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

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

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ON THIS PAGE

• General Information About Plasma Cell Neoplasms
• Stage Information About Plasma Cell Neoplasms
• Treatment Option Overview for Plasma Cell Neoplasms
• Treatment for Amyloidosis Associated With Plasma Cell Neoplasms
• Treatment for Monoclonal Gammopathy of Undetermined Significance
• Treatment for Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)
• Treatment for Isolated Plasmacytoma of Bone
• Treatment for Extramedullary Plasmacytoma
• Treatment for Multiple Myeloma
• Refractory Multiple Myeloma
• Key References for Plasma Cell Neoplasms (Including Multiple Myeloma)
• Changes to This Summary (02/08/2019)
• About This PDQ Summary

General Information About Plasma Cell Neoplasms

In This Section

• Incidence and Mortality
• Clinical Presentation and Evaluation
  • Evaluation of patients with monoclonal (or myeloma) protein (M protein)
• Monoclonal Gammopathy of Undetermined Significance (MGUS)
• Isolated Plasmacytoma of Bone
• Extramedullary Plasmacytoma
• Multiple Myeloma
  • Prognosis
• Amyloidosis Associated With Plasma Cell Neoplasms
• POEMS Syndrome

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 Neoplasm	M Protein Type	Pathology	Clinical Presentation
Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.
MGUS	IgG kappa or lambda; or IgA kappa or lambda	<10% plasma cells in bone marrow	Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein) [2]
Isolated plasmacytoma of bone	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site	Asymptomatic or symptomatic
Extramedullary plasmacytoma	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses [3]	Asymptomatic or symptomatic
Multiple myeloma	IgG kappa or lambda; or IgA kappa or gamma	Often, multiple lesions of bone	Symptomatic

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

• Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin (Ig) assays; however, specific Ig quantification always overestimates the M protein because normal Ig are included in the result. For this reason, the preference is often that baseline and follow-up measurements of the M protein be done by the same method.[8] Quantitative serum-free light chains (FLC) may be helpful to follow response if an M protein is not apparent.
• Measure and follow the amount of M-protein light chains excreted in the urine over 24 hours. Measure the total amount of protein excreted over 24 hours and multiply this value by the percentage of urine protein that is M protein, as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
• Identify the heavy and light chain of the M protein by immunofixation electrophoresis.
• Measure the hemoglobin, leukocyte, platelet, and differential counts.
• Determine the percentage of marrow plasma cells. Be aware that marrow plasma-cell distribution may vary in different sites. Bone marrow is often sent for cytogenetics and fluorescence 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 chain. 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, take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
• Evaluate renal function with serum creatinine and a creatinine clearance.
• Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light-chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin.
  In most myeloma patients, the glomeruli function normally allows only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light-chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
• Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity.
• Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones.
• Obtain a spinal magnetic resonance imaging (MRI) scan (or spinal computed tomography [CT] or positron emission tomography (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 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.

As mentioned before, the major challenge is to separate the stable, asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[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.
• Non-IgG class MGUS.
• A high serum-M protein level (≥15 g/L).[30]

A Swedish cohort study confirmed the higher-risk factors of abnormal serum-FLC ratio and the high serum–monoclonal protein level.[31] They described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (if a patient has an IgG kappa M-protein, the IgM and IgA would be below normal levels with immunoparesis). Incorporation of gene-expression profiles to better assess risk is also under clinical evaluation.[32]

Monoclonal gammopathies that cause organ damage, particularly to the kidney, heart, or peripheral nerves require immediate therapy with the same strategies applied for the conventional plasma-cell dyscrasias. A monoclonal gammopathy causing renal dysfunction—by direct antibody deposition or amyloidosis—is referred to as monoclonal gammopathy of renal significance. Rising serum creatinine, dropping glomerular filtration rates, and increasing urinary–albumin excretion are all parameters that may signify renal damage and are assessed prospectively for high-risk MGUS patients. Although the N-terminal pro-brain natriuretic peptide is a very sensitive marker for amyloid involvement in the heart, the low specificity must be noted. These extra tests are included with the M-protein level, FLC levels, and FLC ratio when following patients with MGUS.[33]

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.[34-36] 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.[37]

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.[38]

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.[39-41]

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.[42-45] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[19,46]

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.[47] In one series of 745 consecutive patients, 20% of patients with non-amyloid light chain amyloidosis (usually transthyretin) had an innocent monoclonal gammopathy, indicating the significant risk of misdiagnosis.[47]

Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum-FLC are poor prognostic factors.[48,49] A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.[48] An increase in levels of serum-FLC over many years can precede the clinical diagnosis of amyloid light-chain (AL) amyloidosis.[50]

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.[51] Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman's histology) may be identified. Anecdotal reports suggest remissions using myeloma-directed therapy.[52-55]

