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Licensed Unlicensed Requires Authentication Published by De Gruyter July 24, 2023

Recommendations for the study of monoclonal gammopathies in the clinical laboratory. A consensus of the Spanish Society of Laboratory Medicine and the Spanish Society of Hematology and Hemotherapy. Part I: Update on laboratory tests for the study of monoclonal gammopathies

  • María C. Cárdenas ORCID logo EMAIL logo , Ramón García-Sanz , Noemí Puig , David Pérez-Surribas , Juan Flores-Montero , María Ortiz-Espejo , Javier de la Rubia and Elena Cruz-Iglesias

Abstract

Monoclonal gammopathies (MG) are characterized by the proliferation of plasma cells that produce identical abnormal immunoglobulins (intact or some of their subunits). This abnormal immunoglobulin component is called monoclonal protein (M-protein), and is considered a biomarker of proliferative activity. The identification, characterization and measurement of M-protein is essential for the management of MG. We conducted a systematic review of the different tests and measurement methods used in the clinical laboratory for the study of M-protein in serum and urine, the biochemistry and hematology tests necessary for clinical evaluation, and studies in bone marrow, peripheral blood and other tissues. This review included literature published between 2009 and 2022. The paper discusses the main methodological characteristics and limitations, as well as the purpose and clinical value of the different tests used in the diagnosis, prognosis, monitoring and assessment of treatment response in MG. Included are methods for the study of M-protein, namely electrophoresis, measurement of immunoglobulin levels, serum free light chains, immunoglobulin heavy chain/light chain pairs, and mass spectrometry, and for the bone marrow examination, morphological analysis, cytogenetics, molecular techniques, and multiparameter flow cytometry.


Corresponding author: María C. Cárdenas, PhD, Department of Clinical Analysis, Institute of Laboratory Medicine, IdSSC, Hospital Clinico San Carlos, Madrid, Spain; and Protein Commission, Spanish Society of Laboratory Medicine (SEQCML), Barcelona, Spain, E-mail:

  1. Research funding: None declared.

  2. Author contribution: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: María C Cárdenas, Noemí Puig, David Pérez-Surribas, Juan Flores-Montero, María Ortiz-Espejo and Elena Cruz-Iglesias state no conflict of interest. Ramón García-Sanz states: Honoraria: Amgen, Millennium/Takeda, Janssen, Incyte, Astellas, BeiGene, AstraZeneca, Pfizer. Research funding: Novartis, Gilead, Astellas, Janssen. Advisory boards: Amgen, Pharmacyclics, Millennium/Takeda. Research support / PI: Spanish National Health System, Regional Health System (Castilla y León), Spanish Association Against Cancer. Ex-president: Spanish Society of Hematology and Hemotherapy. Employee: Spanish National Health System. Javier De la Rubia states: Honoraria: Takeda, Janssen, BMS, Pfizer, GSK, Oncopeptide, Sanofi. Research funding: Takeda. Advisory boards: Amgen, Janssen, Sanofi, GSK. Employee: Spanish National Health System.

  4. Informed consent: Not applicable.

  5. Research ethics: Not applicable.

References

1. Campo, E, Jaffe, ES, Cook, JR, Quintanilla-Martinez, L, Swerdlow, SH, Anderson, KC, et al.. The international consensus classification of mature lymphoid neoplasms: a report from the clinical advisory committee. Blood 2022;140:1229–53. https://doi.org/10.1182/BLOOD.2022015851.Search in Google Scholar PubMed PubMed Central

2. Alaggio, R, Amador, C, Anagnostopoulos, I, Attygalle, AD, Araujo, IBde O, Berti, E, et al.. The 5th edition of the world health organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia 2022;36:1720–48. https://doi.org/10.1038/S41375-022-01620-2.Search in Google Scholar PubMed PubMed Central

3. Mullikin, TC, Rajkumar, SV, Dispenzieri, A, Buadi, FK, Lacy, MQ, Lin, Y, et al.. Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 2016;91:473–5. https://doi.org/10.1002/ajh.24319.Search in Google Scholar PubMed PubMed Central

4. Manson, GV, Campagnaro, E, Balog, A, Kaplan, D, Sommers, SR, Fu, P, et al.. Secondary MGUS after autologous hematopoietic progenitor cell transplantation in plasma cell myeloma: a matter of undetermined significance. Bone Marrow Transplant 2012;47:1212–6. https://doi.org/10.1038/bmt.2011.244.Search in Google Scholar PubMed

5. Mitus, AJ, Stein, R, Rappeport, JM, Antin, JH, Antin, JH, Weinstein, HJ, et al.. Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood 1989;74:2764–8. https://doi.org/10.1182/blood.v74.8.2764.2764.Search in Google Scholar

6. Rajkumar, SV, Dimopoulos, MA, Palumbo, A, Blade, J, Merlini, G, Mateos, MV, et al.. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–48. https://doi.org/10.1016/S1470-2045(14)70442-5.Search in Google Scholar PubMed

7. Kyle, RA, Therneau, TM, Rajkumar, SV, Larson, DR, Plevak, MF, Offord, JR, et al.. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362–9. https://doi.org/10.1056/nejmoa054494.Search in Google Scholar PubMed

8. van de Donk, NWCJ, Palumbo, A, Johnsen, HE, Engelhardt, M, Gay, F, Gregersen, H, et al.. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network. Haematologica 2014;99:984–96. https://doi.org/10.3324/haematol.2013.100552.Search in Google Scholar PubMed PubMed Central

