Vol 8, No 3 (2017)
Review paper
Published online: 2017-11-23

open access

Page views 752
Article views/downloads 2210
Get Citation

Connect on Social Media

Connect on Social Media

Minimal residual disease testing for multiple myeloma

Beatriz Sanchez-Vega12, Rosa Ayala12, Teresa Cedena12, Joaquin Martinez-Lopez12
Hematologia 2017;8(3):219-227.

Abstract

Minimal residual disease (MRD) in a patient with multiple myeloma (MM) is defined as the mini-mum levels of pathological plasma cells remaining after treatment when a patient is in complete response (CR). The ultimate aim of studying MRD is to identify patients with different prognosis and to tailor treatment for individual patients. MRD studies in MM should be recommended in young patients in CR after autologous hematopoietic stem cells transplantation and in older patients in CR after regimens including proteasome inhibitors. Bone marrow is the only recommend location to assess MRD in MM. The recommended methods of MRD testing include next generation sequencing of immunoglobulin genes or multiparametric flow cytometry (MFC), depending on the experience of each center and the possibility of study samples being available in the first 24 hours for MFC analysis. MRD should be considered as a therapeutic objective. However, there is not enough evidence for taking clinical decisions based on MRD status alone, and for this reason we encourage the design of new clinical studies to address these questions.