References

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed January 23, 2019.
2. Kyle RA, Rajkumar SV: Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 139 (5): 730-43, 2007. [PUBMED Abstract]
3. Knowling MA, Harwood AR, Bergsagel DE: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1 (4): 255-62, 1983. [PUBMED Abstract]
4. Zandecki M, Facon T, Preudhomme C, et al.: Significance of circulating plasma cells in multiple myeloma. Leuk Lymphoma 14 (5-6): 491-6, 1994. [PUBMED Abstract]
5. Billadeau D, Van Ness B, Kimlinger T, et al.: Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. Blood 88 (1): 289-96, 1996. [PUBMED Abstract]
6. 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]
7. 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]
8. Riches PG, Sheldon J, Smith AM, et al.: Overestimation of monoclonal immunoglobulin by immunochemical methods. Ann Clin Biochem 28 ( Pt 3): 253-9, 1991. [PUBMED Abstract]
9. Dispenzieri A, Kyle R, Merlini G, et al.: International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23 (2): 215-24, 2009. [PUBMED Abstract]
10. Larsen JT, Kumar SK, Dispenzieri A, et al.: Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 27 (4): 941-6, 2013. [PUBMED Abstract]
11. Horger M, Kanz L, Denecke B, et al.: The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow-up and therapy response monitoring in patients with multiple myeloma. Cancer 109 (8): 1617-26, 2007. [PUBMED Abstract]
12. Walker R, Barlogie B, Haessler J, et al.: Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 25 (9): 1121-8, 2007. [PUBMED Abstract]
13. Kyle RA, Durie BG, Rajkumar SV, et al.: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 24 (6): 1121-7, 2010. [PUBMED Abstract]
14. Moreau P, Attal M, Caillot D, et al.: Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study. J Clin Oncol 35 (25): 2911-2918, 2017. [PUBMED Abstract]
15. Gertz MA, Li CY, Shirahama T, et al.: Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Arch Intern Med 148 (4): 929-33, 1988. [PUBMED Abstract]
16. Greipp PR: Advances in the diagnosis and management of myeloma. Semin Hematol 29 (3 Suppl 2): 24-45, 1992. [PUBMED Abstract]
17. Durie BG, Stock-Novack D, Salmon SE, et al.: Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study. Blood 75 (4): 823-30, 1990. [PUBMED Abstract]
18. Greipp PR, Witzig T: Biology and treatment of myeloma. Curr Opin Oncol 8 (1): 20-7, 1996. [PUBMED Abstract]
19. Pagano L, Valentini CG, De Stefano V, et al.: Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. Ann Oncol 22 (7): 1628-35, 2011. [PUBMED Abstract]
20. Royer B, Minvielle S, Diouf M, et al.: Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome. J Clin Oncol 34 (18): 2125-32, 2016. [PUBMED Abstract]
21. 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]
22. Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354 (13): 1362-9, 2006. [PUBMED Abstract]
23. International Myeloma Working Group: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121 (5): 749-57, 2003. [PUBMED Abstract]
24. 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]
25. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996. [PUBMED Abstract]
26. 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]
27. Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-22, 2009. [PUBMED Abstract]
28. Landgren O, Kyle RA, Pfeiffer RM, et al.: Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113 (22): 5412-7, 2009. [PUBMED Abstract]
29. Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009. [PUBMED Abstract]
30. Rajkumar SV, Kyle RA, Therneau TM, et al.: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 106 (3): 812-7, 2005. [PUBMED Abstract]
31. Turesson I, Kovalchik SA, Pfeiffer RM, et al.: Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood 123 (3): 338-45, 2014. [PUBMED Abstract]
32. Dhodapkar MV, Sexton R, Waheed S, et al.: Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123 (1): 78-85, 2014. [PUBMED Abstract]
33. Merlini G: Determining the significance of MGUS. Blood 123 (3): 305-7, 2014. [PUBMED Abstract]
34. 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]
35. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000. [PUBMED Abstract]
36. Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002. [PUBMED Abstract]
37. 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]
38. 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]
39. Tournier-Rangeard L, Lapeyre M, Graff-Caillaud P, et al.: Radiotherapy for solitary extramedullary plasmacytoma in the head-and-neck region: A dose greater than 45 Gy to the target volume improves the local control. Int J Radiat Oncol Biol Phys 64 (4): 1013-7, 2006. [PUBMED Abstract]
40. Michalaki VJ, Hall J, Henk JM, et al.: Definitive radiotherapy for extramedullary plasmacytomas of the head and neck. Br J Radiol 76 (910): 738-41, 2003. [PUBMED Abstract]
41. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999. [PUBMED Abstract]
42. 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]
43. 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]
44. Brenner H, Gondos A, Pulte D: Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111 (5): 2521-6, 2008. [PUBMED Abstract]
45. Palumbo A, Anderson K: Multiple myeloma. N Engl J Med 364 (11): 1046-60, 2011. [PUBMED Abstract]
46. 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]
47. 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]
48. 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]
49. Pinney JH, Lachmann HJ, Bansi L, et al.: Outcome in renal Al amyloidosis after chemotherapy. J Clin Oncol 29 (6): 674-81, 2011. [PUBMED Abstract]
50. Weiss BM, Hebreo J, Cordaro DV, et al.: Increased serum free light chains precede the presentation of immunoglobulin light chain amyloidosis. J Clin Oncol 32 (25): 2699-704, 2014. [PUBMED Abstract]
51. Dispenzieri A: POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86 (7): 591-601, 2011. [PUBMED Abstract]
52. Humeniuk MS, Gertz MA, Lacy MQ, et al.: Outcomes of patients with POEMS syndrome treated initially with radiation. Blood 122 (1): 68-73, 2013. [PUBMED Abstract]
53. Li J, Zhang W, Jiao L, et al.: Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood 117 (24): 6445-9, 2011. [PUBMED Abstract]
54. Royer B, Merlusca L, Abraham J, et al.: Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol 88 (3): 207-12, 2013. [PUBMED Abstract]
55. Misawa S, Sato Y, Katayama K, et al.: Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 15 (11): 1129-37, 2016. [PUBMED Abstract]

Stage Information About Plasma Cell Neoplasms

In This Section

• Multiple Myeloma
  • International staging system
  • Genetic factors and risk groups

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

Multiple Myeloma

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

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

International staging system

The International Myeloma Working Group (IMWG) studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.[1] The IMWG evaluated 4,445 patients to create a Revised International Staging System (R-ISS) incorporating lactate dehydrogenase (LDH) 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 (R-ISS) for Multiple Myeloma

Stage	Criteria	Median Survival (mo)
I-FISH = interphase fluorescence in situ hybridization; LDH = lactate dehydrogenase; mo = month; R-ISS = Revised International Staging System.
I	Beta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL	Not reached
II	Not R-ISS I or III	83
III	Beta-2-microglobulin ≥5.5 mg/L and either high LDH or high-risk chromosomal abnormalities by I-FISH (defined as presence of del (17p) and/or translocation t(4;14) and/or translocation t(14;16))	43

Genetic factors and risk groups

Newer clinical investigations are stratifying patients with multiple myeloma into so-called good-risk, intermediate-risk, and high-risk groups, based on genetic aberrations detected by I-FISH.[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 Group	Cytogenetic Findings	Disease Characteristics	Median Survival (y)
FISH = fluorescence in situ hybridization.
Good risk	Has any of the following cytogenetic findings: (1) no adverse FISH or cytogenetics, (2) hyperdiploidy, (3) t(11;14) by FISH, or (4) t(6;14) by FISH.	These patients most often have (1) disease that expresses IgG kappa monoclonal gammopathies and (2) lytic bone lesions.	8–10
Intermediate risk	t(4;14) by FISH	These patients often have IgA lambda monoclonal gammopathies and less bone disease.	5
High risk	Has any of the following cytogenetic findings: (1) del 17p by FISH, (2) t(14;16) by FISH, (3) t(4;14), (4) t(14;20), (5) cytogenetic del 13, (6) nonhyperdiploidy without adverse cytogenetic findings, (7) 1q gain, or (8) plasma cell leukemia.	These patients have (1) disease that expresses IgA lambda monoclonal gammopathies (often) and (2) skeletal-related complications (less often).	<2

References

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]
2. Palumbo A, Avet-Loiseau H, Oliva S, et al.: Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 33 (26): 2863-9, 2015. [PUBMED Abstract]
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]
4. Avet-Loiseau H, Attal M, Campion L, et al.: Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol 30 (16): 1949-52, 2012. [PUBMED Abstract]
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

