General Information About Plasma Cell Neoplasms
There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.
(Refer to the Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Incidence and Mortality
Estimated new cases and deaths from multiple myeloma in the United States in 2018:
- New cases: 30,770.
- Deaths: 12,770.
Clinical Presentation and Evaluation
|Plasma Cell Neoplasm||M Protein Type||Pathology||Clinical Presentation|
|Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.|
|MGUS||IgG kappa or lambda; or IgA kappa or lambda||<10% plasma cells in bone marrow||Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein) |
|Isolated plasmacytoma of bone||IgG kappa or lambda; or IgA kappa or gamma||Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site||Asymptomatic or symptomatic|
|Extramedullary plasmacytoma||IgG kappa or lambda; or IgA kappa or gamma||Solitary lesion of soft tissue; most commonly occurs in the nasopharynx, tonsils, or paranasal sinuses ||Asymptomatic or symptomatic|
|Multiple myeloma||IgG kappa or lambda; or IgA kappa or gamma||Often, multiple lesions of bone||Symptomatic|
Evaluation of patients with monoclonal (or myeloma) protein (M protein)
Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.[4,5] For this reason, when treatment is indicated, systemic treatment must be considered for all patients with symptomatic plasma cell neoplasms. Patients with MGUS or asymptomatic, smoldering myeloma do not require immediate treatment but must be followed carefully for signs of disease progression.
The major challenge is to separate the stable, asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[6,7]
Patients with a monoclonal (or myeloma) protein (M protein) in the serum and/or urine are evaluated by some of the following criteria:
- Measure and follow the serum M protein by serum electrophoresis or by specific immunoglobulin (Ig) assays; however, specific Ig quantification always overestimates the M protein because normal Ig are included in the result. For this reason, the preference is often that baseline and follow-up measurements of the M protein be done by the same method. Quantitative serum-free light chains (FLC) may be helpful to follow response if an M protein is not apparent.
- Measure and follow the amount of M-protein light chains excreted in the urine over 24 hours. Measure the total amount of protein excreted over 24 hours and multiply this value by the percentage of urine protein that is M protein, as determined by electrophoresis of concentrated urine protein. An easier, but less accurate, method uses a spot-urine protein electrophoresis.
- Identify the heavy and light chain of the M protein by immunofixation electrophoresis.
- Measure the hemoglobin, leukocyte, platelet, and differential counts.
- Determine the percentage of marrow plasma cells. Be aware that marrow plasma-cell distribution may vary in different sites. Bone marrow is often sent for cytogenetics and fluorescence in situ hybridization testing for genetic markers of high-risk disease. (Refer to the Genetic Factors and Risk Group section of this summary for more information.)
- Measure serum-free kappa and lambda light chain. This is especially useful in cases of oligosecretory plasma-cell dyscrasia or for following cases of light-chain amyloidosis. The FLC ratio of over 100 can predict a greater than 70% progression within 2 years in patients with smoldering myeloma.
- If clinically warranted, take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
- Evaluate renal function with serum creatinine and a creatinine clearance.
- Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light-chain deposition disease, result in the nonselective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern with a preponderance of albumin.
In most myeloma patients, the glomeruli function normally allows only the small molecular weight proteins, such as light chains, to filter into the urine. The concentration of protein in the tubules increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light-chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
- Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity.
- Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones.
- Obtain a spinal magnetic resonance imaging (MRI) scan (or spinal computed tomography [CT] or positron emission tomography (PET)–CT scan depending on availability) if the skeletal survey is negative.[11-13] At diagnosis, whole-body PET scan or MRI of the total spine and pelvis appears equally efficacious in the detection of bone lesions.
- 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.
- Measure serum albumin and beta-2-microglobulin as independent prognostic factors.[16,17]
- The presence of circulating myeloma cells is considered a poor prognostic factor. Primary plasma cell leukemia has a particularly poor prognosis.[19,20]
These initial studies are often compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment, or getting worse.
As mentioned before, the major challenge is to separate the stable, asymptomatic group of patients who do not require treatment from patients with progressive, symptomatic myeloma who may need to be treated immediately.[6,7,21]
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and have fewer than 10% of plasma cells in the bone marrow.[2,22-24] Patients with smoldering myeloma have similar characteristics but may have more than 10% of plasma cells in the bone marrow.
