Multiple myeloma with extramedullary plasmacytoma: pathogenesis and clinical case

Cover Page

Cite item

Full Text

Abstract

Background. Multiple myeloma complicated by extramedullary plasmacytoma is an unfavorable variant of the disease. It remains unknown what triggers tumor transformation. The review presents literature data on the pathogenesis of extramedullary disease, as well as a clinical example of a comprehensive study of the tumor substrate.

Aim. To study the molecular and biological characteristics of the tumor substrate of the bone marrow and extramedullary plasmacytoma using various research methods.

Materials and methods. A 55-year-old patient was admitted to National Medical Research Center for Hematology with a diagnosis of multiple myeloma occurring with extramedullary plasmacytoma of the retroperitoneal space. dNA was isolated from samples of different localization (blood plasma, Cd138+ bone marrow cells, plasmacytoma and buccal epithelial cells). The profile of short tandem dNA repeats (STR) from the obtained samples was studied by multiplex polymerase chain reaction followed by fragment analysis. fluorescent in situ hybridization (fISH) of bone marrow Cd138+ cells was performed using various dNA probes. Comparative genomic hybridization on a microarray (arrayCGH) plasmacytoma dNA was also performed. The mutation profile of the KRAS, NRAS, BRAF genes was studied by Sanger sequencing in tumor samples of various localizations.

Results. The induction therapy (vCd (bortezomib + cyclophosphamide + dexamethasone), vRd (bortezomib + lenalidomide + dexamethasone), daratumumab therapy) was ineffective, death occurred 4 months after the first clinical manifestations appeared. Comparison of STR markers of circulating cell-free tumor dNA (cfdNA), Cd138+ bone marrow cells, and plasmacytoma revealed the largest number of involved loci exactly in plasmacytoma’ dNA. A mutation in the NRAS gene was found only in plasmacytoma’ dNA. This indicates the presence of another clone of tumor cells in the extra-medullary plasmacytoma. Molecular karyotyping of plasmacytoma using the arrayCGH method revealed rearrangements of many chromosomes. 1p32.3 bi-allelic deletion, amplification of 1q21, 8q24/MyC rearrangements and del17p13 were confirmed by arrayCGH molecular karyotyping and fISH studies in bone marrow and plasmacytoma.

Conclusion. A comprehensive molecular genetic study of the extramedullary plasmacytoma’ substrate is necessary to understand the pathogenesis mechanisms and, on this basis, to develop differentiated therapeutic approaches.

About the authors

M. V. Firsova

National Research Center for Hematology, Ministry of Health of Russia

Author for correspondence.
Email: firs-maia@yandex.ru
ORCID iD: 0000-0003-4142-171X