In This Section

• Asymptomatic Plasma Cell Neoplasms (Smoldering Multiple Myeloma)
• Symptomatic Plasma Cell Neoplasms

The major challenge in treating plasma cell neoplasms is to separate the stable, asymptomatic group of patients who do not require immediate treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[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

In This Section

• Treatment Options for Amyloidosis Associated With Plasma Cell Neoplasms
  • Chemotherapy
  • Stem cell rescue
• Current Clinical Trials

Treatment Options for Amyloidosis Associated With Plasma Cell Neoplasms

Treatment depends on assessing the extent of systemic damage from the amyloidosis and the underlying plasma cell dyscrasia. A rising and elevated level of N-terminal pro brain natriuretic peptide (NT-proBNP) may predict impending cardiac failure in the setting of cardiac amyloidosis, and early treatment should be considered for these patients.[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.[1-10]

Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[11,12][Level of evidence: 1iiA]

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.[13] After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 months vs. 22.2 months; P = .04).[13][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.[13-18] Between 2007 and 2012, the International Blood and Marrow Transplant Research Program identified 800 patients with amyloidosis who underwent autologous stem cell transplantation; the 5-year OS was 77% and transplant-related mortality was 5%, suggesting better selection of patients for transplantation.[19][Level of evidence: 3iiiA] A randomized trial confirming the benefit of autologous transplantation is not anticipated.[1,20]

An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.[21]

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. Sanchorawala V, Wright DG, Rosenzweig M, et al.: Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 109 (2): 492-6, 2007. [PUBMED Abstract]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336 (17): 1202-7, 1997. [PUBMED Abstract]
12. Skinner M, Anderson J, Simms R, et al.: Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100 (3): 290-8, 1996. [PUBMED Abstract]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.
21. 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

In This Section

• Treatment Options for Monoclonal Gammopathy of Undetermined Significance (MGUS)
  • Watchful waiting
• Current Clinical Trials

Treatment Options for Monoclonal Gammopathy of Undetermined Significance (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% by 20 years, and 30% by 25 years.

All patients with MGUS are generally kept under observation to detect increases in M protein levels and development of a plasma cell dyscrasia. Higher levels of initial M protein levels may correlate with increased risk of progression to multiple myeloma.[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

In This Section

• Treatment Options for Isolated Plasmacytoma of Bone
  • Radiation therapy
  • Chemotherapy
• Current Clinical Trials

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 following adequate radiation therapy to the lytic lesion.

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

In This Section

• Treatment Options for Extramedullary Plasmacytoma
• Current Clinical Trials

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 types of 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 following adequate radiation.

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

In This Section

• Initial Evaluation
• Therapeutic Overview
• Induction Therapy
  • Induction therapy agents
  • Guidelines for choosing induction therapy
  • Corticosteroids
  • IMiDs (immunomodulatory drugs)
  • Proteasome inhibitors
  • Monoclonal antibodies
  • Conventional-dose chemotherapy
  • Histone deacetylase inhibitors
  • Combination therapy
• Consolidation Chemotherapy
  • Autologous bone marrow or peripheral stem cell transplantation
  • Single autologous bone marrow or peripheral stem cell transplantation
  • Tandem autologous bone marrow or peripheral stem cell transplantation followed by autologous or allogeneic transplantation
  • Allogeneic bone marrow or peripheral stem cell transplantation
  • Salvage autologous bone marrow or peripheral stem cell transplantation after relapse from first transplantation
• Maintenance Therapy
  • Lenalidomide maintenance therapy
  • Bortezomib maintenance therapy
• Management of Lytic Bone Lesions With Bisphosphonates
  • Bisphosphonate therapy
  • Radiation therapy for bone lesions
• Current Clinical Trials

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 scans, or focal bone lesions on positron emission tomography-computed tomography scan.[2]
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 (FLC) ratio.[1,3]
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.

Treatment selection is influenced by the age and general health of the patient, previous therapy, and the presence of complications of the disease.[4]

Therapeutic Overview

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

1. Does a high-dose alkylator-induced immune reset after induction therapy (i.e., autologous stem cell transplant [ASCT] consolidation) result in long-term benefits that outweigh potential toxicities such as the emergence of resistant clones or second malignancies? Some clinicians in the United States and many in Europe consider ASCT to be the backbone after induction therapy or after trials introducing new agents into induction therapy. Other clinicians think that combinations of new agents and the availability of other agents provide the ability to avoid ASCT.
2. In choosing initial induction therapy, should new triple-drug regimens (e.g., lenalidomide, bortezomib, and dexamethasone) be employed to achieve the best response and most durable remission? Or should active agents be used in singlets and doublets in a sequential fashion, using the same approach as for an indolent lymphoma? Should this decision be made in a risk-adaptive way, with favorable-prognosis patients employing the sequential approach? Or should all new patients receive triple-drug regimens? In fit patients, triple-drug regimens that include bortezomib are considered standard treatment in the absence of a clinical trial. The most commonly used triplets include:
   • VRd: lenalidomide + bortezomib + dexamethasone.
   • CyBorD: cyclophosphamide + bortezomib + dexamethasone.
3. 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?
4. Maintenance therapies are under active clinical evaluation; the prolonged remissions and improved progression-free survival (PFS) have not translated into established overall survival (OS) benefits in most trials. (Refer to the Maintenance Therapy section of this summary for more information.) How will this approach augment induction and consolidation therapies?[5-10]
5. How do we incorporate the newer agents such as daratumumab and elotuzumab upfront creating four or five drug regimens? Or can we find a more personalized targeted approach to create a smaller cocktail?
6. The assessment of minimal residual disease is mandatory for the assessment of efficacy in clinical trials.[11,12] Does this testing outside of the trial setting yield meaningful clinical improvement in patient outcomes by informing about selection or duration of therapy?
7. How do we deal with the financial toxicity of all these advances?

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

1. Is the patient eligible for a clinical trial? The sequence and combinations of new and older therapies can be determined only by prospective clinical trials.
2. Does the patient have comorbidities? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications influence the choice of induction therapies and consideration of consolidation therapies, such as ASCT.

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

1. A risk-adapted approach using single agents or doublets sequentially and re-using previous successful regimens before proceeding to newer agents (the indolent lymphoma-leukemia approach). Maintenance therapy can be implemented along the way.
2. Induction using a triple-drug approach to maximize durable response first and then to implement new agents on protocols (avoiding ASCT). Maintenance therapy can be implemented along the way.
3. Induction using a doublet or triplet or using new drugs in an investigative setting en route to ASCT consolidation followed by maintenance therapy.

