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There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.
Incidence and Mortality
Estimated new cases and deaths from multiple myeloma in the United States in 2010:
Clinical Presentation and Evaluation
|Plasma Cell Neoplasm||M Protein Type||Pathology||Clinical Presentation|
|MGUS = monoclonal gammopathy of undetermined significance.|
|MGUS||IgG kappa or lambda; or IgA kappa or lambda||<10% plasma cells in bone marrow||Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein)|
|Isolated plasmacytoma of bone||IgG kappa or lambda; or IgA kappa or gamma||Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site||Symptomatic|
|Extramedullary plasmacytoma||IgG kappa or lambda; or IgA kappa or gamma||Solitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses||Symptomatic|
|Multiple myeloma||IgG kappa or lambda; or IgA kappa or gamma||Often, multiple lesions of bone||Symptomatic|
Evaluation of patients with monoclonal (or myeloma) protein (M protein)
Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[4,5] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.
Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated by some of the following criteria:
In most myeloma patients, the glomeruli function normally allows only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
These initial studies 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] Patients with smoldering myeloma have similar characteristics but may have more than 10% of marrow plasma cells.
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]
Risk factors that predict disease progression include the following:
Isolated Plasmacytoma of Bone
The patient has an isolated plasmacytoma of the bone if the following are found:
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.
A patient has extramedullary plasmacytoma if the following are found:
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.
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 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.[31,32,33]
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 troponins and 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.
|1.||American Cancer Society.: Cancer Facts and Figures 2010. Atlanta, Ga: American Cancer Society, 2010. Also available online. Last accessed January 4, 2012.|
|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.||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.|
|19.||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.|
|20.||Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-22, 2009.|
|21.||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.|
|22.||Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009.|
|23.||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.|
|24.||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.|
|25.||Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000.|
|26.||Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002.|
|27.||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.|
|28.||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.|
|29.||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.|
|30.||Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999.|
|31.||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.|
|32.||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.|
|33.||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.|
|34.||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.|
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 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.
An International Staging System was derived and is shown below in Table 2.
|Stage||Criteria||Median Survival (mo)|
|I||Beta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL||62|
|II||Beta-2-microglobulin <3.5 mg/L and albumin <3.5 g/dL or beta-2-microglobulin 3.5 mg/L to <5.5 mg/L||44|
|III||Beta-2-microglobulin ≥5.5 mg/L||29|
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 below.) This stratification, based on cytogenetic findings, has been derived from retrospective analyses and requires prospective validation. Bone marrow samples are sent for cytogenetic and FISH analysis.
|Risk Group||Cytogenetic Findings||Disease Characteristics|
|FISH = fluorescencein situ hybridization.|
|Standard risk||Has any of the following cytogenetic findings: (1) no adverse FISH or cytogenetics, (2) hyperdiploidy, (3) t(11;14) by FISH, or (4) t(6;14) by FISH.||These patients most often have (1) disease that expresses IgG kappa monoclonal gammopathies and (2) lytic bone lesions.|
|High risk||Has 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).|
|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.||Dispenzieri A, Rajkumar SV, Gertz MA, et al.: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc 82 (3): 323-41, 2007.|
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 Disorders
Symptomatic Plasma Cell Disorders
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.
Current therapy for patients with symptomatic myeloma can be divided into the following categories:
|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.||Hjorth M, Hellquist L, Holmberg E, et al.: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol 50 (2): 95-102, 1993.|
|5.||Durie BG, Harousseau JL, Miguel JS, et al.: International uniform response criteria for multiple myeloma. Leukemia 20 (9): 1467-73, 2006.|
Standard Treatment Options for Amyloidosis Associated With Plasma Cell Disorders
Standard treatment options for amyloidosis associated with plasma cell disorders include the following:
|2.||Stem cell rescue.|
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), for dexamethasone alone and in combination with thalidomide and cyclophosphamide or lenalidomide.[3,4,5,6]
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.
After a median follow-up of 3 years, median OS favored the nontransplant arm (56.9 mo vs. 22.2 mo; P = .04).[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.[7,8,9,10] A randomized trial confirming the benefit of autologous transplantation is not anticipated.
An anecdotal series describes full-intensity and reduced-intensity allogeneic stem cell transplantation.
