Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment

General Information About Plasma Cell Neoplasms

There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.

Incidence and Mortality

Estimated new cases and deaths from multiple myeloma in the United States in 2012:[ 1 ]

  • New cases: 21,700.
  • Deaths: 10,710.

Clinical Presentation and Evaluation

Table 1. 1. Clinical Presentation of Plasma Cell Neoplasms

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

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

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[ 4 , 5 ] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.

The major challenge is to separate the stable, asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who should 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 assays; however, specific immunoglobulin quantification always overestimates the M protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M protein should be done by the same method.[ 8 ] Quantitative serum-free light chains 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.
  • Sometimes, determine the percentage of marrow plasma cells. Be aware that marrow plasma cell distribution may vary in different sites.
  • 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 ]
  • 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. Whole-body, low-dose, nonenhanced multidetector computed tomography and magnetic resonance imaging (MRI) are being evaluated as measures for therapy response monitoring.[ 10 , 11 ] MRI of the spine or long bones is more sensitive in detecting lytic lesions, but any prognostic or therapeutic value for this information remains to be determined.[ 11 ]
  • Perform MRI if a paraspinal mass is detected or if symptoms suggest spinal cord or nerve root compression.
  • 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.[ 12 ]
  • Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[ 13 , 14 ]
  • A high plasma cell labeling index (≥3%) or the presence of circulating myeloma cells are considered poor prognostic factors.[ 15 ]

These initial studies should be 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 should be treated immediately.[ 6 , 7 ]

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 , 16 , 17 , 18 ] 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 should not be treated. They must, however, be followed carefully since about 1% to 2% of MGUS patients per year will progress to develop myeloma (most commonly), amyloidosis, lymphoma, or chronic lymphocytic leukemia and may then require therapy.[ 18 , 19 , 20 ]

Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[ 21 , 22 , 23 ]

Risk factors that predict disease progression include the following:

  • An abnormal serum-free light chain ratio.
  • Non-IgG class MGUS.
  • A high serum M protein level (≥15 g/L).[ 24 ]

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 is found on skeletal survey in an otherwise asymptomatic patient.
  • A bone marrow examination from an uninvolved site contains less than 10% plasma cells.[ 25 , 26 , 27 ]

When clinically indicated, MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine may identify other bony lesions.[ 28 ]

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.[ 29 , 30 , 31 ]

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, bortezomib, and autologous and allogeneic stem cell transplantation, with median survivals of 45 to 60 months.[ 32 , 33 , 34 ]

Multiple myeloma is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. (Refer to the Isolated Plasmacytoma of Bone and Extramedullary Plasmacytoma sections of this summary for more information.)

Amyloidosis Associated With Plasma Cell Neoplasms

Multiple myeloma and other plasma cell neoplasms may cause a condition called amyloidosis. Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Elevated serum levels of cardiac troponinsand brain natriuretic peptide are poor prognostic factors. A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation.[ 35 ]

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed January 4, 2013.
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.
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.
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.
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.
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.
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.
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.
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.
10. 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.
11. 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.
12. 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.
13. Greipp PR: Advances in the diagnosis and management of myeloma. Semin Hematol 29 (3 Suppl 2): 24-45, 1992.
14. 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.
15. Greipp PR, Witzig T: Biology and treatment of myeloma. Curr Opin Oncol 8 (1): 20-7, 1996.
16. Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354 (13): 1362-9, 2006.
17. 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.
18. 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.
19. 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.
20. 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.
21. Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-22, 2009.
22. 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.
23. Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009.
24. 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.
25. 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.
26. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.
27. Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002.
28. 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.
29. 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.
30. 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.
31. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.
32. 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.
33. 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.
34. 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.
35. Dispenzieri A, Gertz MA, Kyle RA, et al.: Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 22 (18): 3751-7, 2004.