References

  1. O'Brien SG, Guilhot F, Larson RA, et al. IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348(11): 994–1004.
  2. Leung W, Pui CH, Coustan-Smith E, et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood. 2012; 120(2): 468–472.
  3. Bader P, Kreyenberg H, von Stackelberg A, et al. Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol. 2015; 33(11): 1275–1284.
  4. Brüggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012; 120(23): 4470–4481.
  5. Campana D, Leung W. Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol. 2013; 162(2): 147–161.
  6. Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol. 2011; 29(12): 1627–1633.
  7. Paiva B, Vidriales MB, Cerveró J, et al. GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Groups. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008; 112(10): 4017–4023.
  8. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013; 31(20): 2540–2547.
  9. Martinez-Lopez J, Fernández-Redondo E, García-Sánz R, et al. GEM (Grupo Español Multidisciplinar de Melanoma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group. Clinical applicability and prognostic significance of molecular response assessed by fluorescent-PCR of immunoglobulin genes in multiple myeloma. Results from a GEM/PETHEMA study. Br J Haematol. 2013; 163(5): 581–589.
  10. Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010; 28(12): 2077–2084.
  11. Lahuerta JJ, Mateos MV, Martínez-López J, et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol. 2008; 26(35): 5775–5782.
  12. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012; 120(9): 1801–1809.
  13. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012; 120(9): 1801–1809.
  14. San Miguel JF, Schlag R, Khuageva NK, et al. VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359(9): 906–917.
  15. Hernández JM, García-Sanz R, Golvano E, et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol. 2004; 127(2): 159–164.
  16. Rosiñol L, Oriol A, Teruel AI, et al. Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012; 120(8): 1589–1596.
  17. Hauwel M, Matthes T. Minimal residual disease monitoring: the new standard for treatment evaluation of haematological malignancies? Swiss Med Wkly. 2014; 144: w13907.
  18. Melchor L, Brioli A, Wardell CP, et al. Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. Leukemia. 2014; 28(8): 1705–1715.
  19. Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014; 28(2): 384–390.
  20. van Rhee F, Giralt S, Barlogie B. The future of autologous stem cell transplantation in myeloma. Blood. 2014; 124(3): 328–333.
  21. Paiva B, Vídriales MB, Rosiñol L, et al. Grupo Español de MM/Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group. A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. Leukemia. 2013; 27(10): 2056–2061.
  22. Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma. J Clin Oncol. 2013; 31(36): 4529–4535.
  23. Paiva B, Gutiérrez NC, Rosiñol L, et al. PETHEMA/GEM (Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma) Cooperative Study Groups. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012; 119(3): 687–691.
  24. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008; 113(2): 355–359.
  25. Martinez-Lopez J, Blade J, Mateos MV, et al. Grupo Español de MM, Programa para el Estudio de la Terapé utica en Hemopatía Maligna. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011; 118(3): 529–534.
  26. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013; 31(4): 448–455.
  27. Rajkumar SV, Harousseau JL, Durie B, et al. International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18): 4691–4695.
  28. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8): e328–e346.
  29. Giarin MM, Giaccone L, Sorasio R, et al. Serum Free Light Chain Ratio, Total  /  Ratio, and Immunofixation Results Are Not Prognostic Factors after Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma. Clin Chem. 2009; 55(8): 1510–1516.
  30. Hari P, Pasquini MC, Logan BR, et al. Immunoglobulin Free Light Chain (FLC) and Heavy Chain/Light Chain (HLC) Assays - Comparison with Electrophoretic Responses in Multiple Myeloma (MM). ASH Annual Meeting Abstracts. 2011; 118(21): 2877.
  31. Kapoor P, Gertz MA, Dispenzieri A, et al. Importance of Achieving Sustained Stringent Complete Response (sCR) Following Autologous Stem Cell Transplantation in Multiple Myeloma. ASH Annual Meeting Abstracts. 2012; 120(21): 1988.
  32. Martínez-López J, Paiva B, López-Anglada L, et al. Spanish Multiple Myeloma Group / Program for the Study of Malignant Blood Diseases Therapeutics (GEM / PETHEMA) Cooperative Study Group. Critical analysis of the stringent complete response in multiple myeloma: contribution of sFLC and bone marrow clonality. Blood. 2015; 126(7): 858–862.
  33. Ludwig H, Slavka G, Hubl W, et al. Usage of HLC-Ratio, FLC-Ratio, Ife, PBMC Infiltration and Isotype Suppression At Best Response Reveals Isotype Suppression As Most Powerful Parameter for Identification of Multiple Myeloma Patients with Long Survival. ASH Annual Meeting Abstracts. 2012; 120(21): 1817.
  34. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012; 119(19): 4375–4382.
  35. Rawstron AC, Fazi C, Agathangelidis A, et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia. 2016; 30(4): 929–936.
  36. Paiva B, Almeida J, Pérez-Andrés M, et al. Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell-related disorders. Cytometry B Clin Cytom. 2010; 78(4): 239–252.
  37. Paiva B, Cedena MT, Puig N, et al. Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas (GEM/PETHEMA) Cooperative Study Groups. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood. 2016; 127(25): 3165–3174.
  38. Sarasquete ME, García-Sanz R, González D, et al. Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica. 2005; 90(10): 1365–1372.
  39. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014; 123(20): 3073–3079.
  40. Fraioli F, Punwani S. Clinical and research applications of simultaneous positron emission tomography and MRI. Br J Radiol. 2014; 87(1033): 20130464.
  41. Martinez-Lopez J, Sanchez-Vega B, Barrio S, et al. Analytical and clinical validation of a novel in-house deep-sequencing method for minimal residual disease monitoring in a phase II trial for multiple myeloma. Leukemia. 2017; 31(6): 1446–1449.
  42. Wale A, Pawlyn C, Kaiser M, et al. Frequency, distribution and clinical management of incidental findings and extramedullary plasmacytomas in whole body diffusion weighted magnetic resonance imaging in patients with multiple myeloma. Haematologica. 2016; 101(4): e142–e144.
  43. Corradini P, Voena C, Tarella C, et al. Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol. 1999; 17(1): 208–215.
  44. Davies FE, Forsyth PD, Rawstron AC, et al. The impact of attaining a minimal disease state after high-dose melphalan and autologous transplantation for multiple myeloma. Br J Haematol. 2001; 112(3): 814–819.
  45. Galimberti S, Benedetti E, Morabito F, et al. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res. 2005; 29(8): 961–966.
  46. Korthals M, Sehnke N, Kronenwett R, et al. The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter. Biol Blood Marrow Transplant. 2012; 18(3): 423–431.e3.
  47. Ladetto M, Brüggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2013; 28(6): 1299–1307.
  48. Martínez-Sánchez P, Montejano L, Sarasquete ME, et al. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. Br J Haematol. 2008; 142(5): 766–774.
  49. Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia. 2014; 28(2): 391–397.
  50. Putkonen M, Kairisto V, Juvonen V, et al. Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. Eur J Haematol. 2010; 85(5): 416–423.
  51. Mateos M, et al. V., Martinez-Lopez J., Hernandez M.-T. Comparison of Sequential Vs Alternating Administration of Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) in Elderly Pts with Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial. Blood. 2014; 124(21): 178–178.
  52. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014; 32(25): 2712–2717.
  53. Paiva B, Chandia M, Puig N, et al. The prognostic value of multiparameter flow cytometry minimal residual disease assessment in relapsed multiple myeloma. Haematologica. 2014; 100(2): e53–e55.
  54. Zent CS, Wilson CS, Tricot G, et al. Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated with high-dose therapy and hematopoietic cell transplantation. Blood. 1998; 91(9): 3518–3523.
  55. Korde N, Mailankody S, Roschewski M, et al. Minimal Residual Disease (MRD) Testing in Newly Diagnosed Multiple myeloma (MM) Patients: A Prospective Head-to-Head Assessment of Cell-Based, Molecular, and Molecular-Imaging Modalities. Blood. 2014; 124(21): 2105–2105.
  56. Moreau P, Attal M, Caillot D, et al. Prospective Evaluation of Magnetic Resonance Imaging and [(18)F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study. J Clin Oncol. 2017; 35(25): 2911–2918.
  57. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011; 118(23): 5989–5995.
  58. Rawstron AC, Gregory WM, de Tute RM, et al. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood. 2015; 125(12): 1932–1935.
  59. Flanders A, Stetler-Stevenson M, Landgren O. Minimal residual disease testing in multiple myeloma by flow cytometry: major heterogeneity. Blood. 2013; 122(6): 1088–1089.
  60. van Dongen JJM, Lhermitte L, Böttcher S, et al. EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708). EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012; 26(9): 1908–1975.
  61. Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia. 2014; 28(2): 391–397.
  62. Ladetto M, Bruggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014; 28(6): 1299–1307.
  63. Takamatsu H, Murata R, Zheng J, et al. Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Multiple Myeloma. Blood. 2014; 124(21): 2003–2003.
  64. Jasielec J, Dytfeld D, Griffith KA, et al. Minimal Residual Disease Status Predicts Progression-Free Survival in Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated with Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (KRd). Blood. 2014; 124(21): 2127–2127.



Hematology in Clinical Practice