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.
|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.||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.|
|8.||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.|
|9.||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.|
|10.||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.|
|11.||Mehta J, Gerta MA, Dispenzieri A: High-dose therapy for amyloidosis: the end of the beginning? Blood 103 (10): 3612-3, 2004.|
|12.||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.|
Standard Treatment Options for Monoclonal Gammopathy of Undetermined Significance (MGUS)
Standard treatment options for MGUS include the following:
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. 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.
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.[2,3,4,5]
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.
|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.||Hjorth M, Hellquist L, Holmberg E, et al.: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol 50 (2): 95-102, 1993.|
|3.||He Y, Wheatley K, Clark O, et al.: Early versus deferred treatment for early stage multiple myeloma. Cochrane Database Syst Rev (1): CD004023, 2003.|
|4.||Riccardi A, Mora O, Tinelli C, et al.: Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 82 (7): 1254-60, 2000.|
|5.||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.|
Refer to the Waldenström macroglobulinemia section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.
Standard Treatment Options for Isolated Plasmacytoma of Bone
Standard treatment options for isolated plasmacytoma of bone include the following:
|1.||Radiation therapyto the lesion.|
|2.||Chemotherapy(if the monoclonal [or myeloma] protein [M protein] increases and other evidence of symptomatic multiple myeloma occurs).|
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.
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.
|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.|
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.|
|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.
|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.|
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.|
Treatment selection is influenced by the age and general health of the patient, prior therapy, and the presence of complications of the disease.
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 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. These include the following:
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.|
|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 theLenalidomide andBortezomibsections of this summary for more information.)|
|3.||The choice of bortezomib or lenalidomide is based on side-effect profile and route of administration.
|4.||Patients with standard-risk disease, as defined in theStage Informationsection of this summary, might receive induction therapy alone, followed by careful observation after best response.|
|5.||Patients with high-risk disease might receive induction therapy until best response, followed by consolidation therapy with allogeneic or autologous stem cell transplantation.|
These guidelines require validation by ongoing clinical trials; participation in clinical trials is the preferred choice, when possible.
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. 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]
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.
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:
Almost all ongoing clinical trials in the United States and Europe have implemented the low-dose dexamethasone schedule with or without other therapeutic agents.
Nine randomized prospective studies (including E-E1A00 and HOVON 50) involving more than 3,500 patients have been published in final or preliminary abstract form examining the introduction of thalidomide as induction therapy for previously untreated symptomatic patients with multiple myeloma.[16,17,18,19,20,21,22,23,24]
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.
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.[21,22,27,28,29,30,31]
Prospective electrophysiologic monitoring provides no clear benefit over clinical evaluation for the development of clinically significant neuropathy while on thalidomide.
|1.||A prospective randomized study of 351 relapsed patients compared lenalidomide, an analogue of thalidomide, plus high-dose dexamethasone with high-dose dexamethasone plus placebo.
|2.||Similarly, another randomized prospective trial (NCT00179647) of 353 previously treated patients favors the lenalidomide plus high-dose dexamethasone arm versus dexamethasone plus placebo.
|3.||A prospective randomized study (ECOG-E4A03) of 445 untreated symptomatic patients, published in abstract form only, 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).
Lenalidomide has substantially greater myelosuppression but less neuropathy than seen with thalidomide; however, both have the same tendency for DVT.[5,32,33] DVT prophylaxis with 81 mg of aspirin has been proposed, but randomized clinical trials have not confirmed any benefit for this recommendation.
|1.||A prospective randomized trial (VISTA) 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.
|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.
|3.||A prospective randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone.
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.[38,39,40,41][Level of evidence: 3iiiD]
Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.
Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results. The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[48,49,50]
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.[51,52,53,54][Level of evidence: 1iiA]
A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.[Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median OS 17 mo) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone or VAD.
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.
Options for combination regimens:
|1.||Bortezomib + dexamethasone (as demonstrated in ECOG-E1A05).[38,56]|
|2.||Lenalidomide + dexamethasone (as demonstrated in SWOG-SO777).[5,32,33]|
|3.||Bortezomib + lenalidomide + dexamethasone (as demonstrated in ECOG-E1A05, SWOG-SO777, EVOLUTION trial, and U.S. Intergroup/IFM trial).[38,56,57]|
|4.||Bortezomib + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).[58,59]|
|5.||Bortezomib + lenalidomide + cyclophosphamide + dexamethasone (as demonstrated in the EVOLUTION trial).|
|6.||Lenalidomide + cyclophosphamide + dexamethasone.|
|7.||Bortezomib + melphalan + prednisone.|
|8.||Bortezomib + liposomal doxorubicin.|
|9.||Melphalan + prednisone + thalidomide.[18,25]|
|10.||Melphalan + prednisone.[18,25]|
High-dose chemotherapy: Autologous bone marrow or peripheral stem cell transplantation
The failure of conventional therapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery made it possible for investigators to test very large doses of chemotherapy.