There are regional geographic variations to the approaches listed. Clinical trials and future discoveries may help to explicate the best therapeutic strategy. Achievement of minimal residual disease after induction therapy (with or without consolidation therapy) is associated with improved OS.[13,14] While this interim marker may be useful for the design of clinical trials, there are no data suggesting that this interim marker improves outcomes by altering subsequent therapy.

Induction Therapy

Induction therapy agents

Multiple therapeutic agents are available for induction therapy, either alone or in combinations.[15] These include the following:

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

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

Guidelines for choosing induction therapy

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

1. In patients younger than 70 years, alkylators are avoided up front to avoid stem cell toxicity with subsequent risks for cytopenias, secondary malignancies, or poor stem cell harvesting if transplantation is considered for consolidation therapy.[16]
2. Bortezomib and/or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[17,18] (Refer to the Lenalidomide and Bortezomib sections of this summary for more information; also refer to the Therapeutic Overview section of this summary for a discussion about the controversy of using doublets or triplets.)
3. The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration.
   • Bortezomib is given subcutaneously and can cause neuropathic toxicities.[18-20] Bortezomib is preferred in the setting of renal impairment.[21]
   • Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT), requiring additional prophylactic medication.[17,22]
4. Patients with standard-risk disease, as defined in the Stage Information About Plasma Cell Neoplasms section of this summary, might receive induction therapy alone, followed by careful observation after best response.[23] (Refer to the Therapeutic Overview section of this summary for a discussion about the controversy of using a risk-adapted approach in some cases.)
5. Patients with high-risk disease might receive triple-drug induction therapy until best response, followed by consolidation therapy with allogeneic or ASCT.[23]

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

Corticosteroids

Since the mid-1980s, dexamethasone has been administered at a dose of 40 mg orally for 4 consecutive days, which is the same schedule used with the vincristine plus doxorubicin plus dexamethasone (VAD) regimen.[24] Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[24,25][Level of evidence: 3iiiDiv]

Evidence (corticosteroids):

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

• With a median follow-up of 7.1 years, no difference was observed in OS (median survival times, 32 months–40 months).[26][Level of evidence: 1iiA]
• The patients on the dexamethasone-based arms had significantly more infections, glucose intolerance, gastrointestinal symptoms, and psychiatric complaints. (Refer to the PDQ summary on Gastrointestinal Complications for more information on gastrointestinal symptoms.)

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

• In the context of melphalan, as evaluated in a National Cancer Institute of Canada trial (CAN-NCIC-MY7 [NCT00002678]).
  • Compared with standard-dose steroids, high-dose dexamethasone was associated with an increased risk of infection in the melphalan trial, but there was no difference in efficacy.[27]
• In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial (ECOG-E4A03 [NCT00098475]).[17]
  • The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone.[17] (Refer to the Lenalidomide section of this summary for more information.)

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

IMiDs (immunomodulatory drugs)

Lenalidomide

Evidence (lenalidomide):

1. A prospective, randomized study of 351 relapsed patients compared lenalidomide, an analog of thalidomide, plus high-dose dexamethasone with high-dose dexamethasone plus placebo.[28]
   • The lenalidomide combination showed a significantly higher time to tumor progression (11.3 months vs. 4.7 months, P < .001) with a 16-month median follow-up, and median OS had not been reached, versus 20.6 months in the placebo group (hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.45–0.96; P = .03).[28][Level of evidence: 1iA]
   • The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[28]
2. Similarly, another randomized, prospective trial (NCT00056160) of 353 previously treated patients favored the lenalidomide plus high-dose dexamethasone arm versus dexamethasone plus placebo.
   • With a median follow-up of 26 months, the median time to progression was 11.1 months versus 4.7 months (P < .001), and the median OS was 29.6 months versus 20.2 months (P < .001).[29][Level of evidence: 1iA]
3. A prospective, randomized study (ECOG-E4A03) of 445 untreated symptomatic patients 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).[17]
   • With a median follow-up of 36 months, this trial showed improved OS for patients in the low-dose dexamethasone arm (87% vs. 75% at 2 years, P = .006), despite no difference in PFS.[17][Level of evidence: 1iiA]
   • The extra deaths on the high-dose dexamethasone arm were attributed to cardiopulmonary toxicity and faster progression with subsequent therapies. DVTs were also more frequent in the high-dose arm (25% vs. 9%).
   • OS favored the low-dose arm with a 2-year survival of 87% versus 75% in the high-dose arm (P = .006).[17][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.
4. A prospective, randomized study of 1,623 transplant-ineligible, untreated patients compared lenalidomide and low-dose dexamethasone when given until progression with a 72-week induction regimen with melphalan plus prednisone plus thalidomide (MPT) for 72 weeks.[30]
   • With a median follow-up of 46 months, this trial showed improved OS for patients on the continuous lenalidomide plus dexamethasone (52% vs. 38% for MPT at 4 years; HR, 0.72; 95% CI, 0.54–0.96; P = .02).[30][Level of evidence: 1iiA]
   • Although median PFS was 5 months longer for continuous lenalidomide plus dexamethasone versus 72 weeks of the same regimen (HR, 0.71; 95% CI, 0.61–0.83; P < .001), there was no difference in OS.[30][Level of evidence: 1iiDiii]
5. A retrospective analysis of 353 patients who received lenalidomide and high-dose dexamethasone found that the 17% of the patients who experienced a thromboembolic episode had no decrease in OS or time to progression.[31][Level of evidence: 3iiiA]

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[17,28,29,31] A randomized, prospective trial of 342 previously untreated patients receiving lenalidomide-containing regimens compared aspirin (100 mg/qd) with enoxaparin (40 mg/qd); the 2% incidence of venous thromboembolic events was similar for both interventions.[32] Empirically, the greater the number of risk factors for DVT, the more intense the recommendation for prophylactic anticoagulation. (Refer to the Thalidomide section of this summary for more information about risk factors.)

