (carfilzomib):
  1. A randomized prospective trial included 578 relapsed or refractory myeloma patients.[8]
    • The median PFS of patients who received carfilzomib once a week was significantly better, 11.2 months (95% CI, 8.6‒13.0 months) than twice a week, 7.6 months (95% CI, 5.8‒9.2 months) (HR, 0.69; 95% CI, 0.54‒0.83; P = .0029).[8][Level of evidence: 1iiDiii]
  2. In a prospective randomized trial of 792 patients with relapsed or refractory myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone was compared with lenalidomide plus dexamethasone.[9]
    • With a median follow-up of 67.1 months, median overall survival (OS) in the carfilzomib arm was 48.3 months (95% CI, 42.4‒52.8 months) versus 40.4 months (95% CI, 33.6‒44.4 months) (HR, 0.79; 95% CI, 0.67‒0.95; one-sided P = .009).[9]
  3. A prospective, randomized study [NCT01568866]Exit Disclaimer of 929 patients compared carfilzomib and dexamethasone with bortezomib and dexamethasone.[10]
    • With a median follow-up of 37 months, the median OS was 47.6 months (95% CI, 42.5–not evaluable) for the carfilzomib combination compared with 40.0 months (95% CI, 32.6–42.3) for the bortezomib combination (HR, 0.79; 95% CI, 0.65–0.96; P = .020).[10][Level of evidence: 1iiA]

Ixazomib

Ixazomib is a second-generation proteosome inhibitor that is given orally on a weekly basis for 3 of every 4 weeks.
Evidence (ixazomib):
  1. In a prospective, randomized trial involving 722 patients with relapsed or refractory myeloma, ixazomib combined with lenalidomide and dexamethasone was compared with a placebo combined with lenalidomide and dexamethasone.[11,12]
    • With a median follow-up of 2 years, the median PFS with the ixazomib combination was, 20.6 months to 14.7 months (HR, 0.66; 95% CI, 0.47–0.93; P = .016).[11][Level of evidence: 1iDiii]
    • Improved PFS was also seen for high-risk patients (defined by fluorescence in situ hybridization and cytogenetics).[12][Level of evidence: 1iDiii]
    • No grade 3 or 4 neuropathy was seen in any patient treated with ixazomib.

Bortezomib

Bortezomib is the first-in-class proteosome inhibitor that is given subcutaneously on a weekly basis for 3 of every 4 weeks; the subcutaneous route is preferred to the IV route because it causes significantly less neuropathy and no loss of responsiveness.[13-15] Bortezomib is metabolized and cleared by the liver, and it appears to be active and well-tolerated in patients with renal impairment.[16,17] More than 6 months after completion of bortezomib induction therapy, bortezomib can be given again with a 40% ORR, according to a meta-analysis of 23 phase II studies.[18][Level of evidence: 3iiiDiv]
Evidence (bortezomib):
  1. A prospective randomized study of 669 patients with relapsed myeloma compared bortezomib given by IV with high-dose oral dexamethasone.[19]
    • 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; P = .027) even though the trial allowed crossover after relapse.[19][Level of evidence: 1iiA]
  2. A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[20]
    • With a median follow-up of 7.0 months, the combination was better for 1-year OS (82% vs. 75%, P = .05).[20][Level of evidence: 1iiA]
  3. A prospective, randomized trial of 260 newly diagnosed patients aged 65 years and older compared bortezomib, melphalan, and prednisone (VMP) with bortezomib, thalidomide, and prednisone (VTP).[21]
    • With a median follow-up of 72 months, the median OS favored the VMP arm, 63 months versus 43 months (HR, 0.67; 95% CI, 0.49–0.91; P = .01).[21][Level of evidence: 1iiA]

Elotuzumab

Elotuzumab is a monoclonal antibody directed at SLAMF7 (single-lymphocyte activating molecular F7).
Evidence (elotuzumab):
  1. A prospective randomized trial of 117 patients who had relapsed or were refractory to both lenalidomide and a proteosome inhibitor were randomly assigned to receive elotuzumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone alone.[22]
    • With a median follow-up of 9.1 months, the median PFS was 10.3 months for the elotuzumab combination compared with 4.7 months for the control group (HR, 0.54; 95% CI, 0.34‒0.86; P = .008).[22][Level of evidence: 1iiDiii]
  2. In a prospective, randomized trial of 646 patients with relapsed or refractory myeloma, elotuzumab, was combined with lenalidomide and dexamethasone and compared with lenalidomide and dexamethasone alone.[23][Level of evidence: 1iiA]
    • With a median follow-up of 2.8 years, the group receiving elotuzumab had a superior 3-year PFS of 26% versus 18% (HR, 0.73; 95% CI, 0.60–0.89; P = .0014) and improved 3-year OS of 44% versus 39% (P = .0257).