Based on the experience of treating thousands of patients in this way, it is possible to draw a few conclusions, including the following:
Single autologous bone marrow or peripheral stem cell transplantation
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,[66,67,68][Level of evidence: 1iiA] other trials have not shown any survival advantage.[69,70,71,72][Level of evidence: 1iiA]
Tandem autologous bone marrow or peripheral stem cell transplantation
|1.||A meta-analysis of six randomized clinical trials enrolling 1,803 patients compared single autologous hematopoietic cell transplantation with tandem autologous hematopoietic cell transplantation.
|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.
|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.
|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.
Interferon maintenance after stem cell transplantation
|1.||In a randomized study of 84 patients following autologous bone marrow transplantation, maintenance therapy with interferon showed a benefit in PFS (46 mo vs. 27 mo,P< .025) and OS (75% vs. 50%,P< .01).[Level of evidence: 1iiA]|
|2.||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.[Level of evidence: 1iiA]|
High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation
In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial OS rate was 28% at 7 years.[Level of evidence: 3iiiA]
Favorable prognostic features included the following:
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.[90,91,92,93]
Allogeneic marrow transplants have significant toxic effects (15%–40% mortality), but the possibility of a potent and possibly curative graft-versus-myeloma effect makes this procedure attractive.[93,94]
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.[95,96,97] Such strategies aim to maintain efficacy (so called graft-versus-tumor effect) while reducing transplant-related mortality.[98,99]
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.
|1.||In a single study,it was observed that maintenance therapy with MP prolonged the initial remission duration (31 mo) compared with no maintenance treatment (23 mo).
|2.||Maintenance interferon-alpha therapy has been reported in several studies to prolong initial remission duration.[101,102,103,104]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).Toxic effects in this population may be substantial and must be balanced against the potential benefits in response duration.|
|3.||Maintenance therapy with interferon showed a benefit in PFS (46 mo vs. 27 mo,P< .025) and OS (75% vs. 50%,P< .01) in a randomized study of 84 patients following autologous bone marrow transplantation.[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.[Level of evidence: 1iiA]|
|4.||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 mo vs. 5 mo,P = .003) and OS (36 mo vs. 26 mo,P = .05) for the patients receiving the higher-dose corticosteroids.[Level of evidence: 1iiA]|
|5.||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.
|6.||Two months after autologous transplantation, 597 patients younger than 65 years were randomly assigned to no maintenance, pamidronate, or pamidronate plus thalidomide.
|7.||After autologous transplantation, 129 patients were randomly assigned to indefinite prednisone versus indefinite prednisone with 12 months of thalidomide.
|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 mo of therapy,P = .015).[Level of evidence: 1iDiii] (For more information on bisphosphonate therapy, refer to the PDQ summary onPain.)|
|2.||A randomized comparison of pamidronate versus zoledronic acid in 518 patients with multiple myeloma showed equivalent efficacy in regard to skeletal-related complications.[Level of evidence: 1iDiii]|
Bisphosphonates are associated with infrequent long-term complications (in 3%–5% of patients), including osteonecrosis of the jaw and avascular necrosis of the hip.[112,113] (For more information on osteonecrosis of the jaw, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation.) These side effects must be balanced against the potential benefits of bisphosphonates when bone metastases are evident.
Lytic lesions of the spine should be radiated if any of the following are true:
Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. (For more information on back pain, refer to the PDQ summary on Pain.)
Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis and is rarely indicated.
Bisphosphonates are useful for slowing or reversing the osteopenia that is common in myeloma patients.