Stage Information About Plasma Cell Neoplasms

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

Multiple Myeloma

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

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

International staging system

The International Myeloma Working Group studied 11,171 patients, of whom 2,901 received high-dose therapy and 8,270 received only standard-dose therapy.[ 1 ]

An International Staging System was derived and is shown below in Table 2 2.[ 1 ]

Table 2. 2. The International Staging System for Multiple Myeloma

StageCriteriaMedian Survival (mo)
IBeta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL62
IIBeta-2-microglobulin <3.5 mg/L and albumin <3.5 g/dL or beta-2-microglobulin 3.5 mg/L to <5.5 mg/L44
IIIBeta-2-microglobulin ≥5.5 mg/L29

Genetic factors and risk groups

Genetic aberrations detected by interphase fluorescence in situ hybridization (FISH) may define prognostic groups in retrospective and prospective analyses.[ 2 , 3 ] Short survival and shorter duration of response to therapy have been reported with t(4;14)(p16;q32), t(14; 16)(q32;q23), cytogenetic deletion of 13q-14, and deletion of 17p13 (p53 locus).[ 2 , 3 , 4 , 5 , 6 ] The question of whether the choice of therapy based on FISH analysis can influence outcome must await further study in prospective trials.

Newer clinical investigations are stratifying patients with multiple myeloma into a so-called standard-risk group, which accounts for 75% of patients and has a median survival of 3 to 6 years, and a high-risk group, which has a median survival of less than 3 years.[ 2 , 3 , 4 , 5 , 6 , 7 ] (See Table 3 3 below.) This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation.[ 7 ] Bone marrow samples are sent for cytogenetic and FISH analysis. Plasma cell leukemia has a particularly poor prognosis.[ 8 ]

Table 3. 3. Risk Groups for Multiple Myeloma

Risk GroupCytogenetic FindingsDisease Characteristics
FISH = fluorescencein situ hybridization.
Standard riskHas any of the following cytogenetic findings: (1) no adverse FISH or cytogenetics, (2) hyperdiploidy, (3) t(11;14) by FISH, or (4) t(6;14) by FISH.These patients most often have (1) disease that expresses IgG kappa monoclonal gammopathies and (2) lytic bone lesions.
High riskHas any of the following cytogenetic findings: (1) del 17p by FISH, (2) t(4;14) by FISH, (3) t(14;16) by FISH, (4) cytogenetic del 13, or (5) hypodiploidy.These patients have (1) disease that expresses IgA lambda monoclonal gammopathies (often) and (2) skeletal-related complications (less often).

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.
2. Fonseca R, Blood E, Rue M, et al.: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 (11): 4569-75, 2003.
3. Avet-Loiseau H, Attal M, Moreau P, et al.: Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 109 (8): 3489-95, 2007.
4. Gertz MA, Lacy MQ, Dispenzieri A, et al.: Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood 106 (8): 2837-40, 2005.
5. Gutiérrez NC, Castellanos MV, Martín ML, et al.: Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21 (1): 143-50, 2007.
6. Sagaster V, Ludwig H, Kaufmann H, et al.: Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia 21 (1): 164-8, 2007.
7. 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.
8. 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.

Treatment Option Overview for Plasma Cell Neoplasms

The major challenge in treating plasma cell neoplasms is to separate the stable, asymptomatic group of patients who do not require immediate treatment from patients with progressive, symptomatic myeloma who should be treated immediately.[ 1 , 2 ] Monoclonal gammopathy of undetermined significance or smoldering myeloma must be distinguished from progressive myeloma.

Asymptomatic Plasma Cell Neoplasms

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 , 3 , 4 ] Increasing anemia is the most reliable indicator of progression.[ 4 ]

Symptomatic Plasma Cell Neoplasms

Treatment should be given to patients with symptomatic advanced disease.

Treatment should be 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. (Refer to the PDQ summary on Hypercalcemia for more information.)

Response criteria have been developed for patients on clinical trials.[ 5 ]

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 Adjuvant drugs section in the Pharmacologic Management section of the PDQ summary on 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.
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.
3. 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.
4. 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.
5. Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006.

Treatment for Amyloidosis Associated With Plasma Cell Neoplasms

Standard Treatment Options for Amyloidosis Associated With Plasma Cell Neoplasms

Standard treatment options for amyloidosis associated with plasma cell neoplasms include the following:

1.Chemotherapy.
2.Stem cell rescue.