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):
  1. A prospective randomized trial of 117 patients who had relapsed or were refractory to both lenalidomide and a proteosome inhibitor were randomly assigned to receive elotuzumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone alone.[22]
    • With a median follow-up of 9.1 months, the median PFS was 10.3 months for the elotuzumab combination compared with 4.7 months for the control group (HR, 0.54; 95% CI, 0.34‒0.86; P = .008).[22][Level of evidence: 1iiDiii]
  2. For 302 patients with relapsed or refractory disease, pomalidomide and dexamethasone (40 mg weekly) was compared with a higher-dose dexamethasone regimen (40 mg daily for 4 days every 8 days).[24]
    • With a median follow-up of 10.0 months, the PFS was superior for the pomalidomide arm at 4.0 months versus 1.9 months (HR, 0.48; 95% CI, 0.39–0.60; P < .0001)[24][Level of evidence: 1iiDiii]

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).[25-28]
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).[29] This risk was confined to the combination of lenalidomide and melphalan (HR, 4.86; 95% CI, 2.79–8.46; P = .0001) but was not higher for lenalidomide with either cyclophosphamide or dexamethasone.[29] 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.[30]
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).[31] Uncontrolled trials have added clarithromycin (500 mg twice a day) to lenalidomide and dexamethasone with reports of increased response rates.[32] Controlled studies are required to establish the value of this approach.
Evidence (lenalidomide):
  1. Two prospective randomized and placebo-controlled studies of 351 and 353 relapsed patients with myeloma compared lenalidomide plus high-dose dexamethasone versus high-dose dexamethasone alone.[33,34]
    • With a median follow-up of 16 to 26 months, the median OS was 29.6 months or more (not reached in one trial) versus 20.2 months to 20.6 months in the control group (HR, 0.66; 95% CI, 0.45‒0.96; P = .03 in one study [33] and P < .001 in the other study).[34][Level of evidence: 1iA]
  2. A prospective, randomized study of 1,623 transplant-ineligible, previously untreated myeloma patients compared lenalidomide and dexamethasone given until progression with a 72-week induction regimen with melphalan, prednisone, and thalidomide (MPT) for 72 weeks.[26]
    • With a median follow-up of 46 months, there was improved OS for the lenalidomide group with 4-year OS of 52% versus 38% (HR, 0.72; 95% CI, 0.54–0.96; P = .02).[26][Level of evidence: 1iiA]

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).[35,36] Very little myelosuppression is seen with this agent.
Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses.[37] By utilizing a low dose (50 mg by mouth every day), significant sedation, constipation, and neuropathy may be avoided. Thromboprophylaxis with aspirin, warfarin, or low molecular–weight heparin is required; the choice of therapy depends on pre-existing risk factors.
Evidence (thalidomide):
  1. A meta-analysis of 1,685 previously untreated patients considered six randomized prospective trials comparing thalidomide, melphalan, and prednisone versus melphalan and prednisone alone.[38]
    • The addition of thalidomide improved median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; P = .004).[38][Level of evidence: 1iiA]

Chemotherapy (cytotoxic agents)

Regimens:
  • Melphalan and prednisone.[39,40]
  • Vincristine + doxorubicin (infusion) + dexamethasone (VAD).[41,42]
  • Cyclophosphamide (+ bortezomib + dexamethasone in the CyBorD regimen).[43,44]
  • Pegylated liposomal doxorubicin (in a modified VAD regimen) [45,46] or combined with bortezomib and dexamethasone.[47]
Evidence (chemotherapy):
  1. A meta-analysis of randomized prospective trials compared melphalan and prednisone to combinations of other cytotoxic agents; no differences were noted in PFS or OS.[40][Level of evidence: 1iiA]
  2. The VAD regimen has shown activity in previously untreated patients and in relapsed patients with response rates ranging from 60% to 80%.[41,42][Level of evidence: 3iiiDiv] Because of logistics problems delivering a 96-hour infusion of doxorubicin, substitution with pegylated liposomal doxorubicin provides comparable response rates.[45,46]
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.