9. Kyle, RA, Larson, DR, Therneau, TM, Dispenzieri, A, Kumar, S, Cerhan, JR, et al.. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med 2018;378:241–9. https://doi.org/10.1056/nejmoa1709974.Search in Google Scholar PubMed PubMed Central

10. El-Khoury, H, Lee, DJ, Alberge, JB, Redd, R, Cea-Curry, CJ, Perry, J, et al.. Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study. Lancet Haematol 2022;9:e340–9. https://doi.org/10.1016/S2352-3026(22)00069-2.Search in Google Scholar PubMed PubMed Central

11. Palladini, G, Schönland, S, Merlini, G, Milani, P, Jaccard, A, Bridoux, F, et al.. The management of light chain (AL) amyloidosis in Europe: clinical characteristics, treatment patterns, and efficacy outcomes between 2004 and 2018. Blood Cancer J 2023;13:19. https://doi.org/10.1038/S41408-023-00789-8.Search in Google Scholar

12. Sabinot, A, Ghetti, G, Pradelli, L, Bellucci, S, Lausi, A, Palladini, G. State-of-the-art review on AL amyloidosis in Western Countries: epidemiology, health economics, risk assessment and therapeutic management of a rare disease. Blood Rev 2023;59. https://doi.org/10.1016/J.BLRE.2023.101040.Search in Google Scholar

13. Kyle, RA, Gertz, MA, Witzig, TE, Lust, JA, Lacy, MQ, Dispenzieri, A, et al.. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21–33. https://doi.org/10.4065/78.1.21.Search in Google Scholar PubMed

14. Landgren, O, Kyle, RA, Pfeiffer, RM, Katzmann, JA, Caporaso, NE, Hayes, RB, et al.. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009;113:5412–7. https://doi.org/10.1182/blood-2008-12-194241.Search in Google Scholar PubMed PubMed Central

15. Weiss, BM, Abadie, J, Verma, P, Howard, RS, Kuehl, WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009;113:5418–22. https://doi.org/10.1182/blood-2008-12-195008.Search in Google Scholar PubMed PubMed Central

16. Kyle, RA, Remstein, ED, Therneau, TM, Dispenzieri, A, Kurtin, PJ, Hodnefield, JM, et al.. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582–90. https://doi.org/10.1056/NEJMoa070389.Search in Google Scholar PubMed

17. Leung, N, Bridoux, F, Hutchison, CA, Nasr, SH, Cockwell, P, Fermand, JP, et al.. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012;120:4292–5. https://doi.org/10.1182/blood-2012-07-445304.Search in Google Scholar PubMed

18. Fermand, JP, Bridoux, F, Dispenzieri, A, Jaccard, A, Kyle, RA, Leung, N, et al.. Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. Blood 2018;132:1478–85. https://doi.org/10.1182/blood-2018-04-839480.Search in Google Scholar PubMed

19. Kyle, RA, Durie, BGM, Rajkumar, SV, Landgren, O, Blade, J, Merlini, G, 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 2010;24:1121–7. https://doi.org/10.1038/leu.2010.60.Search in Google Scholar PubMed PubMed Central

20. Mateos, MV, Kumar, S, Dimopoulos, MA, González-Calle, V, Kastritis, E, Hajek, R, et al.. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J 2020;10. https://doi.org/10.1038/s41408-020-00366-3.Search in Google Scholar PubMed PubMed Central

21. Kumar, S, Paiva, B, Anderson, KC, Durie, B, Landgren, O, Moreau, P, et al.. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328–46. https://doi.org/10.1016/s1470-2045(16)30206-6.Search in Google Scholar PubMed

22. Owen, RG, Kyle, RA, Stone, MJ, Rawstron, AC, Leblond, V, Merlini, G, et al.. Response assessment in waldenstrom macroglobulinaemia: update from the VIth international workshop. Br J Haematol 2013;160:171–6. https://doi.org/10.1111/bjh.12102.Search in Google Scholar PubMed

23. Palladini, G, Dispenzieri, A, Gertz, MA, Kumar, S, Wechalekar, A, Hawkins, PN, et al.. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541–9. https://doi.org/10.1200/JCO.2011.37.7614.Search in Google Scholar PubMed

24. Martínez-Brú, C, García-Sanz, R, Martinez-López, J. Recomendaciones para el estudio de las gammapatías monoclonales. Documentos de La SEQC 2009:30–40.Search in Google Scholar

25. Tate, J, Caldwell, G, Daly, J, Gillis, D, Jenkins, M, Jovanovich, S, et al.. Recommendations for standardized reporting of protein electrophoresis in Australia and New Zealand. Ann Clin Biochem 2012;49:242–56. https://doi.org/10.1258/acb.2011.011158.Search in Google Scholar PubMed

26. Ma, T, Piao, Z, Jin, S, Kwak, Y. Differential expression of serum proteins in multiple myeloma. Exp Ther Med 2019;17:649–56. https://doi.org/10.3892/etm.2018.7010.Search in Google Scholar PubMed PubMed Central

27. Dispenzieri, A, Kyle, R, Merlini, G, Miguel, JS, Ludwig, H, Hajek, R, et al.. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215–24. https://doi.org/10.1038/leu.2008.307.Search in Google Scholar PubMed

28. Seaux, L, Van Houcke, S, Dumoulin, E, Fiers, T, Lecocq, E, Delanghe, JR. Dual-wavelength recording, a simple algorithm to eliminate interferences due to UV-absorbing substances in capillary electrophoresis. Electrophoresis 2014;35:2248–52. https://doi.org/10.1002/elps.201400259.Search in Google Scholar PubMed