Chemotherapy

Two randomized trials showed prolonged overall survival (OS) with the use of oral chemotherapy with melphalan with or without colchicine versus colchicine alone.[ 1 , 2 ][Level of evidence: 1iiA]

As is true for all plasma cell dyscrasias, anecdotal responses for amyloidosis have been reported, as in the Southwest Oncology Group's trial (SWOG-9628 [NCT00002849])Translators: NCT # added after final markup, for dexamethasone alone and in combination, including thalidomide, cyclophosphamide, melphalan, bortezomib, and lenalidomide[ 3 ].[ 4 , 5 , 6 , 7 , 8 ]

Stem cell rescue

A randomized, prospective study of 100 patients with immunoglobulin amyloidosis light chain compared melphalan plus high-dose dexamethasone with high-dose melphalan plus autologous stem cell rescue.[ 9 ]

After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 months vs. 22.2 months; P = .04).[ 9 ][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.[ 9 , 10 , 11 , 12 ] A randomized trial confirming the benefit of autologous transplantation is not anticipated.[ 13 ]

An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.[ 14 ]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with primary systemic amyloidosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

References:

1. 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.
2. 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.
3. Dhodapkar MV, Hussein MA, Rasmussen E, et al.: Clinical efficacy of high-dose dexamethasone with maintenance dexamethasone/alpha interferon in patients with primary systemic amyloidosis: results of United States Intergroup Trial Southwest Oncology Group (SWOG) S9628. Blood 104 (12): 3520-6, 2004.
4. Wechalekar AD, Goodman HJ, Lachmann HJ, et al.: Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 109 (2): 457-64, 2007.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.
14. 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.

Treatment for Monoclonal Gammopathy of Undetermined Significance

Standard Treatment Options for Monoclonal Gammopathy of Undetermined Significance (MGUS)

Standard 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 should be 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 , 4 , 5 , 6 ] Newer therapies have not been proven to prevent or delay the progression of MGUS to a plasma cell dyscrasia.[ 2 ]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with monoclonal gammopathy of undetermined significance. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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.
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.
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.
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.
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.
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.

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

Standard Treatment Options for Isolated Plasmacytoma of Bone

Standard 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; this should disappear 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 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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with isolated plasmacytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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.
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.
3. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.
4. Dimopoulos MA, Goldstein J, Fuller L, et al.: Curability of solitary bone plasmacytoma. J Clin Oncol 10 (4): 587-90, 1992.

Treatment for Extramedullary Plasmacytoma

Standard Treatment Options for Extramedullary Plasmacytoma

Standard 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. These types of patients should be followed closely. Surgery should be 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, should have skeletal x-rays and bone marrow biopsy (both of which should be negative) and evaluation for M protein in serum and urine.[ 1 , 2 , 3 , 4 ]

About 25% of patients have serum and/or urine M protein; this should disappear 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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extramedullary plasmacytoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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.
2. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.
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.
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.
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.

Treatment for Multiple Myeloma

Initial Evaluation

The initial approach to the patient is to evaluate the following parameters:

1.Detection of a monoclonal (or myeloma) protein (M protein) in the serum or urine.
2.Detection of more than 10% of plasma cells on a bone marrow examination.
3.Detection of lytic bone lesions or generalized osteoporosis in skeletal x-rays.
4.Presence of soft tissue plasmacytomas.
5.Serum albumin and beta-2-microglobulin levels.
6.Detection of free kappa and lambda serum immunoglobulin light chain.[ 1 ]

Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.[ 2 ]

Induction Therapy

The choice of induction therapy is unclear at the present time; however, the current basic categories include the use of steroids, thalidomide, and lenalidomide.