Histone deacetylase inhibitors

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.
  1. A prospective, randomized placebo-controlled study of 768 patients with relapsed or relapsed and refractory myeloma compared panobinostat, bortezomib, and dexamethasone with bortezomib plus dexamethasone alone.[48]
    • With a median follow-up of 6 months, the median PFS was longer in the panobinostat group, 12 months versus 8 months (HR, 0.63; 95% CI, 0.52–0.76; P> .0001).[48][Level of evidence: 1iDiii]

Corticosteroids

Dexamethasone dosage has been evaluated in two prospective randomized trials.
  1. A prospective, randomized study (ECOG-E4A03) of 445 previously untreated patients with myeloma compared lenalidomide and high-dose dexamethasone (40 mg on days 1–4, 9–12, and 17–20, every 28 days) with lenalidomide and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22, every 28 days).[25]
    • With a median follow-up of 36 months, 2-year OS favored the low-dose dexamethasone arm (87% vs. 75%, P = .006), despite no difference in PFS.[25][Level of evidence: 1iiA]
    • The extra deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity.
    • Deep venous thromboses (DVTs) were also more frequent in the high-dose arm (25% vs. 9%). The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.
  2. A prospective randomized trial of melphalan and prednisone versus melphalan and high-dose dexamethasone showed no difference in PFS or OS, but there was an increase in infection in the high-dose dexamethasone arm.[49]
On the basis of these trials, all ongoing trials and regimens utilize the low-dose dexamethasone schedule in combination with other therapeutic agents: 40 mg dexamethasone (oral or IV) weekly in younger patients or fit older patients, or 20 mg (oral or IV) in less-fit older patients.

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):
  1. In a phase I study of 66 heavily pretreated patients with relapsed or refractory myeloma, 30 patients harbored a t(11;14) translocation.[50]
    • Among all 66 patients, the ORR was 21%, and 15% of patients achieved very good partial response or better. For those with t(11;14), the ORR was 40%, with 27% achieving a very good partial response or better.[50][Level of evidence: 3iiiDiv]
  2. In a phase I study, 66 patients with relapsed or refractory myeloma received venetoclax, bortezomib, and dexamethasone.[51]
    • The combination resulted in an ORR of 67%, with 42% achieving very good partial response. For those with high BCL-2 expression, especially t(11;14), the ORR was 94%.[51][Level of evidence: 3iiiDiv]
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 ASCT, with anecdotal responses.[52-54] Other molecular targets and expanded clinical approaches are being investigated.[52][Level of evidence: 3iiiDiv]