29. Regeniter, A, Siede, WH. Peaks and tails: evaluation of irregularities in capillary serum protein electrophoresis. Clin Biochem 2018;51:48–55. https://doi.org/10.1016/j.clinbiochem.2017.09.017.Search in Google Scholar PubMed

30. Bird, J, Behrens, J, Westin, J, Turesson, I, Drayson, M, Beetham, R, 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 2009;147:22–42. https://doi.org/10.1111/j.1365-2141.2009.07807.x.Search in Google Scholar PubMed

31. Willrich, MAV, Murray, DL, Kyle, RA. Laboratory testing for monoclonal gammopathies: focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Clin Biochem 2018;51:38–47. https://doi.org/10.1016/j.clinbiochem.2017.05.001.Search in Google Scholar PubMed

32. Aksungar, FB, Ayer, M, Serteser, M, Coskun, A, Unsal, I. A triclonal gammopathy in a relapsing multiple myeloma patient, detected by immunosubtraction method. Ann Clin Biochem 2014;51:606–10. https://doi.org/10.1177/0004563213512801.Search in Google Scholar PubMed

33. Smith, J, Raines, G, Schneider, HG. A comparison between high resolution serum protein electrophoresis and screening immunofixation for the detection of monoclonal gammopathies in serum. Clin Chem Lab Med 2018;56:256–63. https://doi.org/10.1515/cclm-2017-0266.Search in Google Scholar PubMed

34. Litwin, CM, Anderson, SK, Philips, G, Martins, TB, Jaskowski, TD, Hill, HR. Comparison of capillary zone and immunosubtraction with agarose gel and immunofixation electrophoresis for detecting and identifying monoclonal gammopathies. Am J Clin Pathol 1999;112:411–7. https://doi.org/10.1093/ajcp/112.3.411.Search in Google Scholar PubMed

35. Katzmann, JA. Screening panels for monoclonal gammopathies: time to change. Clin Biochem Rev 2009;30:105–11.Search in Google Scholar

36. Willrich, MAV, Katzmann, JA. Laboratory testing requirements for diagnosis and follow-up of multiple myeloma and related plasma cell dyscrasias. Clin Chem Lab Med 2016;54:907–19. https://doi.org/10.1515/cclm-2015-0580.Search in Google Scholar PubMed

37. Murray, DL, Seningen, JL, Dispenzieri, A, Snyder, MR, Kyle, RA, Rajkumar, SV, et al.. Laboratory persistence and clinical progression of small monoclonal abnormalities. Am J Clin Pathol 2012;138:609–13. https://doi.org/10.1309/AJCPT6OWWMHITA1Y.Search in Google Scholar PubMed PubMed Central

38. Vernocchi, A, Longhi, E, Lippi, G, Gelsumini, S. Increased monoclonal components: prevalence in an Italian population of 44 474 outpatients detected by capillary electrophoresis. J Med Biochem 2016;35:50–4. https://doi.org/10.1515/jomb-2015-0007.Search in Google Scholar PubMed PubMed Central

39. Jacobs, JFM, Turner, KA, Graziani, MS, Frinack, JL, Ettore, MW, Tate, JR, et al.. An international multi-center serum protein electrophoresis accuracy and M-protein isotyping study. Part II: limit of detection and follow-up of patients with small M-proteins. Clin Chem Lab Med 2020;58:547–59. https://doi.org/10.1515/cclm-2019-1105.Search in Google Scholar PubMed

40. Murata, K, McCash, SI, Carroll, B, Lesokhin, AM, Hassoun, H, Lendvai, N, et al.. Treatment of multiple myeloma with monoclonal antibodies and the dilemma of false positive M-spikes in peripheral blood. Clin Biochem 2018;51:66–71. https://doi.org/10.1016/j.clinbiochem.2016.09.015.Search in Google Scholar PubMed PubMed Central

41. McCudden, CR, Voorhees, PM, Hainsworth, SA, Whinna, HC, Chapman, JF, Hammett-Stabler, CA, et al.. Interference of monoclonal antibody therapies with serum protein electrophoresis tests. Clin Chem 2010;56:1897–9. https://doi.org/10.1373/clinchem.2010.152116.Search in Google Scholar PubMed

42. Van De Donk, NWCJ, Otten, HG, El Haddad, O, Axel, A, Sasser, AK, Croockewit, S, et al.. Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA). Clin Chem Lab Med 2016;54:1105–9. https://doi.org/10.1515/cclm-2015-0888.Search in Google Scholar PubMed

43. Genzen, JR, Murray, DL, Abel, G, Meng, QH, Baltaro, RJ, Rhoads, DD, et al.. Screening and diagnosis of monoclonal gammopathies: an international survey of laboratory practice. Arch Pathol Lab Med 2018;142:507–15. https://doi.org/10.5858/arpa.2017-0128-CP.Search in Google Scholar PubMed

44. Pérez Surribas, D, Cárdenas Fernández, MC, Zapico Muñiz, D. Recomendaciones sobre la separación electroforética de las proteínas plasmáticas en suero. Recomendación (2014). Documentos de La SEQC 2015:91–104.Search in Google Scholar

45. Clavijo, A, Ryan, N, Xu, H, Singh, G. Measurement of monoclonal immunoglobulin protein concentration in serum protein electrophoresis: comparison of automated vs. manual/human readings. Lab Med 2020;51:252–8. https://doi.org/10.1093/LABMED/LMZ055.Search in Google Scholar PubMed

46. Turner, KA, Frinack, JL, Ettore, MW, Tate, JR, Graziani, MS, Jacobs, JFM, et al.. An international multi-center serum protein electrophoresis accuracy and M-protein isotyping study. Part I: factors impacting limit of quantitation of serum protein electrophoresis. Clin Chem Lab Med 2020;58:533–46. https://doi.org/10.1515/cclm-2019-1104.Search in Google Scholar PubMed