These types of patients are asymptomatic and do not need to be treated. Patients with MGUS and risk factors for disease progression, however, must be followed carefully because they are more likely to develop myeloma (most commonly), amyloidosis, lymphoplasmacytic lymphoma, or chronic lymphocytic leukemia and may then require therapy.[24-26]
Virtually all cases of multiple myeloma are preceded by a gradually rising level of MGUS.[27-29] The annual risk of progression of MGUS to a lymphoid or plasma cell malignancy ranges from 0.5% to 1.0% in population-based cohorts.[30,31] This risk ranges from 2% to more than 20% in higher-risk patients.
Risk factors that predict disease progression include the following:
- An abnormal serum-FLC ratio.
- Non-IgG class MGUS.
- A high serum-M protein level (≥15 g/L).
A Swedish cohort study confirmed the higher-risk factors of abnormal serum-FLC ratio and the high serum–monoclonal protein level. They described the additional risk factor of immunoparesis, which is defined as the reciprocal depression of the other Ig classes (if a patient has an IgG kappa M-protein, the IgM and IgA would be below normal levels with immunoparesis). Incorporation of gene-expression profiles to better assess risk is also under clinical evaluation.
Monoclonal gammopathies that cause organ damage, particularly to the kidney, heart, or peripheral nerves require immediate therapy with the same strategies applied for the conventional plasma-cell dyscrasias. A monoclonal gammopathy causing renal dysfunction—by direct antibody deposition or amyloidosis—is referred to as monoclonal gammopathy of renal significance. Rising serum creatinine, dropping glomerular filtration rates, and increasing urinary–albumin excretion are all parameters that may signify renal damage and are assessed prospectively for high-risk MGUS patients. Although the N-terminal pro-brain natriuretic peptide is a very sensitive marker for amyloid involvement in the heart, the low specificity must be noted. These extra tests are included with the M-protein level, FLC levels, and FLC ratio when following patients with MGUS.
Isolated Plasmacytoma of Bone
The patient has an isolated plasmacytoma of the bone if the following are found:
- A solitary lytic lesion of plasma cells on skeletal survey in an otherwise asymptomatic patient.
- A bone marrow examination from an uninvolved site contains less than 10% plasma cells.[34-36] The absence of plasma cells on flow cytometry of the bone marrow suggests a low (<10%) risk of recurrence after radiation therapy of the isolated bone plasmacytoma.
MRI may reveal unsuspected bony lesions that were undetected on standard radiographs. MRI scans of the total spine and pelvis may identify other bony lesions.
A patient has extramedullary plasmacytoma if the following are found:
- Isolated plasma-cell tumors of soft tissues, most commonly occurring in the tonsils, nasopharynx, or paranasal sinuses.
- Negative findings on skeletal x-rays and bone marrow biopsy.[39-41]
Multiple myeloma 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 rate of 3%. Even further improvements in prognosis have occurred because of the introduction of newer therapies such as pulse corticosteroids, thalidomide, lenalidomide, bortezomib, and autologous and allogeneic stem cell transplantation, with median survivals now exceeding 45 to 60 months.[42-45] Patients with plasma cell leukemia or with soft tissue plasmacytomas (often with plasmablastic morphology) in association with multiple myeloma have poor outcomes.[19,46]
Multiple myeloma is potentially curable when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma. (Refer to the Isolated Plasmacytoma of Boneand Extramedullary Plasmacytoma sections of this summary for more information.)
Amyloidosis Associated With Plasma Cell Neoplasms
Multiple myeloma and other plasma cell neoplasms may cause a condition called amyloidosis. Primary amyloidosis can result in severe organ dysfunction especially in the kidney, heart, or peripheral nerves. Clinical symptoms and signs include the following:
- Enlarged tongue.
- Lower-extremity paresthesias.
Accurate diagnosis of amyloidosis requires histologic evidence of amyloid deposits and characterization of the amyloidogenic protein using immunoelectron microscopy. In one series of 745 consecutive patients, 20% of patients with non-amyloid light chain amyloidosis (usually transthyretin) had an innocent monoclonal gammopathy, indicating the significant risk of misdiagnosis.
Elevated serum levels of cardiac troponins, amino-terminal fragment brain-type natriuretic peptide, and serum-FLC are poor prognostic factors.[48,49] A proposed staging system for primary systemic amyloidosis based on these serum levels requires independent and prospective confirmation. An increase in levels of serum-FLC over many years can precede the clinical diagnosis of amyloid light-chain (AL) amyloidosis.
