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Clinical features, laboratory manifestations, and diagnosis of multiple myeloma

S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD


Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin. The plasma cells proliferate in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. The diagnosis of MM is often suspected because of one (or more) of the following clinical presentations:

Bone pain with lytic lesions discovered on routine skeletal films

An increased total serum protein concentration and/or the presence of a monoclonal protein in the urine or serum

Systemic signs or symptoms suggestive of malignancy, such as unexplained anemia

Hypercalcemia, which is either symptomatic or discovered incidentally


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Literature review current through: Oct 2015. | This topic last updated: Mar 26, 2015.
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  1. Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB. Multiple myeloma: causes and consequences of delay in diagnosis. QJM 2007; 100:635.
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5.
  3. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004; 127:299.
  4. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116:3724.
  5. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer 2011; 105:1684.
  6. Kyle RA, Therneau TM, Rajkumar SV, et al. Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades. Cancer 2004; 101:2667.
  7. Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic. Mayo Clin Proc 2010; 85:225.
  8. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21.
  9. Waxman AJ, Mink PJ, Devesa SS, et al. Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood 2010; 116:5501.
  10. Shirley MH, Sayeed S, Barnes I, et al. Incidence of haematological malignancies by ethnic group in England, 2001-7. Br J Haematol 2013; 163:465.
  11. Huang SY, Yao M, Tang JL, et al. Epidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years. Cancer 2007; 110:896.
  12. Bladé J, Kyle RA. Multiple myeloma in young patients: clinical presentation and treatment approach. Leuk Lymphoma 1998; 30:493.
  13. Lynch HT, Sanger WG, Pirruccello S, et al. Familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst 2001; 93:1479.
  14. Lynch HT, Watson P, Tarantolo S, et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol 2005; 23:685.
  15. Lynch HT, Ferrara K, Barlogie B, et al. Familial myeloma. N Engl J Med 2008; 359:152.
  16. Camp NJ, Werner TL, Cannon-Albright LA. Familial myeloma. N Engl J Med 2008; 359:1734.
  17. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009; 84:34.
  18. Landgren O, Kristinsson SY, Goldin LR, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 2009; 114:791.
  19. Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 2009; 114:785.
  20. Brown LM, Linet MS, Greenberg RS, et al. Multiple myeloma and family history of cancer among blacks and whites in the U.S. Cancer 1999; 85:2385.
  21. Maldonado JE, Kyle RA. Familial myeloma. Report of eight families and a study of serum proteins in their relatives. Am J Med 1974; 57:875.
  22. Deshpande HA, Hu XP, Marino P, et al. Anticipation in familial plasma cell dyscrasias. Br J Haematol 1998; 103:696.
  23. Grosbois B, Jego P, Attal M, et al. Familial multiple myeloma: report of fifteen families. Br J Haematol 1999; 105:768.
  24. Sobol H, Vey N, Sauvan R, et al. Re: familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst 2002; 94:461.
  25. Varettoni M, Corso A, Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol 2010; 21:325.
  26. Satta R, Casu G, Dore F, et al. Follicular spicules and multiple ulcers: cutaneous manifestations of multiple myeloma. J Am Acad Dermatol 2003; 49:736.
  27. Baz R, Alemany C, Green R, Hussein MA. Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer 2004; 101:790.
  28. Winearls CG. Acute myeloma kidney. Kidney Int 1995; 48:1347.
  29. Broderick P, Chubb D, Johnson DC, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat Genet 2012; 44:58.
  30. 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 2011; 29:3805.
  31. Szalat R, Arnulf B, Karlin L, et al. Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy. Blood 2011; 118:3777.
  32. Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol 2012; 8:43.