47. Cárdenas Fernández, MC, Pérez Surribas, D, Pérez Garay, R, Jiménez Jiménez, J, Gella Concustell, A, Zapico Muñiz, E, et al.. Vertical cutoff methods in serum protein electrophoresis for the measurement of monoclonal protein concentrations: which is best? Clin Chim Acta 2020;510:573–80. https://doi.org/10.1016/j.cca.2020.07.051.Search in Google Scholar PubMed

48. Luraschi, P, Infusino, I, Merlotti, C, Franzini, C. Analytical variation in the measurement of serum monoclonal component by capillary electrophoresis. Clin Chim Acta 2004;349:151–6. https://doi.org/10.1016/j.cccn.2004.06.016.Search in Google Scholar PubMed

49. Vallés Díez, I, Fernández-Montes, BG, Cárdenas Fernández, MC, Arroyo Fernández, M. Evaluación de la electroforesis capilar como método de detección y medida de proteína de Bence Jones. Rev. Del Lab. Clin. 2013;6:60–7. https://doi.org/10.1016/j.labcli.2013.01.004.Search in Google Scholar

50. Natali, P, Cigliana, G, Napodano, C, Basile, V, Debbia, D, Pocino, K, et al.. The dark side of current analytic methods for Bence Jones Proteinuria. Eur Rev Med Pharmacol Sci 2022;26:6777–86. https://doi.org/10.26355/EURREV_202209_29779.Search in Google Scholar PubMed

51. Basset, M, Milani, P, Ferretti, VV, Nuvolone, M, Foli, A, Benigna, F, et al.. Prospective urinary albumin/creatinine ratio for diagnosis, staging, and organ response assessment in renal AL amyloidosis: results from a large cohort of patients. Clin Chem Lab Med 2022;60:386–93. https://doi.org/10.1515/CCLM-2021-0912/PDF.Search in Google Scholar

52. Murray, DL, Ryu, E, Snyder, MR, Katzmann, JA. Quantitation of serum monoclonal proteins: relationship between agarose gel electrophoresis and immunonephelometry. Clin Chem 2009;55:1523–9. https://doi.org/10.1373/clinchem.2009.124461.Search in Google Scholar PubMed

53. Milani, P, Palladini, G, Merlini, G. Serum-free light-chain analysis in diagnosis and management of multiple myeloma and related conditions. Scand J Clin Lab Invest 2016;76:S113–8. https://doi.org/10.1080/00365513.2016.1210337.Search in Google Scholar PubMed

54. Tate, JR. The paraprotein - an enduring biomarker. Clin Biochem Rev 2019;40:5–22.Search in Google Scholar

55. Rajkumar, SV. Evolving diagnostic criteria for multiple myeloma. Hematology Am Soc Hematol Educ Program 2015;2015:272–8. https://doi.org/10.1182/ASHEDUCATION-2015.1.272.Search in Google Scholar

56. Keren, DF, Bocsi, G, Billman, BL, Etzell, J, Faix, JD, Kumar, S, et al.. Laboratory detection and initial diagnosis of monoclonal gammopathies: guideline from the college of American pathologists in collaboration with the American association for clinical chemistry and the American society for clinical pathology. Arch Pathol Lab Med 2022;146:575–90. https://doi.org/10.5858/arpa.2020-0794-cp.Search in Google Scholar PubMed

57. Katzmann, JA. Detection of M proteins. In: Multiple myeloma: diagnosis and treatment. New York: Springer; 2014. 17–26 pp.10.1007/978-1-4614-8520-9_2Search in Google Scholar

58. Kastritis, E, Zagouri, F, Symeonidis, A, Roussou, M, Sioni, A, Pouli, A, et al.. Preserved levels of uninvolved immunoglobulins are independently associated with favorable outcome in patients with symptomatic multiple myeloma. Leukemia 2014;28:2075–9. https://doi.org/10.1038/leu.2014.110.Search in Google Scholar PubMed

59. Miyazaki, K, Suzuki, K. Abnormal heavy/light chain ratio and matched pair suppression increase residual disease detection sensitivity in patients with multiple myeloma with deep responses. Clin Lymphoma, Myeloma & Leukemia 2018;18:293–6. https://doi.org/10.1016/j.clml.2018.01.008.Search in Google Scholar PubMed

60. Ríos-Tamayo, R, Puig, N, Algarín, M, García de Veas Silva, JL, Barbosa, N, Encinas, C, et al.. The current role of the heavy/light chain assay in the diagnosis, prognosis and monitoring of multiple myeloma: an evidence-based approach. Diagnostics 2021;11:2020. https://doi.org/10.3390/diagnostics11112020.Search in Google Scholar PubMed PubMed Central

61. Burgos, L, Puig, N, Cedena, MT, Mateos, MV, Lahuerta, JJ, Paiva, B, et al.. Measurable residual disease in multiple myeloma: ready for clinical practice? J Hematol Oncol 2020;13:82. https://doi.org/10.1186/S13045-020-00911-4.Search in Google Scholar PubMed PubMed Central

62. Munshi, NC, Avet-Loiseau, H, Anderson, KC, Neri, P, Paiva, B, Samur, M, et al.. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv 2020;4:5988–99. https://doi.org/10.1182/bloodadvances.2020002827.Search in Google Scholar PubMed PubMed Central

