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Current Hematologic Malignancy Reports

, Volume 14, Issue 3, pp 187–196 | Cite as

Expert Panel Consensus Statement for Proper Evaluation of First Relapse in Multiple Myeloma

  • M. OffidaniEmail author
  • M. Boccadoro
  • F. Di Raimondo
  • M. T. Petrucci
  • P. Tosi
  • M. Cavo
Multiple Myeloma (P Kapoor, Section Editor)
  • 176 Downloads
Part of the following topical collections:
  1. Topical Collection on Multiple Myeloma

Abstract

Purpose of Review

A working group of six expert physicians convened to assess the spectrum of multiple myeloma relapse presentations, discussed the features that can define the disease as aggressive and not aggressive, and established whether this information could help in selecting treatment together with the characteristics of disease and of patients and type of prior therapy.

Recent Findings

The working group agreed that relapse should be distinguished between biochemical and clinical according to IMWG. Moreover, the expert panel defined “aggressive disease” as a clinical condition that requires therapy able to induce a rapid and as deep as possible response to release symptoms and to avoid impending danger of new events. According to this definition, relapse was considered aggressive if it presents with at least one of the following features: doubling of M protein rate over 2 months, renal insufficiency, hypercalcemia, extramedullary disease, elevated LDH, high plasma cell proliferative index, presence of plasma cells in peripheral blood, or skeletal-related complications. Moreover, the panel agreed that this classification can be useful to choose therapy in first relapse together with other patient, disease, and prior therapy characteristics. So, this item was included in a new therapeutic algorithm.

Summary

The treatment choice in MM at relapse is wider than in the past with the availability of many new therapeutic regimens leading to increased diversity of approaches and relevant risk of inappropriate treatment decisions. A practical classification of relapses into aggressive or non-aggressive, included in a decisional algorithm on MM management at first relapse, could help to make the appropriate treatment decisions.

Keywords

Multiple myeloma Refractory plasma cell malignancy Aggressive myeloma Management of relapsed myeloma 