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

N. V. Risinskaya

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-2957-1619

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

M. V. Solovev

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-7944-6202

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

T. N. Obukhova

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-1613-652X

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

M. A. Kislitsyna

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-3337-2487

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

E. E. Nikulina

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-3914-8611

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

I. A. Yakutik

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-5532-1122

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

T. V. Abramova

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-3163-4930

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

A. B. Sudarikov

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0001-9463-9187

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

A. M. Kovrigina

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-1082-8659

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

L. P. Mendeleeva

National Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-4966-8146

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

References

  1. Rajkumar S.V., Dimopoulos M.A., Palumbo A. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15(12):e538–48. doi: 10.1016/S1470­2045(14)70442­5
  2. Usmani S.Z., Heuck C., Mitchell A. et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over­ represented in high­risk disease even in the era of novel agents. Haematologica 2012;97(11):1761–7. doi: 10.3324/haematol.2012.065698
  3. 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(2):325–30. doi: 10.1093/annonc/mdp329
  4. Bladé J., Fernández de Larrea C., Rosiñol L. et al. Soft­tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 2011;29(28):3805–12. doi: 10.1200/JCO.2011. 34.9290
  5. Weinstock M., Aljawai Y., Morgan E.A. et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Haematol 2015;169(6):851–8. doi: 10.1111/bjh.13383
  6. Rasche L., Bernard C., Topp M.S. et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single­center study of 24 cases. Ann Hematol 2012;91(7):1031–7. doi: 10.1007/s00277­012­1414­5
  7. Rosiñol L., Beksac M., Zamagni E. et al. Expert review on soft­ tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations. Br J Haematol 2021;194(3):496–507. doi: 10.1111/bjh.17338
  8. Dahl I.M.S., Rasmussen T., Kauric G., Husebekk A. Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma. Br J Haematol 2002;116(2):273–7. doi: 10.1046/j.1365­2141.2002.03258.x
  9. Liu Y., Jelloul F., Zhang Y. et al. Genetic basis of extramedullary plasmablastic transformation of multiple myeloma. Am J Surg Pathol 2020;44(6):838–48. doi: 10.1097/PAS.0000000000001459
  10. Mantovani F., Collavin L., Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ 2019;26(2):199–212. doi: 10.1038/s41418­018­0246­9
  11. Vande Broek I., Vanderkerken K., van Camp B., van Riet I. Extra­ vasation and homing mechanisms in multiple myeloma. Clin Exp Metastasis 2008;25(4):325–34. doi: 10.1007/s10585­007­9108­4
  12. Yang Y., Macleod V., Bendre M. et al. Heparanase promotes the spontaneous metastasis of myeloma cells to bone. Blood 2004;105(3):1303–9. doi: 10.1182/blood­2004­06­2141
  13. Rasmussen T., Kuehl M., Lodahl M. et al. Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Blood 2005;105(1):317–23. doi: 10.1182/blood­2004­03­0833
  14. Jagosky M.H., Usmani S.Z. Extramedullary disease in multiple myeloma. Curr Hematol Malig Rep 2020;15(2):62–71. doi: 10.1007/s11899­020­00568­3
  15. Bhutani M., Foureau D.M., Atrash S. et al. Extramedullary multiple myeloma. Leukemia 2020;34(1):1–20. doi: 10.1038/s41375­019­ 0660­0
  16. Qu X., Chen L., Qiu H. et al. Extramedullary manifestation in multiple myeloma bears high incidence of poor cytogenetic aberration and novel agents resistance. Biomed Res Int 2015;2015:787809. doi: 10.1155/2015/787809
  17. Rasche L., Chavan S.S., Stephens O.W. et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi­region sequencing. Nat Commun 2017;8(1):268. doi: 10.1038/s41467­017­00296­y
  18. Hanamura I. Gain/Amplification of chromosome arm.1q21 in multiple myeloma. Cancers (Basel) 2021;13(2):1–16. doi: 10.3390/cancers13020256
  19. Kim M.K., Suh C., Lee D.H. et al. Immunoglobulin D multiple myeloma: response to therapy, survival, and prognostic factors in 75 patients. Ann Oncol 2011;22(2):411–6. doi: 10.1093/annonc/mdq393
  20. Bladé J., Lust J.A., Kyle R.A. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol 1994;12(11):2398–404. doi: 10.1200/JCO.1994.12.11.2398
  21. Ravi P., Kumar S.K., Roeker L. et al. Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma. Blood Cancer J 2018;8(12):116. doi: 10.1038/s41408­018­0140­1
  22. Granell M., Calvo X., Garcia­Guiñón A. et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica 2017;102(6):1099–104. doi: 10.3324/haematol.2016.158303
  23. Rajkumar S.V. Multiple myeloma: 2020 update on diagnosis, risk­ stratification and management. Am J Hematol 2020;95(5):548–67. doi: 10.1002/ajh.25791
  24. Xu J.L., Lai R., Kinoshita T. et al. Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade. J Clin Pathol 2002;55(7):530–4. doi: 10.1136/jcp.55.7.530
  25. Shaughnessy J.D., Zhan F., Burington B.E. et al. A validated gene expression model of high­risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007;109(6):2276–84. doi: 10.1182/blood­2006­07­038430