A meta-analysis of 3,254 individual patients from seven randomized trials showed that lenalidomide was associated with an increased risk of hematologic second primary malignancies (3.1% in patients who received lenalidomide vs. 1.4% in those who did not; HR, 3.8; 95% CI, 1.15–12.62; P = .029).[33] 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.[33]

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.[34] As a result of predominant renal clearance, lenalidomide doses need to be reduced in the setting of impaired renal function (creatinine clearance, 30–50: 10 mg qd; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis).[35] Uncontrolled trials, including NCT00151203, have added clarithromycin (500 mg bid) to lenalidomide and dexamethasone with a claim of increased response rates; controlled studies are required to establish the value of this approach.[36]

Pomalidomide

Evidence (pomalidomide):

1. Several trials in heavily pretreated patients after bortezomib and lenalidomide showed a response rate ranging from 26% to 63%.[37,38][Level of evidence: 3iiiDiv] Although pomalidomide is taken orally like thalidomide and lenalidomide, pomalidomide causes less neuropathy and asthenia than thalidomide and less myelosuppression and skin rashes than lenalidomide.
2. For 302 patients with relapsed or refractory disease, a pomalidomide and low-dose dexamethasone regimen was compared with high-dose dexamethasone in a randomized, prospective trial; after a median follow-up of 10.0 months, the PFS favored the pomalidomide arm by 4.0 to 1.9 months (HR, 0.48; 95% CI, 0.39–0.60; P < .0001).[39][Level of evidence: 1iiDiii]

Pomalidomide was approved for patients who relapse after two previous regimens, which must have included bortezomib and lenalidomide. Although some myelosuppression and increased risk of thromboembolic events are noted as with lenalidomide and thalidomide, very little peripheral neuropathy is noted in comparison with the other agents.[40]

Thalidomide

Evidence (thalidomide):

Eleven randomized, prospective studies involving more than 4,600 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[41-50]

• All of the trials reported improved response rates with the introduction of thalidomide and no hematopoietic damage, allowing adequate stem cell collection when applicable or allowing combinations with other myelosuppressive agents.
• A meta-analysis of 1,685 patients from six of the randomized trials confirmed that thalidomide added to MP improves the median OS from 32.7 months to 39.3 months (HR, 0.83; 95% CI, 0.73–0.94; P = .004).[51][Level of evidence: 1iiA]

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

Factors that have been implicated to worsen the risk of DVT include the use of high-dose dexamethasone, concomitant erythropoietic growth factors, and concomitant doxorubicin, liposomal doxorubicin, or alkylating agents.[52,53]

Personal cardiovascular risk factors can also influence the rate of DVT. Various clinical trials have included different DVT prophylaxis measures, including aspirin (81 mg–100 mg qd), warfarin, or low molecular-weight heparin.[45,53,54] In a randomized, prospective trial, 667 previously untreated patients who received thalidomide-containing regimens were randomly assigned to aspirin (100 mg/qd), warfarin (1.25 mg/qd) or enoxaparin (40 mg/qd). The rate of serious thromboembolic events, acute cardiovascular events, or sudden death was 6.5% and similar for all three interventions.[55]

Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.[56]

Late in the disease course, when all other options have failed, thalidomide can be employed, sometimes with durable responses.[52] By utilizing a low dose (50 mg PO qd), significant sedation, constipation, and neuropathy may be avoided. Prophylaxis to avoid thrombosis with aspirin, warfarin, or low molecular–weight heparin is required; the choice of therapy depends on pre-existing risk factors.

Proteasome inhibitors

Bortezomib

Evidence (bortezomib):

• A prospective, randomized trial (the VISTA trial [NCT00111319]) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation (SCT) because of age (one-third of patients >75 years) compared bortezomib combined with melphalan and prednisone with melphalan and prednisone alone.[18]
  • With a median follow-up of 60 months, the median OS favored the bortezomib arm (56.4 vs. 43.1 months, P < .001).[57][Level of evidence: 1iiA]
• A prospective, randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone.
  • With a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR, 0.77; P = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[19][Level of evidence: 1iiA]
  • Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[20,58,59]
• A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[60]
• With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 months vs. 6.5 months, P < .001) and in OS (82% vs. 75%, P = .05).[60][Level of evidence: 1iiA]

1. A prospective, randomized trial of 260 newly diagnosed patients aged 65 years and older compared bortezomib plus melphalan plus prednisone (VMP) with bortezomib plus thalidomide plus prednisone (VTP).[61]
   • 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).[61][Level of evidence: 1iiA]
2. In 511 previously untreated patients who were not eligible for transplant and older than 65 years, a randomized comparison of bortezomib plus melphalan plus prednisone plus thalidomide plus subsequent maintenance using bortezomib plus thalidomide versus bortezomib plus melphalan plus prednisone (with no maintenance) showed the superiority of the arm with thalidomide and bortezomib during induction and maintenance.
   • With a median follow-up of 54 months, 3-year PFS was 35% versus 25% (P < . 001), and 5-year OS was 61% versus 51% (P = .01).[62][Level of evidence: 1iiA] Because of the trial design, it is unclear whether the improved results were caused by the addition of thalidomide during induction or by the use of maintenance therapy with bortezomib and thalidomide.

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[21,63] In several retrospective, nonrandomized comparisons, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (2%–8% vs. 13%–28%) with no loss of efficacy compared with standard biweekly administration.[64,65]

In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11).[66] After a median follow-up of 1 year, grade 3 to 4 neurologic toxicity was reduced from 16% to 6% (P = .026) using the subcutaneous route, with no perceived loss of efficacy in terms of response. However, this study was not powered for noninferiority of response. New clinical trials are employing these changes of weekly treatment and subcutaneous route to improve the safety profile of bortezomib-containing regimens. In this trial, the bisphosphonates were continued until the time of relapse.

More than 6 months after completion of bortezomib induction therapy, bortezomib can be applied again with a 40% overall response rate, according to a meta-analysis of 23 phase II studies.[67][Level of evidence: 3iiiDiv]

Carfilzomib

Evidence (carfilzomib):

1. In a prospective, randomized trial [NCT01568866]Exit Disclaimer of 929 patients with relapsed or refractory multiple myeloma, carfilzomib and dexamethasone were compared with bortezomib and dexamethasone.[68][Level of evidence: 1iiA] With a median follow-up of about 37 months, the median OS was 47.6 months (95% CI, 42.5–not evaluable [NE]) 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).
2. A prospective, randomized study of 792 relapsed patients compared carfilzomib plus lenalidomide plus dexamethasone with lenalidomide plus dexamethasone.[69][Level of evidence: 1iiA]
   • With a median follow-up of 32 months, the median PFS was improved with the addition of carfilzomib: 26.3 months versus 17.6 months (HR, 0.69; 95% CI, 0.57–0.83; P = .0001).
   • The 24-month OS favored the addition of carfilzomib 73% versus 65% (HR, 0.79; 95% CI, 0.63–0.99; P = .04).
3. In two phase II trials of newly diagnosed patients, aged 65 years and older, carfilzomib combined with cyclophosphamide and dexamethasone in 58 patients or with MP in 68 patients achieved at least a partial response in 95% of the patients and a near-complete response (nCR) in 90% of the patients.[70,71][Level of evidence: 3iiiDiv]
4. In two trials of 53 and 45 patients with newly diagnosed disease, carfilzomib combined with lenalidomide and dexamethasone achieved an nCR or stringent complete response in 62% of the patients in both trials and an 18- to 24-month PFS of 92%, also in both trials.[72,73][Level of evidence: 3iiiDiv]

Ixazomib

Evidence (ixazomib):

1. In a prospective, randomized trial involving 722 patients with refractory or resistant myeloma, the oral proteosome inhibitor ixazomib combined with lenalidomide and dexamethasone was compared with a placebo with lenalidomide and dexamethasone only.[74,75][Level of evidence: 1iDiii]
   • With a median follow-up of 2 years, the median PFS favored the ixazomib group, 20.6 months to 14.7 months (HR, 0.66; 95% CI, 0.47–0.93; P = .016).
   • Ixazomib is approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide and dexamethasone for patients with relapsed disease.
   • No grade 3 or 4 neuropathy was seen in any patient treated with ixazomib.