63. Paiva, B, Puig, N, Cedena, MT, Rosiñol, L, Cordón, L, Vidriales, MB, et al.. Measurable residual disease by next-generation flow cytometry in multiple myeloma. J Clin Oncol 2020;38:784–92. https://doi.org/10.1200/JCO.19.01231.Search in Google Scholar PubMed

64. Zajec, M, Langerhorst, P, VanDuijn, MM, Gloerich, J, Russcher, H, van Gool, AJ, et al.. Mass spectrometry for identification, monitoring, and minimal residual disease detection of M-proteins. Clin Chem 2020;66:421–33. https://doi.org/10.1093/clinchem/hvz041.Search in Google Scholar PubMed

65. Murray, D, Barnidge, D. Characterization of immunoglobulin by mass spectrometry with applications for the clinical laboratory. Crit Rev Clin Lab Sci 2013;50:91–102. https://doi.org/10.3109/10408363.2013.838206.Search in Google Scholar PubMed

66. Thoren, KL. Mass spectrometry methods for detecting monoclonal immunoglobulins in multiple myeloma minimal residual disease. Semin Hematol 2018;55:41–3. https://doi.org/10.1053/j.seminhematol.2018.02.008.Search in Google Scholar PubMed

67. Mills, JR, Barnidge, DR, Murray, DL. Detecting monoclonal immunoglobulins in human serum using mass spectrometry. Methods 2015;81:56–65. https://doi.org/10.1016/j.ymeth.2015.04.020.Search in Google Scholar PubMed

68. Botz, CM, Barnidge, DR, Murray, DL, Katzmann, JA. Detecting monoclonal light chains in urine: MicroLC-ESI-Q-TOF mass spectrometry compared to immunofixation electrophoresis. Br J Haematol 2014;167:437–8. https://doi.org/10.1111/bjh.13003.Search in Google Scholar PubMed

69. Mills, JR, Barnidge, DR, Dispenzieri, A, Murray, DL. High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. Blood Cancer J 2017;7:e590. https://doi.org/10.1038/bcj.2017.75.Search in Google Scholar PubMed PubMed Central

70. Kohlhagen, MC, Barnidge, DR, Mills, JR, Stoner, J, Gurtner, KM, Liptac, AM, et al.. Screening method for M-proteins in serum using nanobody enrichment coupled to MALDI-TOF mass spectrometry. Clin Chem 2016;62:1345–52. https://doi.org/10.1373/clinchem.2015.253781.Search in Google Scholar PubMed

71. Long, S, Qin, Q, Wang, Y, Yang, Y, Wang, Y, Deng, A, et al.. Nanoporous silica coupled MALDI-TOF MS detection of Bence-Jones proteins in human urine for diagnosis of multiple myeloma. Talanta 2019;200:288–92. https://doi.org/10.1016/j.talanta.2019.03.067.Search in Google Scholar PubMed

72. Milani, P, Murray, DL, Barnidge, DR, Kohlhagen, MC, Mills, JR, Merlini, G, et al.. The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic. Am J Hematol 2017;92:772–9. https://doi.org/10.1002/ajh.24772.Search in Google Scholar PubMed

73. Puig, N, Contreras, MT, Agulló, C, Martínez-López, J, Oriol, A, Blanchard, MJ, et al.. Mass spectrometry vs. immunofixation for treatment monitoring in multiple myeloma. Blood Adv 2022;6:3234–9. https://doi.org/10.1182/BLOODADVANCES.2021006762.Search in Google Scholar PubMed PubMed Central

74. Eveillard, M, Rustad, E, Roshal, M, Zhang, Y, Ciardiello, A, Korde, N, et al.. Comparison of MALDI-TOF mass spectrometry analysis of peripheral blood and bone marrow-based flow cytometry for tracking measurable residual disease in patients with multiple myeloma. Br J Haematol 2020;189:904–7. https://doi.org/10.1111/bjh.16443.Search in Google Scholar PubMed PubMed Central

75. Mills, JR, Kohlhagen, MC, Willrich, MAV, Kourelis, T, Dispenzieri, A, Murray, DL. A universal solution for eliminating false positives in myeloma due to therapeutic monoclonal antibody interference. Blood 2018;132:670–2. https://doi.org/10.1182/blood-2018-05-848986.Search in Google Scholar PubMed

76. Kourelis, T, Murray, DL, Dasari, S, Kumar, S, Barnidge, D, Madden, B, et al.. MASS-FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms. Am J Hematol 2018;93:E368–70. https://doi.org/10.1002/ajh.25244.Search in Google Scholar PubMed

77. Dispenzieri, A, Larson, DR, Rajkumar, SV, Kyle, RA, Kumar, SK, Kourelis, T, et al.. N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression. Leukemia 2020;34:2749–53. https://doi.org/10.1038/s41375-020-0940-8.Search in Google Scholar PubMed PubMed Central

78. Nevone, A, Girelli, M, Mangiacavalli, S, Paiva, B, Milani, P, Cascino, P, et al.. An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis. Leukemia 2022;36:2076–85. https://doi.org/10.1038/S41375-022-01599-W.Search in Google Scholar PubMed

79. Murray, DL, Puig, N, Kristinsson, S, Usmani, SZ, Dispenzieri, A, Bianchi, G, et al.. Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an international myeloma working group mass spectrometry committee report. Blood Cancer J 2021;11:24. https://doi.org/10.1038/s41408-021-00408-4.Search in Google Scholar PubMed PubMed Central

80. Sargur, R, White, P, Egner, W. Cryoglobulin evaluation: best practice? Ann Clin Biochem 2010;47:8–16.10.1258/acb.2009.009180Search in Google Scholar PubMed