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare paraneoplastic condition associated with a plasma cell dyscrasia of early or late stage. The acronym describes a constellation of findings often marked by polyneuropathy, organomegaly (usually splenomegaly), endocrinopathy, monoclonal plasma cell dyscrasia, and skin changes. Both sclerotic or lytic bone lesions and lymphadenopathy (with possible Castleman’s histology) may be identified. Anecdotal reports suggest remissions using myeloma-directed therapy.[52-55]
- American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 2018.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Larsen JT, Kumar SK, Dispenzieri A, et al.: Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 27 (4): 941-6, 2013. [PUBMED Abstract]
- 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]
- 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]
- Kyle RA, Durie BG, Rajkumar SV, et al.: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 24 (6): 1121-7, 2010. [PUBMED Abstract]
- Moreau P, Attal M, Caillot D, et al.: Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study. J Clin Oncol 35 (25): 2911-2918, 2017. [PUBMED Abstract]
- 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]
- Greipp PR: Advances in the diagnosis and management of myeloma. Semin Hematol 29 (3 Suppl 2): 24-45, 1992. [PUBMED Abstract]
- 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]
- Greipp PR, Witzig T: Biology and treatment of myeloma. Curr Opin Oncol 8 (1): 20-7, 1996. [PUBMED Abstract]
- Pagano L, Valentini CG, De Stefano V, et al.: Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. Ann Oncol 22 (7): 1628-35, 2011. [PUBMED Abstract]
- Royer B, Minvielle S, Diouf M, et al.: Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome. J Clin Oncol 34 (18): 2125-32, 2016. [PUBMED Abstract]
- Rajkumar SV, Dimopoulos MA, Palumbo A, et al.: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15 (12): e538-48, 2014. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 335 (2): 91-7, 1996. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Bladé J, Rosiñol L, Cibeira MT: Are all myelomas preceded by MGUS? Blood 113 (22): 5370, 2009. [PUBMED Abstract]
- 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]
- Turesson I, Kovalchik SA, Pfeiffer RM, et al.: Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood 123 (3): 338-45, 2014. [PUBMED Abstract]
- Dhodapkar MV, Sexton R, Waheed S, et al.: Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123 (1): 78-85, 2014. [PUBMED Abstract]
- Merlini G: Determining the significance of MGUS. Blood 123 (3): 305-7, 2014. [PUBMED Abstract]
- 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]
- Dimopoulos MA, Moulopoulos LA, Maniatis A, et al.: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Blood 96 (6): 2037-44, 2000. [PUBMED Abstract]
- Dimopoulos MA, Hamilos G: Solitary bone plasmacytoma and extramedullary plasmacytoma. Curr Treat Options Oncol 3 (3): 255-9, 2002. [PUBMED Abstract]
- Paiva B, Chandia M, Vidriales MB, et al.: Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma. Blood 124 (8): 1300-3, 2014. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Alexiou C, Kau RJ, Dietzfelbinger H, et al.: Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 85 (11): 2305-14, 1999. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Palumbo A, Anderson K: Multiple myeloma. N Engl J Med 364 (11): 1046-60, 2011. [PUBMED Abstract]
- Bladé J, Fernández de Larrea C, Rosiñol L, et al.: Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 29 (28): 3805-12, 2011. [PUBMED Abstract]
- Fernández de Larrea C, Verga L, Morbini P, et al.: A practical approach to the diagnosis of systemic amyloidoses. Blood 125 (14): 2239-44, 2015. [PUBMED Abstract]
- Kumar S, Dispenzieri A, Lacy MQ, et al.: Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 30 (9): 989-95, 2012. [PUBMED Abstract]
- Pinney JH, Lachmann HJ, Bansi L, et al.: Outcome in renal Al amyloidosis after chemotherapy. J Clin Oncol 29 (6): 674-81, 2011. [PUBMED Abstract]
- Weiss BM, Hebreo J, Cordaro DV, et al.: Increased serum free light chains precede the presentation of immunoglobulin light chain amyloidosis. J Clin Oncol 32 (25): 2699-704, 2014. [PUBMED Abstract]
- Dispenzieri A: POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86 (7): 591-601, 2011. [PUBMED Abstract]
- Humeniuk MS, Gertz MA, Lacy MQ, et al.: Outcomes of patients with POEMS syndrome treated initially with radiation. Blood 122 (1): 68-73, 2013. [PUBMED Abstract]
- Li J, Zhang W, Jiao L, et al.: Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood 117 (24): 6445-9, 2011. [PUBMED Abstract]
- Royer B, Merlusca L, Abraham J, et al.: Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol 88 (3): 207-12, 2013. [PUBMED Abstract]
- Misawa S, Sato Y, Katayama K, et al.: Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 15 (11): 1129-37, 2016. [PUBMED Abstract]