Monoclonal antibodies

Daratumumab

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

Evidence (daratumumab):

1. In a prospective, randomized trial, 498 previously treated patients were randomly assigned to receive daratumumab plus bortezomib plus dexamethasone or bortezomib plus dexamethasone.[76]
   • With a median follow-up of 7.4 months, the median PFS was not reached in the daratumumab group and was 7.2 months in the control group (HR, 0.39; 95% CI, 0.28‒0.53; P < .001).[76][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.[77]
   • 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).[77][Level of evidence: 1iiDiii]
3. Several phase I and phase II trials evaluated the CD38-targeting monoclonal antibody daratumumab as a single agent for relapsed or refractory multiple myeloma.[78-80][Level of evidence: 3iiiDiv]
   • With a median follow-up of 12 to 17 months, the overall response rate was 31% and 36%, with minimal response or stable disease in about 40% of patients. Responders had an 80% OS at 2 years. The minimal response or stable disease patients had a 40% OS at 2 years.
4. A phase I/II study of 45 patients with relapsed myeloma studied daratumumab in combination with lenalidomide and dexamethasone.
   • With a median follow-up of 15.6 months, the 18-month PFS was 72% (95% CI, 51.7%‒85.0%), and OS was 90% (95% CI, 73.1%‒96.8%).[80][Level of evidence: 3iiiDiii]
5. In a phase II trial (NCT01998971) of 103 patients with relapsed and/or refractory myeloma, daratumumab was studied in combination with pomalidomide and dexamethasone.[81]
   • With a median follow-up of 13.1 months, the median PFS was 8.8 months (95% CI, 4.6–15.4), and the median OS was 17.5 months.[81][Level of evidence: 3iiiD]

Elotuzumab

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

Evidence (elotuzumab):

1. 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.[82][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).

Conventional-dose chemotherapy

Evidence (conventional-dose chemotherapy):

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[83-86][Level of evidence: 3iiiDiv]

• No randomized studies support the widespread use of this regimen in untreated patients.
• This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia.
• Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low CR rate.
• An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[87,88][Level of evidence: 3iiiDiv]

Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results.[89] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[89-91]

Combinations, such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[92-95][Level of evidence: 1iiA]

A meta-analysis of studies comparing MP with drug combinations concluded that both forms of treatment were equally effective.[89][Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median OS, 17 months) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone or VAD.[96][Level of evidence: 1iiA]

Histone deacetylase inhibitors

Evidence (panobinostat):

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

1. A prospective, randomized study of 768 patients with relapsed or relapsed and refractory myeloma compared panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone.[97][Level of evidence: 1iDiii]
   • 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).

Combination therapy

Evidence (combination therapy):

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

• Bortezomib, lenalidomide, and dexamethasone (VRd) versus lenalidomide and dexamethasone (Rd). In a prospective, randomized trial in 474 newly diagnosed patients with myeloma, VRd was compared with Rd.[98][Level of evidence: 1iiA]
  • With a median follow-up of 55 months, the VRd group had superior PFS (median PFS, 43 months vs. 30 months; HR, 0.71; 95% CI, 0.58–0.95; P = .013) and superior OS (median OS, 75 months vs. 64 months; HR, 0.79; 95% CI, 0.52–0.97; P = .025).
• EVOLUTION (NCT00507442) trial: Bortezomib + lenalidomide + dexamethasone versus bortezomib + cyclophosphamide + dexamethasone versus bortezomib + lenalidomide + cyclophosphamide + dexamethasone.
• U.S. Intergroup/Intergroupe Francais du Myélome trial (IFM): Lenalidomide + bortezomib + dexamethasone for three cycles; responders are then randomly assigned to five more cycles of lenalidomide + bortezomib + dexamethasone or high-dose melphalan + stem cell transplantation.

Options for combination regimens:

1. Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-S0777, EVOLUTION trial, and the U.S. Intergroup/IFM trial).[99]
2. Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[100,101]
3. Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[102,103]
4. Lenalidomide + dexamethasone (as demonstrated in SWOG-S0777).[17,28,29]
   Triplets including either melphalan or cyclophosphamide combined with lenalidomide and dexamethasone were compared with a doublet of lenalidomide and dexamethasone in 662 patients; there were no differences in outcome for PFS or OS, but the doublet showed less toxicity.[104]
5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[105]
6. Carfilzomib + cyclophosphamide + dexamethasone.[70]
7. Carfilzomib + lenalidomide + dexamethasone.[72]
8. Carfilzomib + pomalidomide + dexamethasone.[106]
9. Pomalidomide + cyclophosphamide + dexamethasone.[107]
10. Melphalan + prednisone + thalidomide.[43,108]
11. Melphalan + prednisone.[43,108]

Consolidation Chemotherapy

Autologous bone marrow or peripheral stem cell transplantation

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

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

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

• The risk of early death caused by treatment-related toxic effects has been reduced to less than 3% in highly selected populations.[109]
• Chemotherapy patients can now be treated as outpatients.
• Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemopoiesis and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.[16]
• Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.[110-112]
• 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.[113] New monoclonal gammopathies of an isotype (heavy and/or light chain) distinct from the original clone can emerge in long-term follow-up.[114]

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,[7,115-117][Level of evidence: 1iiA] other trials have not shown any survival advantage.[118-123][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.[124] 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).[124][Level of evidence: 1iiDiii]
3. Two meta-analyses of almost 3,000 patients showed no survival advantage.[125,126][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.[7,115-117,127] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[128,129] Consequently, there is no clear consensus on whether to do transplantations early, or to give chemotherapy and do transplantations at the time of relapse.