Current Clinical Trials
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.
|1.||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.|
|2.||Rajkumar SV, Kyle RA: Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 80 (10): 1371-82, 2005.|
|3.||Palumbo A, Rajkumar SV: Treatment of newly diagnosed myeloma. Leukemia 23 (3): 449-56, 2009.|
|4.||Goldschmidt H, Hegenbart U, Wallmeier M, et al.: Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma. Br J Haematol 98 (3): 736-44, 1997.|
|5.||Rajkumar SV, Jacobus S, Callander N, et al.: A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. [Abstract] Blood 110 (11): A-74, 2007.|
|6.||San Miguel JF, Schlag R, Khuageva NK, et al.: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359 (9): 906-17, 2008.|
|7.||Richardson PG, Sonneveld P, Schuster M, et al.: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110 (10): 3557-60, 2007.|
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|9.||San-Miguel JF, Richardson PG, Sonneveld P, et al.: Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 22 (4): 842-9, 2008.|
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|12.||Alexanian R, Dimopoulos MA, Delasalle K, et al.: Primary dexamethasone treatment of multiple myeloma. Blood 80 (4): 887-90, 1992.|
|13.||Kumar S, Lacy MQ, Dispenzieri A, et al.: Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant 34 (6): 485-90, 2004.|
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|15.||Shustik C, Belch A, Robinson S, et al.: A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136 (2): 203-11, 2007.|
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|17.||Barlogie B, Tricot G, Anaissie E, et al.: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354 (10): 1021-30, 2006.|
|18.||Palumbo A, Bringhen S, Liberati AM, et al.: Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 112 (8): 3107-14, 2008.|
|19.||Goldschmidt H, Sonneveld P, Breitkreuz I, et al.: HOVON 50/GMMG-HD3-trial: phase III study on the effect of thalidomide combined with high dose melphalan in myeloma patients up to 65 years. [Abstract] Blood 106 (11): A-424, 2005.|
|20.||Facon T, Mary J, Harousseau J, et al.: Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma. [Abstract] J Clin Oncol 24 (Suppl 18): A-1, 2006.|
|21.||Hulin C, Facon T, Rodon P, et al.: Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. [Abstract] Blood 110 (11): A-75, 2007.|
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|26.||Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111 (8): 3968-77, 2008.|
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|31.||Niesvizky R, Martínez-Baños D, Jalbrzikowski J, et al.: Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma. Leuk Lymphoma 48 (12): 2330-7, 2007.|
|32.||Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357 (21): 2123-32, 2007.|
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|35.||Argyriou AA, Iconomou G, Kalofonos HP: Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 112 (5): 1593-9, 2008.|
|36.||Richardson PG, Xie W, Mitsiades C, et al.: Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 27 (21): 3518-25, 2009.|
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|39.||Jagannath S, Richardson PG, Sonneveld P, et al.: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21 (1): 151-7, 2007.|
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|41.||Chang H, Trieu Y, Qi X, et al.: Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res 31 (6): 779-82, 2007.|
|42.||Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33 (2): 86-9, 1990.|
|43.||Segeren CM, Sonneveld P, van der Holt B, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 105 (1): 127-30, 1999.|
|44.||Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 71 (2): 326-30, 1995.|
|45.||Browman GP, Belch A, Skillings J, et al.: Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group. Br J Haematol 82 (3): 555-9, 1992.|
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|57.||Richardson P, Lonial S, Jakubowiak A, et al.: Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a phaseI/II study. [Abstract] Blood 112 (11): A-92, 2008.|
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|60.||Kumar S, Flinn IW, Noga SJ, et al.: Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the phase I/II multi-center EVOLUTION study. [Abstract] Blood 112 (11): A-93, 2008.|
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|65.||Lenhoff S, Hjorth M, Westin J, et al.: Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group. Br J Haematol 133 (4): 389-96, 2006.|
|66.||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.|
|67.||Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348 (19): 1875-83, 2003.|
|68.||Palumbo A, Bringhen S, Petrucci MT, et al.: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 104 (10): 3052-7, 2004.|
|69.||Segeren CM, Sonneveld P, van der Holt B, et al.: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 101 (6): 2144-51, 2003.|
|70.||Fermand JP, Katsahian S, Divine M, et al.: High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23 (36): 9227-33, 2005.|
|71.||Bladé J, Rosiñol L, Sureda A, et al.: High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106 (12): 3755-9, 2005.|
