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NCI/PDQ^® Health professionals: Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 28 de diciembre del 2012

TABLE OF CONTENTS

• General Information About Plasma Cell Neoplasms
  • 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

• Stage Information About Plasma Cell Neoplasms
  • Multiple Myeloma
    • International staging system
    • Genetic factors and risk groups

• Treatment Option Overview for Plasma Cell Neoplasms
  • Asymptomatic Plasma Cell Neoplasms
  • Symptomatic Plasma Cell Neoplasms

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

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

• Treatment for Waldenstrím Macroglobulinemia (Lymphoplasmacytic Lymphoma)

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

• Treatment for Extramedullary Plasmacytoma
  • Standard Treatment Options for Extramedullary Plasmacytoma
  • Current Clinical Trials

• Treatment for Multiple Myeloma
  • Initial Evaluation
  • Induction Therapy
    • Induction therapy agents
    • Guidelines for choosing induction therapy
    • Corticosteroids
    • Thalidomide
    • Lenalidomide
    • Bortezomib
    • Conventional-dose chemotherapy
    • Combination therapy
  • Consolidation Chemotherapy
    • High-dose 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
    • High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation
  • Maintenance Therapy
  • Supportive care
    • Bisphosphonate therapy
    • Bone lesions
  • Current Clinical Trials

• Refractory Multiple Myeloma
  • Current Clinical Trials

• Changes to This Summary (12/28/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
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General Information About Plasma Cell Neoplasms

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

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

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 [PUBMED Abstract]
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. 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]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
13. Greipp PR: Advances in the diagnosis and management of myeloma. Semin Hematol 29 (3 Suppl 2): 24-45, 1992. [PUBMED Abstract]
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. [PUBMED Abstract]
15. Greipp PR, Witzig T: Biology and treatment of myeloma. Curr Opin Oncol 8 (1): 20-7, 1996. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
19. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Franíais du Myélome. N Engl J Med 335 (2): 91-7, 1996. [PUBMED Abstract]
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. [PUBMED Abstract]
21. 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]
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. [PUBMED Abstract]
23. Bladé J, Rosiíol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
26. Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000. [PUBMED Abstract]
27. Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
31. Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

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 22. 1

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 33 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

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. Fonseca R, Blood E, Rue M, et al.: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101 (11): 4569-75, 2003. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

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. [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. 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]
4. Bladé J, Dimopoulos M, Rosiíol 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]
5. 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

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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
13. Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004. [PUBMED Abstract]
14. Schínland 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

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. [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, Rosiíol 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 Waldenstrím Macroglobulinemia (Lymphoplasmacytic Lymphoma)

Refer to the Lymphoplasmacytic Lymphoma (Waldenstrím 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. [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]

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