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).[130-134]

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).[135][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 VAD for two cycles followed by two sequential episodes of high-dose therapy (melphalan 100 mg/m2) with stem cell support.[117]
   • 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).[117][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.[136-139]
4. A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous SCT followed by 6 months of maintenance therapy with thalidomide.
   • With a median follow-up of 33 months, the thalidomide maintenance arm showed a benefit in PFS (85% vs. 57% at 3 years, P = .02) and OS (85% vs. 65% at 3 years, P = .04).[140][Level of evidence: 1iiA]
5. 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.[141,142][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.[143] None of the trials employed bortezomib or lenalidomide, and the sharp decrease in compliance with a second transplant complicated sample-size calculations for sufficient statistical power.

Allogeneic bone marrow or peripheral stem cell transplantation

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

Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses following the infusion of donor lymphocytes.[144]

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.[144-146] 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.[147]

The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[146] 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.[148][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.[138,149][Level of evidence: 3iiiA] Given the lack of evidence so far that the high-risk patients benefit from allogeneic stem cell transplantation in this era of novel new agents, it remains debatable whether ASCT should be offered in the first-line setting outside the context of a clinical trial.[146,150]

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.[141,142][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.[151] With a median follow-up of 52 months, the median OS was superior for salvage ASCT: 67 months (95% CI, 55–NE) versus 52 months (42–60); HR, 0.56 (0.35–0.90, P = .017).[151][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.[152] Most clinical trials employ one or both.[153,154] Maintenance trials with glucocorticosteroids [27,155] and with interferon [156] 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.[152]

Lenalidomide maintenance therapy

After ASCT, three randomized, prospective trials showed benefit in median EFS or PFS (40–43 months vs. 21–27 months),[5-7] one with OS benefit (at a median follow-up of 34 months, 85% vs. 77%; P = .03).[5][Level of evidence: 1iiA] 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.[8][Level of evidence: 1iiDi] All three trials showed an increase in myelodysplasia or acute leukemia from 3% to 7%, consistent with other studies of lenalidomide. Doses of 5 mg to 15 mg a day have been utilized either continuously or with 1 week off every month.

Bortezomib maintenance therapy

For 178 elderly, untreated patients with an induction combination regimen including bortezomib, maintenance using bortezomib plus thalidomide versus bortezomib plus prednisone was not significantly different in PFS or OS, but both resulted in median PFS of 32 to 39 months and a 5-year OS over 50%.[9][Level of evidence: 1iiDiv]

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

With a median follow-up of 47 months, 3-year PFS was 55% versus 33% (P < .01), and 5-year OS was 59% versus 46% (P = .04).[10][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.

Management of Lytic Bone Lesions With Bisphosphonates

Bisphosphonate therapy

Evidence (bisphosphonate therapy):

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).[157][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.[158][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).[159][Level of evidence: 1iDiii]
4. 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.[160] 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).[160][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).[161,162]
5. The improvement of median OS with zoledronate was confirmed in a Cochrane network meta-analysis.[163][Level of evidence: 1A]
6. Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[164,165] (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.[166] The optimal use and duration of bisphosphonates for bony involvement in myeloma have not been studied. 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.[167,168] The aforementioned randomized trial,[161] which showed OS advantage, continued patients on bisphosphonates monthly until time of relapse.
7. 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.[169] However, this study included only 278 myeloma patients, and evaluation of this subgroup was insufficiently powered to establish noninferiority for the 12-week regimen.

Radiation therapy for bone lesions

Lytic lesions of the spine generally require radiation if any of the following are true:

1. If they are associated with an extramedullary (paraspinal) plasmacytoma.
2. If a painful destruction of a vertebral body occurred.
3. If computed tomography or MRI scans present evidence of spinal cord compression.[170]

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.[171]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[157]

