THE SIGNIFICANCE OF PROGNOSTIC PROFILING IN THE TREATMENT OF PATIENTS WITH MULTIPLE MYELOMA
Keywords:
Multiple myeloma, prognostic profile
Abstract
Multiple myeloma (MM) is a hematological neoplasia characterized by clonal expansion of the most mature B lymphocytes, plasma cells (Plc), in the bone marrow (BM). Due to new treatment modalities, the 5-years survival has improved in the last 15 years, and nowdays ranges from 60-70%. The individual prognostic profile is based on the biological characteristics of the disease, clinical characteristics of patients and therapeutics response characteristics. The biological characteristics of the disease are defined by the clinical stage according to the Durie-Salmon classification and prognostic indices such the international staging system (ISS) and revised ISS (R-ISS). Numerous different mutations of prognostic significance have been discovered applying methods of molecular genetics such as next generation sequencing (NGS). The age and comorbity status of patients are the most important clinical characteristics because they are crucial for therapeutic choice and suitability for treatment with high-dose chemotherapy and autologous stem cell transplantation. The prognostic influence of therapeutic response is very important and the most powerful prognostic factors are achievements of complete remission (CR) and minimal residual disease (MRD) negativity.
References
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8. Zagouri F, Kastritis E, Symeonidis AS, Giannakoulas N, Katodritou E, Delimpasi S, et al. Immunoglobulin D myeloma: Clinical features and outcome in the era of novel agents. Eur J Haematol. 2014;
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10. Bhole M V., Sadler R, Ramasamy K. Serum-free light-chain assay: Clinical utility and limitations. Ann Clin Biochem. 2014;51(5):528–42.
11. Bladé J, Fernández De Larrea C, Rosiñol L, Cibeira MT, Jiménez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: Incidence, mechanisms of extramedullary spread, and treatment approach. Journal of Clinical Oncology. 2011.
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23. Ziogas DC, Dimopoulos MA, Kastritis E. Prognostic factors for multiple myeloma in the era of novel therapies. Expert Review of Hematology. 2018.
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25. Greipp PR, Kumar S. Plasma cell labeling index. Methods Mol Med. 2005;
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27. Ribourtout B, Zandecki M. Plasma cell morphology in multiple myeloma and related disorders. Morphologie. 2015.
28. Kuehl WM, Bergsagel PL. Multiple myeloma: Evolving genetic events and host interactions. Nature Reviews Cancer. 2002.
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31. Chng WJ, Glebov O. Genetic events in the pathogenesis of multiple myeloma. 2007;20(4):571–96.
32. Fassas ABT, Spencer T, Sawyer J, Zangari M, Lee CK, Anaissie E, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol. 2002;118(4):1041–7.
33. 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. Lancet. 2010;
34. Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: A meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013;
35. Sonneveld P, Schmidt-Wolf IGH, Van Der Holt B, El Jarari L, Bertsch U, Salwender H, 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;
36. Usmani SZ, Rodriguez-Otero P, Bhutani M, Mateos M V., Miguel JS. Defining and treating high-risk multiple myeloma. Leukemia. 2015.
37. Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A, et al. Combining information regarding chromosomal aberrations t(4;14) and del(17pl3) with the international staging system classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica. 2010;
38. Merz M, Hielscher T, Seckinger A, Hose D, Mai EK, Raab MS, et al. Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma. Am J Hematol. 2016;
39. Ry SUMMA. Prognostic value of 1p deletion for multiple myeloma : a. 2014;555–65.
40. Chim CS, Sim J, Tam S, Tse E, Lie AKW, Kwong YL. LDH is an adverse prognostic factor independent of ISS in transplant-eligible myeloma patients receiving bortezomib-based induction regimens. Eur J Haematol. 2015;
41. Bila J, Jelicic J, Dencic Fekete M, Trajkovic G, Sretenovic A, Perunicic Jovanovic M, et al. The revised international staging system compared to the classical international staging system better discriminates risk groups among transplant-ineligible multiple myeloma patients. Oncol Res Treat. 2017;
42. Marzin Y, Jamet D, Douet-Guilbert N, Morel F, Le Bris MJ, Morice P, et al. Chromosome 1 abnormalities in multiple myeloma. Anticancer Res. 2006;26(2 A):953–9.
43. Caltagirone S, Ruggeri M, Aschero S, Gilestro M, Oddolo D, Gay F, et al. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies. Haematologica. 2014;
44. Baysal M, Demirci U, Umit E, Kirkizlar HO, Atli EI, Gurkan H, et al. Concepts of Double Hit and Triple Hit Disease in Multiple Myeloma, Entity and Prognostic Significance. Sci Rep. 2020;
45. Jovanović KK, Escure G, Demonchy J, Willaume A, Van De Wyngaert Z, Farhat M, et al. Deregulation and targeting of TP53 pathway in multiple myeloma. Frontiers in Oncology. 2019.
46. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;
47. Broyl A, Hose D, Lokhorst H, De Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;
48. Decaux O, Lodé L, Magrangeas F, Charbonnel C, Gouraud W, Jézéquel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: A study of the Intergroupe Francophone du Myélom. J Clin Oncol. 2008;
49. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;
50. Bolli N, Genuardi E, Ziccheddu B, Martello M, Oliva S, Terragna C. Next-Generation Sequencing for Clinical Management of Multiple Myeloma : Ready for Prime Time ? 2020;10(February).
51. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood. 2015;
52. Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos M V., et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: A report of the European Myeloma Network (EMN). Blood. 2011.
53. Mina R, Bringhen S, Wildes TM, Zweegman S, Rosko AE. Approach to the Older Adult With Multiple Myeloma. Am Soc Clin Oncol Educ B. 2019;(39):500–18.
54. Kleber M, Ihorst G, Groß B, Koch B, Reinhardt H, Wäsch R, et al. Validation of the Freiburg Comorbidity Index in 466 Multiple Myeloma Patients and Combination With the International Staging System Are Highly Predictive for Outcome. Clin Lymphoma, Myeloma Leuk [Internet]. 2013;13(5):541–51. Available from: http://dx.doi.org/10.1016/j.clml.2013.03.013
55. Engelhardt M, Domm AS, Dold SM, Ihorst G, Reinhardt H, Zober A, et al. A concise revised myeloma comorbidity index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;
56. Fulciniti M, Munshi NC, Martinez-Lopez J. Deep Response in Multiple Myeloma: A Critical Review. Biomed Res Int. 2015;2015(Table 2).
57. Lonial S, Anderson KC. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia [Internet]. 2014;28(2):258–68. Available from: http://dx.doi.org/10.1038/leu.2013.220
58. 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. In: Blood. 2011.
59. 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. The Lancet Oncology. 2016.
2. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ CK (eds). Myeloma - Cancer Stat Facts. SEER Cancer Statistics Review, 1975-2014. 2017.
3. Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, et al. Risk of plasma cell and lymphoproliferative disorders among 14 621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009;
4. Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: Support for genetic factors in pathogenesis. Leukemia. 2009.
5. Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia. 2014.
6. Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood. 2002;
7. Pandey S, Kyle RA. Unusual myelomas: A review of IgD and IgE variants. ONCOLOGY (United States). 2013.
8. Zagouri F, Kastritis E, Symeonidis AS, Giannakoulas N, Katodritou E, Delimpasi S, et al. Immunoglobulin D myeloma: Clinical features and outcome in the era of novel agents. Eur J Haematol. 2014;
9. Rafae A, Malik MN, Abu Zar M, Durer S, Durer C. An Overview of Light Chain Multiple Myeloma: Clinical Characteristics and Rarities, Management Strategies, and Disease Monitoring. Cureus. 2018;
10. Bhole M V., Sadler R, Ramasamy K. Serum-free light-chain assay: Clinical utility and limitations. Ann Clin Biochem. 2014;51(5):528–42.
11. Bladé J, Fernández De Larrea C, Rosiñol L, Cibeira MT, Jiménez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: Incidence, mechanisms of extramedullary spread, and treatment approach. Journal of Clinical Oncology. 2011.
12. Touzeau C, Moreau P. How i treat extramedullary myeloma. Blood. 2016;
13. Fernández De Larrea C, Kyle RA, Durie BGM, Ludwig H, Usmani S, Vesole DH, et al. Plasma cell leukemia: Consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013.
14. Beksac M, Seval GC, Kanellias N, Coriu D, Rosiñol L, Ozet G, et al. A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: Analysis of parameters that improve outcome. Haematologica. 2020;
15. Boyd KD, Ross FM, Chiecchio L, Dagrada GP, Konn ZJ, Tapper WJ, et al. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: Analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012;
16. 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. J Clin Oncol. 2015;
17. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;
18. Ludwig H, Hajek R, Tothova E, Drach J, Zdenek A, Labar B, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2009;
19. Ríos-Tamayo R, Sáinz J, Martínez-López J, Puerta JM, Chang DYL, Rodríguez T, et al. Early mortality in multiple myeloma: the time-dependent impact of comorbidity: A population-based study in 621 real-life patients. Am J Hematol. 2016;
20. Dimopoulos MA, Delimpasi S, Katodritou E, Vassou A, Kyrtsonis MC, Repousis P, et al. Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents. Ann Oncol. 2014;
21. Filonzi G, Mancuso K, Zamagni E, Nanni C, Spinnato P, Cavo M, et al. A comparison of different staging systems for multiple myeloma: Can the mri pattern play a prognostic role? In: American Journal of Roentgenology. 2017.
22. 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. Ziogas DC, Dimopoulos MA, Kastritis E. Prognostic factors for multiple myeloma in the era of novel therapies. Expert Review of Hematology. 2018.
24. Solimando AG, Da Vià MC, Cicco S, Leone P, Di Lernia G, Giannico D, et al. High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment. J Clin Med. 2019;
25. Greipp PR, Kumar S. Plasma cell labeling index. Methods Mol Med. 2005;
26. Aljama MA, Hasib Sidiqi M, Lakshman A, Dispenzieri A, Jevremovic D, Gertz MA, et al. Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma. Blood Adv. 2018;
27. Ribourtout B, Zandecki M. Plasma cell morphology in multiple myeloma and related disorders. Morphologie. 2015.
28. Kuehl WM, Bergsagel PL. Multiple myeloma: Evolving genetic events and host interactions. Nature Reviews Cancer. 2002.
29. Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nature Reviews Clinical Oncology. 2017.
30. Chretien ML, Corre J, Lauwers-Cances V, Magrangeas F, Cleynen A, Yon E, et al. Understanding the role of hyperdiploidy in myeloma prognosis: Which trisomies really matter? Blood. 2015;
31. Chng WJ, Glebov O. Genetic events in the pathogenesis of multiple myeloma. 2007;20(4):571–96.
32. Fassas ABT, Spencer T, Sawyer J, Zangari M, Lee CK, Anaissie E, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol. 2002;118(4):1041–7.
33. 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. Lancet. 2010;
34. Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, et al. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: A meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013;
35. Sonneveld P, Schmidt-Wolf IGH, Van Der Holt B, El Jarari L, Bertsch U, Salwender H, 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;
36. Usmani SZ, Rodriguez-Otero P, Bhutani M, Mateos M V., Miguel JS. Defining and treating high-risk multiple myeloma. Leukemia. 2015.
37. Neben K, Jauch A, Bertsch U, Heiss C, Hielscher T, Seckinger A, et al. Combining information regarding chromosomal aberrations t(4;14) and del(17pl3) with the international staging system classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica. 2010;
38. Merz M, Hielscher T, Seckinger A, Hose D, Mai EK, Raab MS, et al. Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma. Am J Hematol. 2016;
39. Ry SUMMA. Prognostic value of 1p deletion for multiple myeloma : a. 2014;555–65.
40. Chim CS, Sim J, Tam S, Tse E, Lie AKW, Kwong YL. LDH is an adverse prognostic factor independent of ISS in transplant-eligible myeloma patients receiving bortezomib-based induction regimens. Eur J Haematol. 2015;
41. Bila J, Jelicic J, Dencic Fekete M, Trajkovic G, Sretenovic A, Perunicic Jovanovic M, et al. The revised international staging system compared to the classical international staging system better discriminates risk groups among transplant-ineligible multiple myeloma patients. Oncol Res Treat. 2017;
42. Marzin Y, Jamet D, Douet-Guilbert N, Morel F, Le Bris MJ, Morice P, et al. Chromosome 1 abnormalities in multiple myeloma. Anticancer Res. 2006;26(2 A):953–9.
43. Caltagirone S, Ruggeri M, Aschero S, Gilestro M, Oddolo D, Gay F, et al. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies. Haematologica. 2014;
44. Baysal M, Demirci U, Umit E, Kirkizlar HO, Atli EI, Gurkan H, et al. Concepts of Double Hit and Triple Hit Disease in Multiple Myeloma, Entity and Prognostic Significance. Sci Rep. 2020;
45. Jovanović KK, Escure G, Demonchy J, Willaume A, Van De Wyngaert Z, Farhat M, et al. Deregulation and targeting of TP53 pathway in multiple myeloma. Frontiers in Oncology. 2019.
46. Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;
47. Broyl A, Hose D, Lokhorst H, De Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;
48. Decaux O, Lodé L, Magrangeas F, Charbonnel C, Gouraud W, Jézéquel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: A study of the Intergroupe Francophone du Myélom. J Clin Oncol. 2008;
49. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;
50. Bolli N, Genuardi E, Ziccheddu B, Martello M, Oliva S, Terragna C. Next-Generation Sequencing for Clinical Management of Multiple Myeloma : Ready for Prime Time ? 2020;10(February).
51. Palumbo A, Bringhen S, Mateos MV, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood. 2015;
52. Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos M V., et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: A report of the European Myeloma Network (EMN). Blood. 2011.
53. Mina R, Bringhen S, Wildes TM, Zweegman S, Rosko AE. Approach to the Older Adult With Multiple Myeloma. Am Soc Clin Oncol Educ B. 2019;(39):500–18.
54. Kleber M, Ihorst G, Groß B, Koch B, Reinhardt H, Wäsch R, et al. Validation of the Freiburg Comorbidity Index in 466 Multiple Myeloma Patients and Combination With the International Staging System Are Highly Predictive for Outcome. Clin Lymphoma, Myeloma Leuk [Internet]. 2013;13(5):541–51. Available from: http://dx.doi.org/10.1016/j.clml.2013.03.013
55. Engelhardt M, Domm AS, Dold SM, Ihorst G, Reinhardt H, Zober A, et al. A concise revised myeloma comorbidity index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;
56. Fulciniti M, Munshi NC, Martinez-Lopez J. Deep Response in Multiple Myeloma: A Critical Review. Biomed Res Int. 2015;2015(Table 2).
57. Lonial S, Anderson KC. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia [Internet]. 2014;28(2):258–68. Available from: http://dx.doi.org/10.1038/leu.2013.220
58. 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. In: Blood. 2011.
59. 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. The Lancet Oncology. 2016.