Several questions are raised when therapy is being chosen for a patient with symptomatic myeloma at first presentation, including the following:

1.Is the patient eligible for a clinical trial? The sequence and combinations of new and older therapies can only be determined by prospective clinical trials.
2.Is autologous stem cell transplantation (ASCT) a possible consolidation option for this patient? If so, alkylating agents should be avoided during induction therapy to avoid compromise of stem cell collection and to lessen leukemogenic risk.
3.Does the patient have comorbidities? Age, organ dysfunction, and risk of cardiovascular and thrombotic complications would influence the choice of induction therapies as well as the choice of whether to consider consolidation therapies.

Induction therapy agents

Multiple therapeutic agents are available for induction therapy, either alone or in combinations.[ 3 ] These include the following:

  • Steroids (e.g., dexamethasone and prednisone).
  • Thalidomide.
  • Lenalidomide.
  • Bortezomib.
  • Alkylating agents (e.g., melphalan and cyclophosphamide).
  • Other cytotoxic drugs (e.g., vincristine, doxorubicin, and liposomal doxorubicin).

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.[ 4 ]
2.Bortezomib or lenalidomide is combined with dexamethasone for at least 8 months or until best response if consolidation therapy is planned.[ 5 , 6 ] (Refer to the Lenalidomide and Bortezomib sections of this summary for more information.)
3.The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration.
  • Bortezomib is given in frequent intravenous doses and can cause significant neuropathic toxicities.[ 6 , 7 , 8 ] Bortezomib is preferred in the setting of renal impairment.[ 9 ]
  • Lenalidomide is given orally and can cause an increased risk for deep venous thrombosis (DVT), requiring additional prophylactic medication.[ 5 , 10 ]
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.[ 11 ]
5. Patients with high-risk disease might receive induction therapy until best response, followed by consolidation therapy with allogeneic or ASCT.[ 11 ]

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.[ 12 ] Response rates of 60% to 70% in previously untreated patients appeared to be as high as those in patients treated with VAD.[ 12 , 13 ][Level of evidence: 3iiiDiv]

Evidence:

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 overall survival (OS) (median survival times were 32 months–40 months).[ 14 ][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 a day 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).
    • 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.[ 15 ]
  • In the context of lenalidomide, as evaluated in an Eastern Cooperative Oncology Group trial (ECOG-E4A03).[ 5 ]
    • The lenalidomide study questioned the safety and efficacy of high-dose dexamethasone.[ 5 ] (Refer to the Lenalidomide section of this summary for more information.)

Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.

Thalidomide

Evidence:

Ten randomized prospective studies involving more than 4,500 patients have examined the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]

  • 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.
  • Only two of the ten randomized studies reported a survival advantage using thalidomide. In these trials, the patients older than 65 or 75 years at the 2-year follow-ups showed a 44- to 56-month median OS for MP plus thalidomide versus 28- to 30-month median OS for MP (P < .03 in both studies).[ 22 , 25 ][Level of evidence: 1iiA]
  • A possible explanation is that these two trials used a lower dose of thalidomide than the other studies (100 mg vs. ≥200 mg), a lower dose of steroids (60 mg of prednisone vs. high-dose dexamethasone), and involved the use of alkylating agents.

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.[ 26 , 27 ]

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 a day), warfarin, or low molecular-weight heparin, but the validity of these measures has not been studied prospectively in a randomized study.[ 20 , 22 , 27 , 28 , 29 ]

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

Lenalidomide

Evidence:

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.[ 30 ]
  • 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).[ 30 ][Level of evidence: 1iA]
  • The lenalidomide-containing arm had more DVT (11.4% vs. 4.6%).[ 30 ]
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).[ 31 ][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).[ 5 ]
  • 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 progression-free survival (PFS).[ 5 ][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).[ 5 ][Level of evidence: 1iiA] The low-dose dexamethasone arm with lenalidomide had less than 5% DVT with aspirin alone.
4.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.[ 32 ][Level of evidence: 3iiiA]

Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[ 5 , 30 , 31 , 32 ] DVT prophylaxis with 81 mg of aspirin has been proposed, but randomized clinical trials have not confirmed any benefit for this recommendation.[ 29 ] 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.) 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 per day; creatinine clearance, <30: 15 mg every other day; dialysis, 15 mg on day after dialysis).[ 33 ]