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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64. 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]
65. 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]
66. 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]
67. 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]
68. 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]
69. Stewart AK, Rajkumar SV, Dimopoulos MA, et al.: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372 (2): 142-52, 2015. [PUBMED Abstract]
70. Bringhen S, Petrucci MT, Larocca A, et al.: Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 124 (1): 63-9, 2014. [PUBMED Abstract]
71. Moreau P, Kolb B, Attal M, et al.: Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood 125 (20): 3100-4, 2015. [PUBMED Abstract]
72. Jakubowiak AJ, Dytfeld D, Griffith KA, et al.: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120 (9): 1801-9, 2012. [PUBMED Abstract]
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75. Avet-Loiseau H, Bahlis NJ, Chng WJ, et al.: Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood 130 (24): 2610-2618, 2017. [PUBMED Abstract]
76. 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]
77. 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]
78. 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]
79. 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]
80. Plesner T, Arkenau HT, Gimsing P, et al.: Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood 128 (14): 1821-1828, 2016. [PUBMED Abstract]
81. Chari A, Suvannasankha A, Fay JW, et al.: Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 130 (8): 974-981, 2017. [PUBMED Abstract]
82. 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]
83. Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33 (2): 86-9, 1990. [PUBMED Abstract]
84. 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]
85. 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]
86. Browman GP, Belch A, Skillings J, et al.: Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group. Br J Haematol 82 (3): 555-9, 1992. [PUBMED Abstract]
87. 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]
88. 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]
89. 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]
90. 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]
91. Bergsagel DE, Stewart AK: Conventional-dose chemotherapy of myeloma. In: Malpas JS, Bergsagel DE, Kyle RA, et al.: Myeloma: Biology and Management. 3rd ed. Philadelphia, Pa: WB Saunders Co, 2004, pp 203-17.
92. Pavlovsky S, Corrado C, Santarelli MT, et al.: An update of two randomized trials in previously untreated multiple myeloma comparing melphalan and prednisone versus three- and five-drug combinations: an Argentine Group for the Treatment of Acute Leukemia Study. J Clin Oncol 6 (5): 769-75, 1988. [PUBMED Abstract]
93. Bladé J, San Miguel JF, Alcalá A, et al.: Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. J Clin Oncol 11 (6): 1165-71, 1993. [PUBMED Abstract]
94. Oken MM, Harrington DP, Abramson N, et al.: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 79 (8): 1561-7, 1997. [PUBMED Abstract]
95. Gertz MA, Lacy MQ, Lust JA, et al.: Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis. J Clin Oncol 17 (1): 262-7, 1999. [PUBMED Abstract]
96. Mineur P, Ménard JF, Le Loët X, et al.: VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Br J Haematol 103 (2): 512-7, 1998. [PUBMED Abstract]
97. 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]
98. Durie B, Hoering A, Rajkumar SV, et al.: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. [Abstract] Blood 126 (23), 25, 2015.
99. Richardson PG, Weller E, Lonial S, et al.: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116 (5): 679-86, 2010. [PUBMED Abstract]
100. 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]
101. 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.
102. Fonseca R, Rajkumar SV: Consolidation therapy with bortezomib/lenalidomide/ dexamethasone versus bortezomib/dexamethasone after a dexamethasone-based induction regimen in patients with multiple myeloma: a randomized phase III trial. Clin Lymphoma Myeloma 8 (5): 315-7, 2008. [PUBMED Abstract]
103. Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352 (24): 2487-98, 2005. [PUBMED Abstract]
104. Magarotto V, Bringhen S, Offidani M, et al.: Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood 127 (9): 1102-8, 2016. [PUBMED Abstract]
105. Khan ML, Reeder CB, Kumar SK, et al.: A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br J Haematol 156 (3): 326-33, 2012. [PUBMED Abstract]
106. Shah JJ, Stadtmauer EA, Abonour R, et al.: Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood 126 (20): 2284-90, 2015. [PUBMED Abstract]
107. Baz RC, Martin TG 3rd, Lin HY, et al.: Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood 127 (21): 2561-8, 2016. [PUBMED Abstract]
108. Facon T, Mary JY, Hulin C, et al.: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 370 (9594): 1209-18, 2007. [PUBMED Abstract]
109. Bladé J, Vesole DH, Gertz Morie: High-dose therapy in multiple myeloma. Blood 102 (10): 3469-70, 2003. [PUBMED Abstract]
110. Siegel DS, Desikan KR, Mehta J, et al.: Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 93 (1): 51-4, 1999. [PUBMED Abstract]
111. Badros A, Barlogie B, Siegel E, et al.: Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 114 (3): 600-7, 2001. [PUBMED Abstract]
112. Lenhoff S, Hjorth M, Westin J, et al.: Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group. Br J Haematol 133 (4): 389-96, 2006. [PUBMED Abstract]
113. Barlogie B, Attal M, Crowley J, et al.: Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol 28 (7): 1209-14, 2010. [PUBMED Abstract]
114. Wadhera RK, Kyle RA, Larson DR, et al.: Incidence, clinical course, and prognosis of secondary monoclonal gammopathy of undetermined significance in patients with multiple myeloma. Blood 118 (11): 2985-7, 2011. [PUBMED Abstract]
115. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996. [PUBMED Abstract]
116. 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]
117. 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]
118. 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]
119. 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]
120. 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]
121. 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]
122. 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]
123. 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]
124. Attal M, Lauwers-Cances V, Hulin C, et al.: Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med 376 (14): 1311-1320, 2017. [PUBMED Abstract]
125. 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]
126. 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]
127. 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]
128. 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]
129. Harousseau JL: Hematopoietic stem cell transplantation in multiple myeloma. J Natl Compr Canc Netw 7 (9): 961-70, 2009. [PUBMED Abstract]
130. 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]
131. 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]
132. 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]
133. 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]
134. 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]
135. 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]
136. 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]
137. 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]
138. 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]
139. 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]
140. Abdelkefi A, Ladeb S, Torjman L, et al.: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 111 (4): 1805-10, 2008. [PUBMED Abstract]
141. 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]
142. 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]
143. 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]
144. 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]
145. 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]
146. 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]
147. 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]
148. 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]
149. 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]
150. Moreau P: Death of frontline allo-SCT in myeloma. Blood 119 (26): 6178-9, 2012. [PUBMED Abstract]
151. 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]
152. Ludwig H, Durie BG, McCarthy P, et al.: IMWG consensus on maintenance therapy in multiple myeloma. Blood 119 (13): 3003-15, 2012. [PUBMED Abstract]
153. 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]
154. 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]
155. 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]
156. 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]
157. 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]
158. 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]
159. 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]
160. 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]
161. 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]
162. 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]
163. 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]
164. 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]
165. 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]
166. 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]
167. 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]
168. 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]
169. 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]
170. 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]
171. 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 Multiple Myeloma

In This Section

• Current Clinical Trials

There are two main types of refractory myeloma patients:

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

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients.[1,2] When the stable nature of the disease becomes established, these types of patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy. (Refer to the Treatment for Multiple Myeloma section of this summary for more information.)

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

A cellular therapy for refractory myeloma has been introduced that consists of autologous T-cells transduced with an anti-CD19 chimeric antigen receptor (so-called CAR T-cells) after myeloablative chemotherapy and autologous stem cell transplantation, with anecdotal responses.[3-5] Other molecular targets and expanded clinical approaches are being investigated.[3][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

1. Riccardi A, Mora O, Tinelli C, et al.: Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol. Eur J Cancer 39 (1): 31-7, 2003. [PUBMED Abstract]
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. 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]
4. 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]
5. Mikkilineni L, Kochenderfer JN: Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 130 (24): 2594-2602, 2017. [PUBMED Abstract]

Key References for Plasma Cell Neoplasms (Including Multiple Myeloma)

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of plasma cell neoplasms and multiple myeloma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for plasma cell neoplasms and multiple myeloma. Listed after each reference are the sections within this summary where the reference is cited.

• Dimopoulos MA, Oriol A, Nahi H, et al.: Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 375 (14): 1319-1331, 2016.[PUBMED Abstract]
  Cited in:
  • Treatment for Multiple Myeloma.
• Moreau P, Masszi T, Grzasko N, et al.: Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 374 (17): 1621-34, 2016.[PUBMED Abstract]
  Cited in:
  • Treatment for Multiple Myeloma.
• Morgan GJ, Davies FE, Gregory WM, et al.: First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376 (9757): 1989-99, 2010.[PUBMED Abstract]
  Cited in:
  • Treatment for Multiple Myeloma.
• Palumbo A, Avet-Loiseau H, Oliva S, et al.: Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol 33 (26): 2863-9, 2015.[PUBMED Abstract]
  Cited in:
  • Stage Information About Plasma Cell Neoplasms
• Palumbo A, Chanan-Khan A, Weisel K, et al.: Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 375 (8): 754-66, 2016.[PUBMED Abstract]
  Cited in:
  • Treatment for Multiple Myeloma.
• Rajkumar SV, Dimopoulos MA, Palumbo A, et al.: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15 (12): e538-48, 2014.[PUBMED Abstract]
  Cited in:
  • General Information About Plasma Cell Neoplasms.
  • Treatment Option Overview for Plasma Cell Neoplasms.
• Richardson PG, Weller E, Lonial S, et al.: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116 (5): 679-86, 2010.[PUBMED Abstract]
  Cited in:
  • Treatment for Multiple Myeloma.

Changes to This Summary (02/08/2019)

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.

General Information About Plasma Cell Neoplasms

Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer Society as reference 1).

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]

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

Disclaimer

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

Contact Us

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

• Updated: February 8, 2019