  26. Menges C.W., Altomare D.A., Testa J.R. FAS­associated factor 1 (FAF1): diverse functions and implications for oncogenesis. Cell Cycle 2009;8(16):2528–34. doi: 10.4161/cc.8.16.9280
  27. Leone P.E., Walker B.A., Jenner M.W. et al. Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin Cancer Res 2008;14(19):6033–41. doi: 10.1158/1078­0432. CCR­08­0347
  28. Dib A., Peterson T.R., Raducha­Grace L. et al. Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi­allelic deletion vs increased expression. Cell Div 2006;1:23. doi: 10.1186/1747­1028­1­23
  29. Zhan F., Colla S., Wu X. et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2­ and p27Kip1­dependent and ­independent mechanisms.Blood 2007;109(11):4995–5001. DOI: 10.1182/ blood­2006­07­038703
  30. Shaughnessy J. Amplification and overexpression of CKS1B at chro­ mosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Hematology 2005;10 Suppl 1:117–26. doi: 10.1080/10245330512331390140
  31. Misiewicz­Krzeminska I., de Ramón C., Corchete L.A. et al. Quantitative expression of Ikaros, IRF4, and PSMD10 proteins predicts survival in VRD­treated patients with multiple myeloma. Blood Adv 2020;4(23):6023–33. doi: 10.1182/bloodadvances.2020002711
  32. Shaughnessy J.D., Qu P., Usmani S. et al. Pharmacogenomics of bortezomib test­dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high­risk feature in myeloma treated with Total Therapy 3. Blood 2011;118(13):3512–24. doi: 10.1182/blood­2010­12­328252
  33. Mulligan G., Lichter D.I., Di Bacco A. et al. Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single­agent bortezomib therapy. Blood 2014;123(5):632. doi: 10.1182/blood­2013­05­504340
  34. Chng W.J., Gonzalez­Paz N., Price­Troska T. et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia 2008;22(12):2280–4. doi: 10.1038/leu.2008.142
  35. Staniek J., Lorenzetti R., Heller B. et al. TRAIL­R1 and TRAIL­R2 mediate TRAIL­dependent apoptosis in activated primary human B lymphocytes. Front Immunol 2019;10:951. doi: 10.3389/fimmu.2019.00951
  36. Mlynarcikova M., Balcarkova J., Mickova P. et al. Molecular cytogenetic analysis of chromosome 8 aberrations in patients with multiple myeloma examined in 2 different stages, at diagnosis and at progression/relapse. Clin Lymphoma Myeloma Leuk 2016;16(6):358–65. doi: 10.1016/j.clml.2016.02.038
  37. Wang S.Y., Hao H.L., Deng K. et al. Expression levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and focal adhesion kinase in patients with multiple myeloma and their relationship to clinical stage and extramedullary infiltration. Leuk Lymphoma 2012;53(6):1162–8. doi: 10.3109/10 428194.2011.647311
  38. Fonseca R., Blood E., Rue M. et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101(11):4569–75. doi: 10.1182/blood­2002­10­3017
  39. Abdallah N., Rajkumar S.V., Greipp P. et al. Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response. Blood Cancer J 2020;10(8):82. doi: 10.1038/s41408­020­00348­5
  40. Kienast J., Berdel W.E. C­maf in multiple myeloma: an oncogene enhancing tumor­stroma interactions. Cancer Cell 2004;5(2):109– 10. doi: 10.1016/s1535­6108(04)00030­3
  41. Chang H., Qi Q., Xu W., Patterson B. c­Maf nuclear oncoprotein is frequently expressed in multiple myeloma. Leukemia 2007;21(7):1572–4. doi: 10.1038/sj.leu.2404669
  42. Wei G.Q., Wang L.J., Yang H.J. et al. Clinical implications of c­maf expression in plasma cells from patients with multiple myeloma. Exp Hematol Oncol 2017;6:16. doi: 10.1186/s40164­017­0076­3
  43. Sawyer J.R. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet 2011;204(1):3–12. doi: 10.1016/j.cancergencyto.2010.11.002
  44. Rana S., Sreedharanunni S., Panakkal V. et al. 16q23/MAF gene deletion is a frequent cytogenetic abnormality in multiple myeloma associated with IgH deletion but significantly lower incidence of high­risk translocations. Clin Lymphoma Myeloma Leuk 2021;21(4):e398–401. doi: 10.1016/j.clml.2020.11.012
  45. Xu Y., Zou R., Wang J. et al. The role of the cancer testis antigen PRAME in tumorigenesis and immunotherapy in human cancer. Cell Prolif 2020;53(3):e12770. doi: 10.1111/cpr.12770
  46. De Carvalho F., Vettore A.L., Colleoni G.W.B. Cancer/testis antigen MAGE­C1/CT7: new target for multiple myeloma therapy. Clin Dev Immunol 2012;2012:257695. doi: 10.1155/2012/257695
  47. Sticca T., Caberg J.H., Wenric S. et al. Genomic studies of multiple myeloma reveal an association between X chromosome alterations and genomic profile complexity. Genes Chromosomes Cancer 2017;56(1):18–27. doi: 10.1002/gcc.22397
  48. Palumbo A., Avet­Loiseau H., Oliva S. et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol 2015;33(26):2863–9. doi: 10.1200/JCO.2015.61.2267
  49. Thakurta A., Ortiz M., Blecua P. et al. High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma. Blood 2019;133(11):1217–21. doi: 10.1182/blood­2018­10­880831
  50. Flynt E., Bisht K., Sridharan V. et al. Prognosis, biology, and targeting of TP53 dysregulation in multiple myeloma. Cells 2020;9(2):287. doi: 10.3390/cells9020287
  51. Walker B.A., Mavrommatis K., Wardell C.P. et al. A high­risk, Double­ Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia 2019;33(1):159–70. doi: 10.1038/s41375­018­0196­8
  52. Corre J., Perrot A., Caillot D. et al. del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma. Blood 2021;137(9):1192. doi: 10.1182/blood.2020008346

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c)


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-36928 от  21.07.2009.