81. Ravi, P, Kumar, S, Larsen, JT, Gonsalves, W, Buadi, F, Lacy, MQ, et al.. Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma. Blood Cancer J 2016;6:e454.10.1038/bcj.2016.65Search in Google Scholar PubMed PubMed Central

82. Murthy, HS, Sheets, K, Kumar, A, Nishihori, T, Mina, A, Chavez, JC, et al.. Hypoalbuminemia at day +90 is associated with inferior nonrelapse mortality and overall survival in allogeneic hematopoietic cell transplantation recipients: a Confirmatory study. Biology of Blood and Marrow Transplantation 2018;24:400–5.10.1016/j.bbmt.2017.09.022Search in Google Scholar PubMed

83. Bender, LM, Cotten, SW, Fedoriw, Y, Willis, MS, McCudden, CR. Evaluation of digital images for identification and characterization of monoclonal immunoglobulins by immunofixation. Clin Biochem 2013;46:255–8.10.1016/j.clinbiochem.2012.10.030Search in Google Scholar PubMed

84. Greipp, PR, Miguel, JS, Dune, BGM, Crowley, JJ, Barlogie, B, Bladé, J, et al.. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412–20.10.1200/JCO.2005.04.242Search in Google Scholar PubMed

85. Harousseau, JL, Dreyling, M. Multiple myeloma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Annals of Oncology 2009;20.10.1093/annonc/mdp140Search in Google Scholar PubMed

86. Bladé, J, Dimopoulos, M, Rosiñol, L, Rajkumar, SV, Kyle, RA. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. Journal of Clinical Oncology 2010;28:690–7.10.1200/JCO.2009.22.2257Search in Google Scholar PubMed PubMed Central

87. Palumbo, A, Avet-Loiseau, H, Oliva, S, Lokhorst, HM, Goldschmidt, H, Rosinol, L, et al.. Revised international staging system for multiple myeloma: a report from international myeloma working group. Journal of Clinical Oncology 2015;33:2863–9.10.1200/JCO.2015.61.2267Search in Google Scholar PubMed PubMed Central

88. Pratt, G, El-Sharkawi, D, Kothari, J, D’Sa, S, Auer, R, McCarthy, H, et al.. Diagnosis and management of waldenström macroglobulinaemia—a British society for haematology guideline. Br J Haematol 2022;197:171–87. https://doi.org/10.1111/bjh.18036.Search in Google Scholar PubMed

89. Gertz, MA. Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management. Am J Hematol 2021;96:258–69. https://doi.org/10.1002/ajh.26082.Search in Google Scholar PubMed

90. Rajkumar, SV. Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol 2018;93:1091–110. https://doi.org/10.1002/ajh.25117.Search in Google Scholar PubMed PubMed Central

91. Medina, A, Jiménez, C, Sarasquete, ME, González, M, Chillón, MC, Balanzategui, A, et al.. Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients. Blood Cancer J 2020;10:14. https://doi.org/10.1038/s41408-020-0283-8.Search in Google Scholar PubMed PubMed Central

92. Walker, BA, Boyle, EM, Wardell, CP, Murison, A, Begum, DB, Dahir, NM, et al.. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol 2015;33:3911–20. https://doi.org/10.1200/JCO.2014.59.1503.Search in Google Scholar PubMed PubMed Central

93. Ashby, C, Tytarenko, RG, Wang, Y, Weinhold, N, Johnson, SK, Bauer, M, et al.. Poor overall survival in hyperhaploid multiple myeloma is defined by double-hit bi-allelic inactivation of TP53. Oncotarget 2019;10:732–7. https://doi.org/10.18632/oncotarget.26589.Search in Google Scholar PubMed PubMed Central

94. Alcoceba, M, García-álvarez, M, Medina, A, Maldonado, R, González-Calle, V, Chillón, MC, et al.. MYD88 mutations: transforming the landscape of IgM monoclonal gammopathies. Int J Mol Sci 2022;23:5570. https://doi.org/10.3390/IJMS23105570.Search in Google Scholar PubMed PubMed Central

95. Kuiper, R, Van Duin, M, Van Vliet, MH, Broijl, A, Van Der Holt, B, Jarari, LE, et al.. Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System. Blood 2015;126:1996–2004. https://doi.org/10.1182/BLOOD-2015-05-644039.Search in Google Scholar PubMed PubMed Central

96. Swerdlow, SH, Campo, E, Harris, NL, Jaffe, ES, Pileri, SA, Stein, H, et al.. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th ed. Lyon: International Agency for Research on Cancer; 2017.Search in Google Scholar

97. Kroft, SH, Harrington, AM. Flow cytometry of B-cell neoplasms. Clin Lab Med 2017;37:697–723. https://doi.org/10.1016/j.cll.2017.07.001.Search in Google Scholar PubMed

98. Paiva, B, Montes, MC, García-Sanz, R, Ocio, EM, Alonso, J, De Las Heras, N, et al.. Multiparameter flow cytometry for the identification of the Waldenström’s clone in IgM-MGUS and Waldenström’s Macroglobulinemia: new criteria for differential diagnosis and risk stratification. Leukemia 2014;28:166–73. https://doi.org/10.1038/leu.2013.124.Search in Google Scholar PubMed

99. Gascue, A, Merino, J, Paiva, B. Flow cytometry. Hematol Oncol Clin N Am 2018;32:765–75. https://doi.org/10.1016/j.hoc.2018.05.004.Search in Google Scholar PubMed

100. Puig, N, Paiva, B, Lasa, M, Burgos, L, Perez, JJ, Merino, J, et al.. Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis. Leukemia 2019;33:1256–67. https://doi.org/10.1038/s41375-018-0308-5.Search in Google Scholar PubMed