|72.||Barlogie B, Kyle RA, Anderson KC, et al.: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 24 (6): 929-36, 2006.|
|73.||Lévy V, Katsahian S, Fermand JP, et al.: A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 84 (4): 250-60, 2005.|
|74.||Koreth J, Cutler CS, Djulbegovic B, et al.: High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13 (2): 183-96, 2007.|
|75.||Pineda-Roman M, Barlogie B, Anaissie E, et al.: High-dose melphalan-based autotransplants for multiple myeloma: the Arkansas experience since 1989 in 3077 patients. Cancer 112 (8): 1754-64, 2008.|
|76.||Barlogie B, Tricot GJ, van Rhee F, et al.: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135 (2): 158-64, 2006.|
|77.||Barlogie B, Tricot G, Rasmussen E, et al.: Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies. Blood 107 (7): 2633-8, 2006.|
|78.||Barlogie B, Zangari M, Bolejack V, et al.: Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 6 (6): 469-74, 2006.|
|79.||Bruno B, Rotta M, Patriarca F, et al.: Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 113 (14): 3375-82, 2009.|
|80.||Rotta M, Storer BE, Sahebi F, et al.: Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 113 (14): 3383-91, 2009.|
|81.||Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al.: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst 101 (2): 100-6, 2009.|
|82.||Bruno B, Rotta M, Patriarca F, et al.: A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356 (11): 1110-20, 2007.|
|83.||Garban F, Attal M, Michallet M, et al.: Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 107 (9): 3474-80, 2006.|
|84.||Moreau P, Garban F, Attal M, et al.: Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood 112 (9): 3914-5, 2008.|
|85.||Rosiñol L, Pérez-Simón JA, Sureda A, et al.: A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 112 (9): 3591-3, 2008.|
|86.||Abdelkefi A, Ladeb S, Torjman L, et al.: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 111 (4): 1805-10, 2008.|
|87.||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.|
|88.||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.|
|89.||Gahrton G, Tura S, Ljungman P, et al.: Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13 (6): 1312-22, 1995.|
|90.||Tricot G, Vesole DH, Jagannath S, et al.: Graft-versus-myeloma effect: proof of principle. Blood 87 (3): 1196-8, 1996.|
|91.||Verdonck LF, Lokhorst HM, Dekker AW, et al.: Graft-versus-myeloma effect in two cases. Lancet 347 (9004): 800-1, 1996.|
|92.||Lokhorst HM, Schattenberg A, Cornelissen JJ, et al.: Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 18 (16): 3031-7, 2000.|
|93.||Reynolds C, Ratanatharathorn V, Adams P, et al.: Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27 (8): 801-7, 2001.|
|94.||Arora M, McGlave PB, Burns LJ, et al.: Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35 (12): 1133-40, 2005.|
|95.||Einsele H, Schäfer HJ, Hebart H, et al.: Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 121 (3): 411-8, 2003.|
|96.||Maloney DG, Molina AJ, Sahebi F, et al.: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102 (9): 3447-54, 2003.|
|97.||Badros A, Barlogie B, Morris C, et al.: High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 97 (9): 2574-9, 2001.|
|98.||Crawley C, Lalancette M, Szydlo R, et al.: Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 105 (11): 4532-9, 2005.|
|99.||Badros A, Barlogie B, Siegel E, et al.: Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20 (5): 1295-303, 2002.|
|100.||Belch A, Shelley W, Bergsagel D, et al.: A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 57 (1): 94-9, 1988.|
|101.||Mandelli F, Avvisati G, Amadori S, et al.: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 322 (20): 1430-4, 1990.|
|102.||Westin J, Rödjer S, Turesson I, et al.: Interferon alfa-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Cooperative Study Group. Br J Haematol 89 (3): 561-8, 1995.|
|103.||Osterborg A, Björkholm M, Björeman M, et al.: Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood 81 (6): 1428-34, 1993.|
|104.||Browman GP, Bergsagel D, Sicheri D, et al.: Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 13 (9): 2354-60, 1995.|
|105.||The Myeloma Trialists' Collaborative Group.: Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113 (4): 1020-34, 2001.|
|106.||Zee B, Cole B, Li T, et al.: Quality-adjusted time without symptoms or toxicity analysis of interferon maintenance in multiple myeloma. J Clin Oncol 16 (8): 2834-9, 1998.|
|107.||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.|
|108.||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.|
|109.||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.|
|110.||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.|
|111.||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.|
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|115.||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.|
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There are two main types of refractory myeloma patients:
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.
|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.|
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary has been reformatted. The content has been reorganized, and some content has been added.
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