Bortezomib

Evidence:

1.A prospective, randomized trial (NCT00111319) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation because of age (one-third of patients >75 years) compared bortezomib combined with melphalan and prednisone with melphalan and prednisone alone.[ 6 ]
  • With a median follow-up of 37 months, the OS favored the bortezomib arm in the 3-year OS rates (69% vs. 54%, P = .03).[ 6 ][Level of evidence: 1iiA]
2.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.[ 7 ][Level of evidence: 1iiA]
  • Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[ 8 , 34 , 35 , 36 , 37 ]
3.A prospective, randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.[ 38 ]
  • 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).[ 38 ][Level of evidence: 1iiA]

When bortezomib was incorporated with induction therapy, patients with unfavorable molecular cytogenetics did not show any difference in PFS or OS compared with patients with more favorable risk factors. The benefit from bortezomib appears to be maintained across risk groups, but not reproducibly in all studies.[ 39 , 40 , 41 , 42 , 43 ][Level of evidence: 3iiiD]

Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[ 9 , 44 , 45 ] In a retrospective, nonrandomized comparison, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (8% vs. 28%, P < .001) with no loss of efficacy compared with standard biweekly administration.[ 46 ]

Conventional-dose chemotherapy

Evidence:

The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[ 47 , 48 , 49 , 50 ][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 complete response rate.
  • An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[ 51 , 52 ][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.[ 53 ] The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[ 53 , 54 , 55 ]

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.[ 56 , 57 , 58 , 59 ][Level of evidence: 1iiA]

A meta-analysis of studies comparing MP with drug combinations concluded that both forms of treatment were equally effective.[ 53 ][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.[ 60 ][Level of evidence: 1iiA]

Combination therapy

Evidence:

Several national and international trials have been implemented to define the optimal combination regimens. Participation in these trials should be 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.

  • ECOG-E1A05: Bortezomib + dexamethasone versus lenalidomide + bortezomib + dexamethasone.[ 61 ]
  • SWOG-S0777: Lenalidomide + dexamethasone versus lenalidomide + bortezomib + dexamethasone.
  • 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.
  • ECOG-E1A06: Thalidomide + melphalan + prednisone versus lenalidomide + melphalan + prednisone.

Options for combination regimens:

1.Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[ 39 , 61 ]
2.Lenalidomide + dexamethasone (as demonstrated in SWOG-S0777).[ 5 , 30 , 31 ]
3.Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-S0777, EVOLUTION trial, and the U.S. Intergroup/IFM trial).[ 39 , 61 , 62 ]
4.Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[ 63 , 64 ]
5.Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[ 65 ]
6.Lenalidomide + cyclophosphamide + dexamethasone.[ 66 ]
7.Bortezomib + melphalan + prednisone.[ 6 ]
8.Bortezomib + liposomal doxorubicin +/- dexamethasone.[ 38 , 67 ]
9.Melphalan + prednisone + thalidomide.[ 18 , 25 ]
10.Melphalan + prednisone.[ 18 , 25 ]

Consolidation Chemotherapy

High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation

Evidence:

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.[ 68 ]
  • 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.[ 4 ]
  • Younger patients in good health tolerate high-dose therapy better than patients with a poor performance status.[ 69 , 70 , 71 ]
  • 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.[ 72 ]

Single autologous bone marrow or peripheral stem cell transplantation

Evidence:

While some prospective randomized trials, such as the U.S. Intergroup trial SWOG-9321, have shown improved survival for patients who received autologous peripheral stem cell or bone marrow transplantation after induction chemotherapy versus chemotherapy alone,[ 73 , 74 , 75 ][Level of evidence: 1iiA] other trials have not shown any survival advantage.[ 76 , 77 , 78 , 79 ][Level of evidence: 1iiA]

Two meta-analyses of almost 3,000 patients showed no survival advantage.[ 80 , 81 ][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.[ 73 , 74 , 75 , 82 ] The role of ASCT has also been questioned with the advent of novel induction therapies with high complete-remission rates.[ 83 , 84 ]