Notes

Compliance with Ethical Standards

Conflict of Interest

M. Boccadoro, M. Cavo, F. Di Raimondo, M. Offidani, M.T. Petrucci, and P. Tosi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    RWKR M, Kuehl WM, Grogan TM, Harris NL, Coupland RW. Plasma cell neoplasms. In: Swerdlow SHCE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO classification of tumors of hematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 200–13.Google Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.CrossRefGoogle Scholar
  3. 3.
    Ludwig H, Fritz E, Friedl HP. Epidemiologic and age-dependent data on multiple myeloma in Austria. J Natl Cancer Inst. 1982;68:729–33.Google Scholar
  4. 4.
    Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol. 2007;25:1993–9.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758–65.CrossRefGoogle Scholar
  7. 7.
    Costa LJ, Brill IL, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and serviva by age, race, and ethnicity in the United States. Blood Adv. 2017;1:282–7.CrossRefGoogle Scholar
  8. 8.
    Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.CrossRefGoogle Scholar
  9. 9.
    Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3–9.CrossRefGoogle Scholar
  10. 10.
    Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691–5.CrossRefGoogle Scholar
  11. 11.
    Alegre A, Granda A, Martínez-Chamorro C, Díaz-Mediavilla J, Martínez R, García-Laraña J, et al. Spanish Registry of Transplants in Multiple Myelomas; Spanish Group of Hemopoietic Transplant (GETH); PETHEMA. Different patterns of relapse after autologous peripheral blood stem cell transplantation in multiple myeloma: clinical results of 280 cases from the Spanish Registry. Haematologica. 2002;87:609–14.Google Scholar
  12. 12.
    Lenhoff S, Hjorth M, Turesson I, Westin J, Gimsing P, Wislöff F, et al. Intensive therapy for multiple myeloma in patients younger than 60 years. Long-term results focusing on the effect of the degree of response on survival and relapse pattern after transplantation. Haematologica. 2006;91:1228–33.Google Scholar
  13. 13.
    Zamarin D, Giralt S, Landau H, Lendvai N, Lesokhin A, Chung D, et al. Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients’ monitoring after transplantation. Bone Marrow Transplant. 2013;48:419–24.CrossRefGoogle Scholar
  14. 14.
    Fernández de Larrea C, Jiménez R, Rosiñol L, Giné E, Tovar N, Cibeira MT, et al. Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma. Bone Marrow Transplant. 2014;49:223–7.CrossRefGoogle Scholar
  15. 15.
    Lopez A, Mateos MV, Oriol A, Valero M, Martínez J, Lorenzo JI, et al. Patterns of relapse and outcome of elderly multiple myeloma patients treated as front-line therapy with novel agents combinations. Leuk Res Rep. 2015;4:64–9.Google Scholar
  16. 16.
    Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia. 2016;30:1005–17.CrossRefGoogle Scholar
  17. 17.
    Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica. 2016;101:396–406.CrossRefGoogle Scholar
  18. 18.
    Mikhael JR. A practical approach to relapsed multiple myeloma. Hematology Am Soc Hematol Educ Program. 2014;1:262–7.CrossRefGoogle Scholar
  19. 19.
    Nooka AK, Kastritis E, Dimopoulos MA, Lonial S. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125:3085–99.CrossRefGoogle Scholar
  20. 20.
    Mohty B, El-Cheikh J, Yakoub-Agha I, Avet-Loiseau H, Moreau P, Mohty M. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia. 2012;26:73–85.CrossRefGoogle Scholar
  21. 21.
    Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R, et al. Therapy for relapsed multiple myeloma: guidelines from the Mayo stratification for myeloma and risk-adapted therapy. Mayo Clin Pr Sonneveld P, Schmidt IGH, van er Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946–55.CrossRefGoogle Scholar
  22. 22.
    Sonneveld P, Schmidt IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946–55.CrossRefGoogle Scholar
  23. 23.
    Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075–85.CrossRefGoogle Scholar
  24. 24.
    Rosinol L, Oriol A, Teruel AI, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589–96.CrossRefGoogle Scholar
  25. 25.
    Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519–27.CrossRefGoogle Scholar
  26. 26.
    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17.CrossRefGoogle Scholar
  27. 27.
    • Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906–17 Based on the results of this phase III clinical trial, the combination lenalidomide and dexamethasone became a new standard therapy for patients not eligible to autologous transplant. CrossRefGoogle Scholar