101. Paiva, B, Chandia, M, Vidriales, MB, Colado, E, Caballero-Velázquez, T, Escalante, F, et al.. Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma. Blood 2014;124:1300–3. https://doi.org/10.1182/blood-2014-04-567909.Search in Google Scholar PubMed

102. Paiva, B, Almeida, J, Pérez-Andrés, M, Mateo, G, López, A, Rasillo, A, et al.. Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell-related disorders. Cytometry B Clin Cytometry 2010;78:239–52. https://doi.org/10.1002/cyto.b.20512.Search in Google Scholar PubMed

103. Van Dongen JJM, Lhermitte, L, Böttcher, S, Almeida, J, Van Der Velden, VHJ, Flores-Montero, J, et al.. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia 2012;26:1908–75. https://doi.org/10.1038/leu.2012.120.Search in Google Scholar PubMed PubMed Central

104. Flores-Montero, J, de Tute, R, Paiva, B, Perez, JJ, Böttcher, S, Wind, H, et al.. Immunophenotype of normal vs. myeloma plasma cells: toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytometry 2016;90:61–72. https://doi.org/10.1002/cyto.b.21265.Search in Google Scholar PubMed

105. Soh, KT, Tario, JD, Wallace, PK. Diagnosis of plasma cell dyscrasias and monitoring of minimal residual disease by multiparametric flow cytometry. Clin Lab Med 2017;37:821–53. https://doi.org/10.1016/j.cll.2017.08.001.Search in Google Scholar PubMed PubMed Central

106. Paiva, B, Vidriales, MB, Pérez, JJ, Mateo, G, Montalbán, MA, Mateos, MV, et al.. Multiparameter flow cytometry quantification of bone marrow plasma cells at diagnosis provides more prognostic information than morphological assessment in myeloma patients. Haematologica 2009;94:1599–602. https://doi.org/10.3324/haematol.2009.009100.Search in Google Scholar PubMed PubMed Central

107. Pérez-Persona, E, Mateo, G, García-Sanz, R, Mateos, MV, De Las Heras, N, De Coca, AG, et al.. Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol 2010;148:110–4. https://doi.org/10.1111/j.1365-2141.2009.07929.x.Search in Google Scholar PubMed

108. Burgos, L, Tamariz-Amador, L-E, Puig, N, Cedena, M-T, Guerrero, C, Jelínek, T, et al.. Definition and clinical significance of the monoclonal gammopathy of undetermined significance-like phenotype in patients with monoclonal gammopathies. J Clin Oncol 2023;41:3019–31. https://doi.org/10.1200/JCO.22.01916.Search in Google Scholar PubMed

109. Mateo, G, Montalbán, MA, Vidriales, MB, Lahuerta, JJ, Mateos, MV, Gutiérrez, N, et al.. Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol 2008;26:2737–44. https://doi.org/10.1200/JCO.2007.15.4120.Search in Google Scholar PubMed

110. Paiva, B, Gutierrez, NC, Chen, X, Vidriales, MB, Montalban, MA, Rosinol, L, et al.. Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients. Leukemia 2012;26:1862–9. https://doi.org/10.1038/leu.2012.42.Search in Google Scholar PubMed

111. Kastritis, E, Kostopoulos, IV, Terpos, E, Paiva, B, Fotiou, D, Gavriatopoulou, M, et al.. Evaluation of minimal residual disease using next-generation flow cytometry in patients with AL amyloidosis. Blood Cancer J 2018;8:46. https://doi.org/10.1038/s41408-018-0086-3.Search in Google Scholar PubMed PubMed Central

112. Flores-Montero, J, Sanoja-Flores, L, Paiva, B, Puig, N, García-Sánchez, O, Böttcher, S, et al.. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia 2017;31:2094–103. https://doi.org/10.1038/leu.2017.29.Search in Google Scholar PubMed PubMed Central

113. Medina, A, Puig, N, Flores-Montero, J, Jimenez, C, Sarasquete, ME, Garcia-Alvarez, M, et al.. Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma. Blood Cancer J 2020;10:108. https://doi.org/10.1038/s41408-020-00377-0.Search in Google Scholar PubMed PubMed Central

114. Paiva, B, Martinez-Lopez, J, Vidriales, MB, Mateos, MV, Montalban, MA, Fernandez-Redondo, E, et al.. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol 2011;29:1627–33. https://doi.org/10.1200/JCO.2010.33.1967.Search in Google Scholar PubMed

115. Jiménez-Ubieto, A, Paiva, B, Puig, N, Cedena, MT, Martínez-López, J, Oriol, A, et al.. Validation of the International Myeloma Working Group standard response criteria in the PETHEMA/GEM2012MENOS65 study: are these times of change? Blood 2021;138:1901–5. https://doi.org/10.1182/blood.2021012319.Search in Google Scholar PubMed PubMed Central

116. Tschautscher, M, Jevremovic, D, Buadi, FK, Lacy, MQ, Gertz, MA, Dispenzieri, A, et al.. Implications and outcomes of MRD-negative multiple myeloma patients with immunofixation positivity. Am J Hematol 2020;95:E60–2. https://doi.org/10.1002/ajh.25702.Search in Google Scholar PubMed

117. Terpos, E, Kostopoulos, IV, Kastritis, E, Ntanasis-Stathopoulos, I, Migkou, M, Rousakis, P, et al.. Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy. Hemasphere 2019;3:1. https://doi.org/10.1097/HS9.0000000000000300.Search in Google Scholar PubMed PubMed Central