  33. Annesley TM, Burritt MF, Kyle RA. Artifactual hypercalcemia in multiple myeloma. Mayo Clin Proc 1982; 57:572.
  34. Petersen SL, Wagner A, Gimsing P. Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature. Am J Hematol 1999; 62:228.
  35. Fassas AB, Muwalla F, Berryman T, et al. Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations. Br J Haematol 2002; 117:103.
  36. Schluterman KO, Fassas AB, Van Hemert RL, Harik SI. Multiple myeloma invasion of the central nervous system. Arch Neurol 2004; 61:1423.
  37. Chang H, Sloan S, Li D, Keith Stewart A. Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions. Br J Haematol 2004; 127:280.
  38. Chamberlain MC, Glantz M. Myelomatous meningitis. Cancer 2008; 112:1562.
  39. Lee D, Kalff A, Low M, et al. Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains. Br J Haematol 2013; 162:371.
  40. Gozzetti A, Cerase A, Lotti F, et al. Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer 2012; 118:1574.
  41. Chen CI, Masih-Khan E, Jiang H, et al. Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents. Br J Haematol 2013; 162:483.
  42. Chang H, Bartlett ES, Patterson B, et al. The absence of CD56 on malignant plasma cells in the cerebrospinal fluid is the hallmark of multiple myeloma involving central nervous system. Br J Haematol 2005; 129:539.
  43. Kwan L, Wang C, Levitt L. Hyperammonemic encephalopathy in multiple myeloma. N Engl J Med 2002; 346:1674.
  44. Matsuzaki H, Hata H, Sonoki T, et al. Serum amino acid disturbance in multiple myeloma with hyperammonemia. Int J Hematol 1995; 61:131.
  45. Talamo G, Cavallo F, Zangari M, et al. Hyperammonemia and encephalopathy in patients with multiple myeloma. Am J Hematol 2007; 82:414.
  46. Otsuki T, Yamada O, Sakaguchi H, et al. In vitro excess ammonia production in human myeloma cell lines. Leukemia 1998; 12:1149.
  47. Bladé J, Lust JA, Kyle RA. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol 1994; 12:2398.
  48. Kastritis E, Zagouri F, Symeonidis A, et al. Preserved levels of uninvolved immunoglobulins are independently associated with favorable outcome in patients with symptomatic multiple myeloma. Leukemia 2014; 28:2075.
  49. Matta GM, Battaglio S, Dibello C, et al. Polyclonal immunoglobulin E levels are correlated with hemoglobin values and overall survival in patients with multiple myeloma. Clin Cancer Res 2007; 13:5348.
  50. Drayson M, Tang LX, Drew R, et al. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 2001; 97:2900.
  51. Singhal S, Vickrey E, Krishnamurthy J, et al. The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios. Blood 2009; 114:38.
  52. Katzmann JA, Abraham RS, Dispenzieri A, et al. Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005; 51:878.
  53. Dimopoulos MA, Kastritis E, Terpos E. Non-secretory myeloma: one, two, or more entities? Oncology (Williston Park) 2013; 27:930.
  54. Chawla SS, Kumar SK, Dispenzieri A, et al. Clinical course and prognosis of non-secretory multiple myeloma. Eur J Haematol 2015; 95:57.
  55. Larson D, Kyle RA, Rajkumar SV. Prevalence and monitoring of oligosecretory myeloma. N Engl J Med 2012; 367:580.
  56. Rajkumar SV, Merlini G, San Miguel JF. Haematological cancer: Redefining myeloma. Nat Rev Clin Oncol 2012; 9:494.
  57. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple myeloma. N Engl J Med 2011; 365:474.
  58. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538.
  59. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  60. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59:225.
  61. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23:2210.
  62. Kyrtsonis MC, Vassilakopoulos TP, Kafasi N, et al. Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma. Br J Haematol 2007; 137:240.
  63. Snozek CL, Katzmann JA, Kyle RA, et al. Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system. Leukemia 2008; 22:1933.
  64. Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 2013; 88:360.
  65. Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 2013; 27:941.
  66. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008; 111:785.
  67. D'Sa S, Abildgaard N, Tighe J, et al. Guidelines for the use of imaging in the management of myeloma. Br J Haematol 2007; 137:49.
  68. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117:4701.