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
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  2. Durie BG, Jacobson J, Barlogie B, et al.: Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in southwest oncology group chemotherapy trials. J Clin Oncol 22 (10): 1857-63, 2004. [PUBMED Abstract]
  3. 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]
  4. 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]
  5. Usmani SZ, Weiss BM, Plesner T, et al.: Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128 (1): 37-44, 2016. [PUBMED Abstract]
  6. Lokhorst HM, Plesner T, Laubach JP, et al.: Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 373 (13): 1207-19, 2015. [PUBMED Abstract]
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  8. Moreau P, Mateos MV, Berenson JR, et al.: Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 19 (7): 953-964, 2018. [PUBMED Abstract]
  9. Siegel DS, Dimopoulos MA, Ludwig H, et al.: Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol 36 (8): 728-734, 2018. [PUBMED Abstract]
  10. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al.: Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol 18 (10): 1327-1337, 2017. [PUBMED Abstract]
  11. 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]
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  13. Bringhen S, Larocca A, Rossi D, et al.: Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116 (23): 4745-53, 2010. [PUBMED Abstract]
  14. Mateos MV, Oriol A, Martínez-López J, et al.: Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11 (10): 934-41, 2010. [PUBMED Abstract]
  15. Moreau P, Pylypenko H, Grosicki S, et al.: Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 12 (5): 431-40, 2011. [PUBMED Abstract]
  16. San-Miguel JF, Richardson PG, Sonneveld P, et al.: Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22 (4): 842-9, 2008. [PUBMED Abstract]
  17. Dimopoulos MA, Terpos E, Chanan-Khan A, et al.: Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 28 (33): 4976-84, 2010. [PUBMED Abstract]
  18. Knopf KB, Duh MS, Lafeuille MH, et al.: Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma. Clin Lymphoma Myeloma Leuk 14 (5): 380-8, 2014. [PUBMED Abstract]
  19. Richardson PG, Sonneveld P, Schuster M, et al.: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110 (10): 3557-60, 2007. [PUBMED Abstract]
  20. Orlowski RZ, Nagler A, Sonneveld P, et al.: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25 (25): 3892-901, 2007. [PUBMED Abstract]
  21. Mateos MV, Oriol A, Martínez-López J, et al.: GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood 124 (12): 1887-93, 2014. [PUBMED Abstract]
  22. Dimopoulos MA, Dytfeld D, Grosicki S, et al.: Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med 379 (19): 1811-1822, 2018. [PUBMED Abstract]
  23. Lonial S, Dimopoulos M, Palumbo A, et al.: Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 373 (7): 621-31, 2015. [PUBMED Abstract]
  24. San Miguel J, Weisel K, Moreau P, et al.: Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 14 (11): 1055-66, 2013. [PUBMED Abstract]
  25. Rajkumar SV, Jacobus S, Callander NS, et al.: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11 (1): 29-37, 2010. [PUBMED Abstract]
  26. Hulin C, Belch A, Shustik C, et al.: Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial. J Clin Oncol 34 (30): 3609-3617, 2016. [PUBMED Abstract]
  27. Zangari M, Tricot G, Polavaram L, et al.: Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol 28 (1): 132-5, 2010. [PUBMED Abstract]
  28. Larocca A, Cavallo F, Bringhen S, et al.: Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 119 (4): 933-9; quiz 1093, 2012. [PUBMED Abstract]
  29. Palumbo A, Bringhen S, Kumar SK, et al.: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol 15 (3): 333-42, 2014. [PUBMED Abstract]
  30. Dimopoulos MA, Richardson PG, Brandenburg N, et al.: A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 119 (12): 2764-7, 2012. [PUBMED Abstract]
  31. Dimopoulos MA, Christoulas D, Roussou M, et al.: Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 85 (1): 1-5, 2010. [PUBMED Abstract]
  32. Rossi A, Mark T, Jayabalan D, et al.: BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood 121 (11): 1982-5, 2013. [PUBMED Abstract]
  33. Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357 (21): 2123-32, 2007. [PUBMED Abstract]
  34. Weber DM, Chen C, Niesvizky R, et al.: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357 (21): 2133-42, 2007. [PUBMED Abstract]
  35. Palumbo A, Cavo M, Bringhen S, et al.: Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 29 (8): 986-93, 2011. [PUBMED Abstract]
  36. Delforge M, Bladé J, Dimopoulos MA, et al.: Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11 (11): 1086-95, 2010. [PUBMED Abstract]
  37. Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111 (8): 3968-77, 2008. [PUBMED Abstract]
  38. Fayers PM, Palumbo A, Hulin C, et al.: Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood 118 (5): 1239-47, 2011. [PUBMED Abstract]
  39. Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10 (2): 334-42, 1992. [PUBMED Abstract]
  40. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 16 (12): 3832-42, 1998. [PUBMED Abstract]
  41. Segeren CM, Sonneveld P, van der Holt B, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105 (1): 127-30, 1999. [PUBMED Abstract]
  42. Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 (2): 326-30, 1995. [PUBMED Abstract]
  43. Reece DE, Rodriguez GP, Chen C, et al.: Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 26 (29): 4777-83, 2008. [PUBMED Abstract]
  44. Knop S, Liebisch H, Wandt H, et al.: Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-8516, 2009.
  45. Dimopoulos MA, Pouli A, Zervas K, et al.: Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 14 (7): 1039-44, 2003. [PUBMED Abstract]
  46. Rifkin RM, Gregory SA, Mohrbacher A, et al.: Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial. Cancer 106 (4): 848-58, 2006. [PUBMED Abstract]
  47. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.: Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27 (30): 5015-22, 2009. [PUBMED Abstract]
  48. San-Miguel JF, Hungria VT, Yoon SS, et al.: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15 (11): 1195-206, 2014. [PUBMED Abstract]
  49. Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007. [PUBMED Abstract]
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  52. Garfall AL, Maus MV, Hwang WT, et al.: Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med 373 (11): 1040-7, 2015. [PUBMED Abstract]
  53. Ali SA, Shi V, Maric I, et al.: T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128 (13): 1688-700, 2016. [PUBMED Abstract]
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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.

Changes to This Summary (07/19/2019)

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.
This summary was comprehensively reviewed and extensively revised.
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 <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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