  28. 28.
    Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–52.CrossRefGoogle Scholar
  29. 29.
    Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27–38.CrossRefGoogle Scholar
  30. 30.
    Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621–31.CrossRefGoogle Scholar
  31. 31.
    Jakubowiak A, Offidani M, Pégourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127:2833–40.CrossRefGoogle Scholar
  32. 32.
    Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319–31.CrossRefGoogle Scholar
  33. 33.
    Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.CrossRefGoogle Scholar
  34. 34.
    Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621–34.CrossRefGoogle Scholar
  35. 35.
    Caillon H, Attal M, Avet-Loiseau H, Touzeau C, Moreau, Dejoie T. Free light chain escape in multiple myeloma: an exceptional phenomenon. Blood. 2016;128:4428.Google Scholar
  36. 36.
    Brioli A, Giles H, Pawlyn C, Campbell JP, Kaiser MF, Melchor L, et al. Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome. Blood. 2014;123:3414–9.CrossRefGoogle Scholar
  37. 37.
    Dimopoulos MA, Hillengass J, Usmani S, Zamagni E, Lenttzsch S, Davies FE, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33:657–64.CrossRefGoogle Scholar
  38. 38.
    •• Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48 This study is essential since updated diagnostic criteria for multiple myeloma. CrossRefGoogle Scholar
  39. 39.
    Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment. J Clin Oncol. 2016;34:1544–57.CrossRefGoogle Scholar
  40. 40.
    Morabito F, Gentile M, Ciolli S, Petrucci MT, Galimberti S, Mele G, et al. Safety and efficacy of bortezomib-based regimens for multiple myeloma patients with renal impairment: a retrospective study of Italian Myeloma Network GIMEMA. Eur J Haematol. 2010;84:223–8.CrossRefGoogle Scholar
  41. 41.
    Rasche L, Bernard C, Topp MS, Kapp M, Duell J, Wesemeier C, et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol. 2012;91:1031–7.CrossRefGoogle Scholar
  42. 42.
    Papanikolaou X, Repousis P, Tzenou T, Maltezas D, Kotsopoulou M, Megalakaki K, et al. Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse. Leuk Lymphoma. 2013;54:1459–64.CrossRefGoogle Scholar
  43. 43.
    •• Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report for international myeloma working group. J Clin Oncol. 2015;33:2863–9 This study provided the new prognostic stratification of MM patients and was obtained combining the International Staging System (ISS) with chromosomal abnormalities (CA) and serum lactate dehydrogenase (LDH). CrossRefGoogle Scholar
  44. 44.
    Lee H, Duggan P, Chaudhry A, et al. Early relapse for multiple myeloma patients undergoing single autologous stem cell therapy: a single-center experience. Clin Lymphoma Myeloma Leuk. 2018;18:e69–75.CrossRefGoogle Scholar
  45. 45.
    Rodriguez-Otero P, Mateos MV, Martinez-Lopez J, et al. Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role. Leukemia. 2018;32:2427–34.Google Scholar
  46. 46.
    Fernandez de Larrea C, Kyle RA, Durie BG, et al. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013;27:780–91.CrossRefGoogle Scholar
  47. 47.
    Gonsalves WI, Morice WG, Rajkumar VS, Gupta V, Timm MM, Dispenzieri A, et al. Quantification of clonal circulating plasma cells in relapsed multiple myeloma. Br J Haematol. 2014;167:500–5.CrossRefGoogle Scholar
  48. 48.
    An G, Qin X, Acharya C, Xu Y, Deng S, Shi L, et al. Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients. Ann Hematol. 2015;94:257–64.CrossRefGoogle Scholar
  49. 49.
    Granell M, Calvo X, Garcia-Guinon A, Escoda L, Abella E, Martinez CM, et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica. 2010;102:1099–104.CrossRefGoogle Scholar
  50. 50.
    Ravi P, Kumar SK, Roeker L, Gonsalves W, Buadi F, Lacy MQ, 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;8:116.CrossRefGoogle Scholar
  51. 51.
    Aljama MA, Sidiqi MH, Lakshman A, Dispenzieri A, Jevremovic D, Gertzz M, et al. Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma. Blood Adv. 2018;2:3149–54.CrossRefGoogle Scholar
  52. 52.
    Sidiqi MH, Aljama MA, Jevremovic D, Morice WG, Timm M, et al. Plasma cell proliferative index post-transplant is a powerful predictor of prognosis in myeloma patients failing to achieve a complete response. Bone Marrow Transplant. 2019;54:442–47.Google Scholar
  53. 53.