  69. Dimopoulos MA, Hillengass J, Usmani S, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol 2015; 33:657.
  70. Kim PJ, Hicks RJ, Wirth A, et al. Impact of 18F-fluorodeoxyglucose positron emission tomography before and after definitive radiation therapy in patients with apparently solitary plasmacytoma. Int J Radiat Oncol Biol Phys 2009; 74:740.
  71. Tryciecky EW, Gottschalk A, Ludema K. Oncologic imaging: interactions of nuclear medicine with CT and MRI using the bone scan as a model. Semin Nucl Med 1997; 27:142.
  72. Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia 2009; 23:1545.
  73. Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc 1975; 50:29.
  74. Lahtinen R, Laakso M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992; 340:1049.
  75. Angtuaco EJ, Fassas AB, Walker R, et al. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004; 231:11.
  76. Kyle RA, Schreiman JS, McLeod RA, Beabout JW. Computed tomography in diagnosis and management of multiple myeloma and its variants. Arch Intern Med 1985; 145:1451.
  77. Moulopoulos LA, Dimopoulos MA. Magnetic resonance imaging of the bone marrow in hematologic malignancies. Blood 1997; 90:2127.
  78. Mahnken AH, Wildberger JE, Gehbauer G, et al. Multidetector CT of the spine in multiple myeloma: comparison with MR imaging and radiography. AJR Am J Roentgenol 2002; 178:1429.
  79. Baur-Melnyk A, Buhmann S, Becker C, et al. Whole-body MRI versus whole-body MDCT for staging of multiple myeloma. AJR Am J Roentgenol 2008; 190:1097.
  80. Baur A, Stäbler A, Nagel D, et al. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon? Cancer 2002; 95:1334.
  81. Mariette X, Zagdanski AM, Guermazi A, et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma. Br J Haematol 1999; 104:723.
  82. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007; 25:1121.
  83. Bäuerle T, Hillengass J, Fechtner K, et al. Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging. Radiology 2009; 252:477.
  84. Ailawadhi S, Abdelhalim AN, Derby L, et al. Extent of disease burden determined with magnetic resonance imaging of the bone marrow is predictive of survival outcome in patients with multiple myeloma. Cancer 2010; 116:84.
  85. Durie BG, Nguyen K, Joselson M, et al. Technetium-99-MIBI scanning in multiple myeloma: Comparison with PET (FDG) scanning. Cancer Res Ther Control 1998; 6:93.
  86. el-Shirbiny AM, Yeung H, Imbriaco M, et al. Technetium-99m-MIBI versus fluorine-18-FDG in diffuse multiple myeloma. J Nucl Med 1997; 38:1208.
  87. Bredella MA, Steinbach L, Caputo G, et al. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol 2005; 184:1199.
  88. Shortt CP, Gleeson TG, Breen KA, et al. Whole-Body MRI versus PET in assessment of multiple myeloma disease activity. AJR Am J Roentgenol 2009; 192:980.
  89. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010; 28:1606.
  90. Kastritis E, Moulopoulos LA, Terpos E, et al. The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (smoldering) multiple myeloma. Leukemia 2014; 28:2402.
  91. Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia 2014; 28:1902.
  92. van Lammeren-Venema D, Regelink JC, Riphagen II, et al. ¹⁸F-fluoro-deoxyglucose positron emission tomography in assessment of myeloma-related bone disease: a systematic review. Cancer 2012; 118:1971.
  93. McCarthy CS, Becker JA. Multiple myeloma and contrast media. Radiology 1992; 183:519.
  94. Pahade JK, LeBedis CA, Raptopoulos VD, et al. Incidence of contrast-induced nephropathy in patients with multiple myeloma undergoing contrast-enhanced CT. AJR Am J Roentgenol 2011; 196:1094.
  95. Smith A, Wisloff F, Samson D, et al. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol 2006; 132:410.
  96. 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 2003; 121:749.
  97. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009; 23:3.
  98. 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 2009; 23:215.
  99. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980; 302:1347.
  100. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346:564.
  101. Schuster SR, Rajkumar SV, Dispenzieri A, et al. IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia. Am J Hematol 2010; 85:853.
  102. Rajkumar SV, Gertz MA, Kyle RA. Primary systemic amyloidosis with delayed progression to multiple myeloma. Cancer 1998; 82:1501.
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