Tandem autologous bone marrow or peripheral stem cell 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).[ 85 , 86 , 87 , 88 , 89 ]

Evidence:

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).[ 90 ][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.[ 75 ]
  • 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).[ 75 ][Level of evidence: 1iiA]
3.Three different groups have compared two 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.
  • One study showed a survival advantage for the two tandem autologous transplants.
  • One study showed a survival advantage for the autologous transplant followed by an allogeneic transplant.
  • One study showed no difference in OS.[ 91 , 92 , 93 , 94 ][Level of evidence: 3iiiA]
4.A trial of 195 patients younger than 60 years with newly diagnosed myeloma randomly compared two tandem transplants with a single autologous stem cell transplant 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).[ 95 ][Level of evidence: 1iiA]

High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation

Evidence:

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.[ 96 ][Level of evidence: 3iiiA]

Favorable prognostic features included the following:

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

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.[ 97 , 98 , 99 , 100 ]

Myeloablative allogeneic stem cell transplantation has significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect in a minority of patients may offset the high transplant-related mortality.[ 100 , 101 , 102 ]

Further research is required to make allogeneic transplants less dangerous and to find methods for initiating an autoimmune response to the myeloma cells. Nonmyeloablative allogeneic stem cell transplant is under development.[ 103 , 104 , 105 ] Such strategies aim to maintain efficacy (so called graft-versus-tumor effect) while reducing transplant-related mortality.[ 106 , 107 ] The lower transplant-related mortality from nonmyeloablative approaches has been accompanied by a greater risk of relapse.[ 102 ] 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 allogeneic stem cell transplantation should be offered in the first-line setting outside the context of a clinical trial.[ 102 ]

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.

Evidence:

1.In a single study,[ 108 ] it was observed that maintenance therapy with MP prolonged the initial remission duration (31 months) compared with no maintenance treatment (23 months).
  • No effect on OS was found because the majority of patients who relapsed in the no maintenance arm responded again to MP, while those on maintenance MP did not respond to further treatment.
  • The Canadian group [ 108 ] suggests that induction chemotherapy be continued as long as the M protein continues to fall; therapy can be discontinued after the M protein reaches a plateau that remains stable for 4 months.
2.Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration after conventional chemotherapy.[ 109 , 110 , 111 , 112 ] While the impact of interferon maintenance on disease-free survival and OS has significantly varied among trials, a meta-analysis of 1,543 patients treated on 12 trials randomizing between interferon maintenance and observation indicated that interferon maintenance was associated with improved relapse-free survival (27% vs. 19% at 3 years, P < .001) and OS (12% odds reduction, P = .04).[ 113 ] Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.[ 114 ]
3.A randomized study compared maintenance interferon with maintenance thalidomide in 103 previously untreated and treated patients who had at least a minimal response to induction chemotherapy with thalidomide, pegylated liposomal doxorubicin, and dexamethasone. With a median follow-up of 30 months, the thalidomide maintenance arm was better, with 2-year PFS of 63% versus 32% (P = .024) and a 2-year OS of 84% versus 68% (P = .03).[ 115 ][Level of evidence: 1iiA]
4.In a trial of 556 previously untreated patients induced with thalidomide, doxorubicin, dexamethasone, and followed by high-dose melphalan with stem cell support, patients were randomly assigned to alpha interferon or to thalidomide maintenance. With a median follow-up of 52 months, there was no significant difference in median survival (P = .77) 60 months for interferon and 73 months for thalidomide.[ 24 ][Level of evidence: 1iiA]
5.Maintenance therapy with interferon showed a benefit in PFS (46 months vs. 27 months, P < .025) and OS (75% vs. 50%, P < .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[ 116 ][Level of evidence: 1iiA] A larger randomized trial of 805 patients showed no difference in PFS or OS with interferon given after peripheral stem cell transplantation or conventional chemotherapy.[ 117 ][Level of evidence: 1iiA]
6.In a randomized trial, 269 patients with newly diagnosed myeloma were given maintenance thalidomide plus prednisolone versus prednisolone alone following both induction therapy and high-dose melphalan with ASCT. The trial showed a benefit in favor of the thalidomide arm after a median follow-up of 3 years: 3-year PFS, 43% versus 23% (P < .001); 3-year OS, 86% versus 75% (P = .004).[ 118 ][Level of evidence: 1iiA] As a result of these varying outcomes, further clinical trial results are required to determine whether there is a benefit of maintenance therapy.
7.A study of 125 responding patients with first-line VAD induction who were randomly assigned to maintenance corticosteroids at 10 mg or 50 mg on alternate days showed improved PFS (14 months vs. 5 months, P = .003) and OS (36 months vs. 26 months, P = .05) for the patients receiving the higher-dose corticosteroids.[ 119 ][Level of evidence: 1iiA]
8.In a larger trial by the National Cancer Institute of Canada (CAN-NCIC-MY7) of 585 patients treated with first-line MP, 292 patients were randomly assigned to pulse dexamethasone (40 mg a day for 4 days monthly) versus no maintenance.
  • PFS favored the dexamethasone maintenance arm (2.8 years vs. 2.1 years, P = .002), but there was no difference in OS (4.1 years vs. 3.8 years, P = .4).[ 15 ][Level of evidence: 1iiDiii]
9.Two months after autologous transplantation, 597 patients younger than 65 years were randomly assigned to no maintenance, pamidronate, or pamidronate plus thalidomide.
  • The thalidomide arm was favored by EFS (36% vs. 37% vs. 52%, P < .009) and by OS at 4 years (77% vs. 74% vs. 87%, P < .04), while no differences were seen for skeletal events.[ 120 ][Level of evidence: 1iiA]
10.After autologous transplantation, 129 patients were randomly assigned to indefinite prednisone versus indefinite prednisone with 12 months of thalidomide.
  • With a median follow-up of 3 years, the thalidomide arm was favored by PFS (42% vs. 23%, P < .001) and by OS at 3 years (86% vs. 75%, P = .004).[ 118 ][Level of evidence: 1iiA]