    Jimenez-Zepeda VH, Reece DE, Trudel S, et al. Early relapse after single auto-SCT for multiple myeloma is a major predictor of survival in the era of novel agents. Bone Marrow Transplant. 2015;50:204–8.CrossRefGoogle Scholar
  54. 54.
    Majithia N, Rajkumar SV, Lacy MQ, et al. Early relapse following initial therapy for multiple myeloma predicts poor outcome in the era of novel agents. Leukemia. 2016;30:2208–13.CrossRefGoogle Scholar
  55. 55.
    Palumbo A, Bringhen S, Falco P, et al. Time of first disease progression, but not beta2-microglobulin, predicts outcome in myeloma patients who receive thalidomide as salvage therapy. Cancer. 2007;110:824–9.CrossRefGoogle Scholar
  56. 56.
    Yong K, Delforge M, Driessen C, et al. Multiple myeloma: patients outcomes in real-world practice. Br J Haematol. 2016;175:252–64.CrossRefGoogle Scholar
  57. 57.
    Egan JB, Shi CX, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120:1060–6.CrossRefGoogle Scholar
  58. 58.
    Bolli N, Avet-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997.CrossRefGoogle Scholar
  59. 59.
    Kortüm KM, Langer C, Monge J, et al. Targeted sequencing using a 47 gene multiple myeloma mutation panel (M(3)P) in -17p high risk disease. Br J Haematol. 2015;168:507–10.CrossRefGoogle Scholar
  60. 60.
    Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;27:4585–90.CrossRefGoogle Scholar
  61. 61.
    Chang H, Qi X, Jiang A, Xu W, Young T, Reece D. 1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Bone Marrow Transplant. 2010;45:117–21.CrossRefGoogle Scholar
  62. 62.
    Avet-Loiseau H, Attal M, Campion L, et al. Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol. 2012;30:1949–52.CrossRefGoogle Scholar
  63. 63.
    Affer M, Chesi M, Chen WD, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly superenhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725–35.CrossRefGoogle Scholar
  64. 64.
    Walker BA, Wardell CP, Brioli A, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 2014;4:e191.CrossRefGoogle Scholar
  65. 65.
    Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C, et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexaméthasone. Leukemia. 2010;24:623–8.CrossRefGoogle Scholar
  66. 66.
    Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114:522–5.CrossRefGoogle Scholar
  67. 67.
    Chang H, Trieu Y, Qi X, Jiang NN, Xu W, Reece D. Impact of cytogenetics in patients with relapsed or refractory multiple myeloma treated with bortezomib: adverse effect of 1q21 gains. Leuk Res. 2011;35:95–8.CrossRefGoogle Scholar
  68. 68.
    Boudreault JS, Touzeau C, Moreau P. triplet combinations in relapsed/refractory myeloma: update on recent phase 3 trials. Expert Rev Hematol. 2017;10:2017–215.CrossRefGoogle Scholar
  69. 69.
    Offidani M, Corvatta L, Gentili S. Triplet vs doublet drug regimens for managing multiple myeloma. Expert Opin Pharmacother. 2018;19:137–49.CrossRefGoogle Scholar
  70. 70.
    Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98:980–7.CrossRefGoogle Scholar
  71. 71.
    Bila J, Jelicic J, Djurasinovic V, Vukovic V, Sretenovic A, Andjelic B, et al. Prognostic effect of comorbidity indices in elderly patients with multiple myeloma. Clin Lymphoma Myeloma Leuk. 2015;15:416–9.CrossRefGoogle Scholar
  72. 72.
    Offidani M, Corvatta L, Polloni C, Centurioni R, Visani G, et al. Assessment of vulnerability measures and their effect on survival in a real-life population of multiple myeloma patients registered at Marche Region multiple myeloma registry. Clin Lymphoma Myeloma Leuk. 2012;12:423–32.CrossRefGoogle Scholar
  73. 73.
    • Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068–74 The IMWG frailty score, combining age, functional status, and comorbidities, represents a useful tool to choose the most appropriate treatment in newly diagnosed MM patients. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • M. Offidani
    • 1
    Email author
  • M. Boccadoro
    • 2
  • F. Di Raimondo
    • 3
  • M. T. Petrucci
    • 4
  • P. Tosi
    • 5
  • M. Cavo
    • 6
  1. 1.Clinica di EmatologiaA.O.U. Ospedali Riuniti di AnconaAnconaItaly
  2. 2.Myeloma Unit, Division of Hematology, University of TorinoAzienda Ospedaliero-Universitaria Città della Salute e della Scienza di TorinoTorinoItaly
  3. 3.Division of Hematology, AOU Policlinico-OVEUniversity of CataniaCataniaItaly
  4. 4.Department of Cellular Biotechnologies and HematologySapienza University of RomeRomeItaly
  5. 5.Hematology UnitInfermi Hospital RiminiRiminiItaly
  6. 6.Institute of Hematology Seragnoli, DIMESUniversity of BolognaBolognaItaly

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