118. Puig, N, Flores-Montero, J, Burgos, L, Cedena, MT, Cordón, L, Pérez, JJ, et al.. Reference values to assess hemodilution and warn of potential false-negative minimal residual disease results in myeloma. Cancers 2021;13:4924. https://doi.org/10.3390/CANCERS13194924.Search in Google Scholar PubMed PubMed Central

119. Tschautscher, MA, Jevremovic, D, Rajkumar, V, Dispenzieri, A, Lacy, MQ, Gertz, MA, et al.. Prognostic value of minimal residual disease and polyclonal plasma cells in myeloma patients achieving a complete response to therapy. Am J Hematol 2019;94:751–6. https://doi.org/10.1002/AJH.25481.Search in Google Scholar PubMed

120. Pojero, F, Casuccio, A, Giambanco, C, Bulati, M, Buffa, S, Di Bassiano, F, et al.. Bone marrow B lymphocytes in multiple myeloma and MGUS: focus on distribution of naïve cells and memory subsets. Leuk Res 2016;49:51–9. https://doi.org/10.1016/j.leukres.2016.08.008.Search in Google Scholar PubMed

121. Sanoja-Flores, L, Flores-Montero, J, Pérez-Andrés, M, Puig, N, Orfao, A. Detection of circulating tumor plasma cells in monoclonal gammopathies: methods, pathogenic role, and clinical implications. Cancers 2020;12:1–26. https://doi.org/10.3390/cancers12061499.Search in Google Scholar PubMed PubMed Central

122. Levin, A, Hari, P, Dhakal, B. Novel biomarkers in multiple myeloma. Transl Res 2018;201:49–59. https://doi.org/10.1016/j.trsl.2018.05.003.Search in Google Scholar PubMed

123. Sanoja-Flores, L, Flores-Montero, J, Garcés, JJ, Paiva, B, Puig, N, García-Mateo, A, et al.. Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). Blood Cancer J 2018;8:117. https://doi.org/10.1038/s41408-018-0153-9.Search in Google Scholar PubMed PubMed Central

124. Gonsalves, WI, Jevremovic, D, Nandakumar, B, Dispenzieri, A, Buadi, FK, Dingli, D, et al.. Enhancing the R-ISS classification of newly diagnosed multiple myeloma by quantifying circulating clonal plasma cells. Am J Hematol 2020;95:310–5. https://doi.org/10.1002/ajh.25709.Search in Google Scholar PubMed PubMed Central

125. Bae, MH, Park, CJ, Kim, BH, Cho, YU, Jang, S, Lee, DH, et al.. Increased circulating plasma cells detected by flow cytometry predicts poor prognosis in patients with plasma cell myeloma. Cytometry B Clin Cytometry 2018;94:493–9. https://doi.org/10.1002/cyto.b.21606.Search in Google Scholar PubMed

126. Sidana, S, Tandon, N, Dispenzieri, A, Gertz, MA, Dingli, D, Jevremovic, D, et al.. Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis. Leukemia 2018;32:1421–6. https://doi.org/10.1038/S41375-018-0063-7.Search in Google Scholar PubMed PubMed Central

127. Gonsalves, WI, Rajkumar, SV, Gupta, V, Morice, WG, Timm, MM, Singh, PP, et al.. Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma. Leukemia 2014;28:2060–5. https://doi.org/10.1038/leu.2014.98.Search in Google Scholar PubMed PubMed Central

128. Sanoja-Flores, L, Flores-Montero, J, Puig, N, Contreras-Sanfeliciano, T, Pontes, R, Corral-Mateos, A, et al.. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood 2019;134:2218–22. https://doi.org/10.1182/blood.2019002610.Search in Google Scholar PubMed PubMed Central

129. Fernández de Larrea, C, Kyle, R, Rosiñol, L, Paiva, B, Engelhardt, M, Usmani, S, et al.. Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood Cancer J 2021;11:192. https://doi.org/10.1038/S41408-021-00587-0.Search in Google Scholar PubMed PubMed Central

130. Jelinek, T, Bezdekova, R, Zihala, D, Sevcikova, T, Sithara, AA, Pospisilova, L, et al.. More than 2% of circulating tumor plasma cells defines plasma cell leukemia-like multiple myeloma. J Clin Oncol 2023;41:1383–92. https://doi.org/10.1200/JCO.22.01226.Search in Google Scholar PubMed PubMed Central

131. López-Anglada, L, Gutiérrez, NC, García, JL, Mateos, MV, Flores, T, San Miguel, JF. P53 deletion may drive the clinical evolution and treatment response in multiple myeloma. Eur J Haematol 2010;84:359–61. https://doi.org/10.1111/j.1600-0609.2009.01399.x.Search in Google Scholar PubMed

132. Katodritou, E, Kastritis, E, Gatt, M, Cohen, YC, Avivi, I, Pouli, A, et al.. Real-world data on incidence, clinical characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) in the era of novel therapies: a study of the Greco-Israeli collaborative myeloma working group. Am J Hematol 2020;95:465–71. https://doi.org/10.1002/ajh.25755.Search in Google Scholar PubMed

133. Dispenzieri, A. Monoclonal gammopathies of clinical significance. Hematology Am Soc Hematol Educ Program 2020;2020:380–8. https://doi.org/10.1182/HEMATOLOGY.2020000122.Search in Google Scholar PubMed PubMed Central


Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-0326).


Received: 2023-03-30
Accepted: 2023-05-29
Published Online: 2023-07-24
Published in Print: 2023-11-27

© 2023 Walter de Gruyter GmbH, Berlin/Boston

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