Supportive care

Bisphosphonate therapy

Evidence:

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).[ 121 ][Level of evidence: 1iDiii] (Refer to the PDQ summary on 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.[ 122 ][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.[ 123 ][Level of evidence: 1iDiii]
4. Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[ 124 , 125 ] (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.[ 126 ] 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.[ 67 , 127 ]

Bone lesions

Lytic lesions of the spine should be radiated 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.[ 128 ]

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (Refer to the PDQ summary on 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.[ 129 ]

Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.[ 121 ]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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115. Offidani M, Corvatta L, Polloni C, et al.: Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study. Br J Haematol 144 (5): 653-9, 2009.
116. Cunningham D, Powles R, Malpas J, et al.: A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol 102 (2): 495-502, 1998.
117. Barlogie B, Kyle R, Anderson K, et al.: Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/m2 + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321. [Abstract] Blood 102 (11): A-135, 2003.
118. Spencer A, Prince HM, Roberts AW, et al.: Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27 (11): 1788-93, 2009.
119. 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.
120. Attal M, Harousseau JL, Leyvraz S, et al.: Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108 (10): 3289-94, 2006.
121. 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.
122. 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.
123. 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.
124. 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.
125. 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.
126. 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.
127. 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.
128. 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.
129. 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.

Refractory Multiple Myeloma

There are two main types of refractory myeloma patients:

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

A subgroup of patients who do not achieve a response to induction chemotherapy have stable disease and enjoy a survival prognosis that is as good as that for responding patients.[ 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.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with refractory multiple myeloma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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.
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.

Changes to This Summary (12 / 28 / 2012)

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.

Treatment for Waldenström Macroglobulinemia (Lymphoplasmacytic Lymphoma)

An editorial change was made to this section.

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).

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The lead reviewers for Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment are:

  • Steven D. Gore, MD (Johns Hopkins University)
  • Mark J. Levis, MD, PhD (Johns Hopkins University)
  • Eric J. Seifter, MD (Johns Hopkins University)

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National Cancer Institute: PDQ® Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/healthprofessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2012-12-28

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