Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10-4-10-5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

Azienda Ospedaliero Universitaria di Bologna Seràgnoli Institute of Hematology Department of Experimental Diagnostic and Specialty Medicine Bologna University School of Medicine S Orsola Malpighi Hospital Bologna Italy

Clinica di Ematologia Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto 1 G M Lancisi G Salesi di Ancona Ancona Italy

Department of Clinical Hematology University Hospital Brno Brno Czech Republic

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Hematology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Immunology Laboratory Medical Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Dipartimento di Oncologia ed Ematologia ASST Papa Giovanni XXIII Bergamo Italy

Division of Hematology ASST Spedali Civili di Brescia Brescia Italy

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Hematology Department of Translational and Precision Medicine Azienda Ospedaliera Policlinico Umberto 1 Sapienza University of Rome Rome Italy

HOVON Data Center Department of Hematology Erasmus MC Cancer Institute Rotterdam The Netherlands

Laboratory Medical Immunology Department of Immunology Erasmus University Medical Center Rotterdam The Netherlands

Myeloma Unit Division of Hematology University of Torino Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Torino Italy

Zobrazit více v PubMed

D’Agostino M., Bertamini L., Oliva S., Boccadoro M. & Gay F. Pursuing a curative approach in multiple myeloma: a review of new therapeutic strategies. Cancers (Basel)11, 10.3390/cancers11122015 (2019). PubMed PMC

Munshi NC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3:28–35. doi: 10.1001/jamaoncol.2016.3160. PubMed DOI PMC

Lahuerta J-J, et al. Depth of response in multiple myeloma: a pooled analysis of three PETHEMA/GEM clinical trials. J. Clin. Oncol. 2017;35:2900–2910. doi: 10.1200/JCO.2016.69.2517. PubMed DOI PMC

Kumar S, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–e346.. doi: 10.1016/S1470-2045(16)30206-6. PubMed DOI

Landgren O, Owen RG. Better therapy requires better response evaluation: paving the way for minimal residual disease testing for every myeloma patient. Cytom. Part B Clin. Cytom. 2016;90:14–20. doi: 10.1002/cyto.b.21273. PubMed DOI

Cavo M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a mult. Lancet Haematol. 2020;7:e456–e468.. doi: 10.1016/S2352-3026(20)30099-5. PubMed DOI

Kalina T, et al. EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia. 2012;26:1986–2010. doi: 10.1038/leu.2012.122. PubMed DOI PMC

van Dongen JJM, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26:1908–75. doi: 10.1038/leu.2012.120. PubMed DOI PMC

Hofste op Bruinink, D. et al. Standardization of flow cytometric minimal residual disease assessment in 2 international clinical trials–a feasibility study from the European Myeloma Network. Haematologica10.3324/haematol.2020.267831 (2021). PubMed PMC

Perrot A, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132:2456–2464. doi: 10.1182/blood-2018-06-858613. PubMed DOI PMC

Simon R, Makuch RW. A non‐parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non‐responder bias. Stat. Med. 1984;3:35–44. doi: 10.1002/sim.4780030106. PubMed DOI

Landgren O, Devlin S, Boulad M, Mailankody S. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. Bone Marrow Transplant. 2016;51:1565–1568. doi: 10.1038/bmt.2016.222. PubMed DOI PMC

Paiva B, et al. Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. Blood. 2016;127:3165–3174. doi: 10.1182/blood-2016-03-705319. PubMed DOI

Papadimitriou K, et al. Deep phenotyping reveals distinct immune signatures correlating with prognostication, treatment responses, and MRD status in multiple myeloma. Cancers (Basel) 2020;12:1–19. PubMed PMC

Paiva B, et al. 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;27:2056–2061. doi: 10.1038/leu.2013.166. PubMed DOI

Michor F, et al. Dynamics of chronic myeloid leukaemia. Nature. 2005;435:1267–1270. doi: 10.1038/nature03669. PubMed DOI

Tang M, et al. Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood. 2011;118:1622–1631. doi: 10.1182/blood-2011-02-339267. PubMed DOI PMC

Hoffmann H, et al. The prognostic potential of monitoring disease dynamics in NPM1-positive acute myeloid leukemia. Leukemia. 2019;33:1531–1534. doi: 10.1038/s41375-018-0371-y. PubMed DOI

Lee S, et al. Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2012;26:2367–2374. doi: 10.1038/leu.2012.164. PubMed DOI

Attal M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N. Engl J. Med. 2017;376:1311–1320. doi: 10.1056/NEJMoa1611750. PubMed DOI PMC

Palumbo A, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N. Engl J. Med. 2014;371:895–905. doi: 10.1056/NEJMoa1402888. PubMed DOI

McCarthy PL, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N. Engl J. Med. 2012;366:1770–1781. doi: 10.1056/NEJMoa1114083. PubMed DOI PMC

Attal M, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl J. Med. 2012;366:1782–1791. doi: 10.1056/NEJMoa1114138. PubMed DOI

Palumbo A, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N. Engl J. Med. 2012;366:1759–1769. doi: 10.1056/NEJMoa1112704. PubMed DOI

Goldschmidt H, et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020;34:1853–1865. doi: 10.1038/s41375-020-0724-1. PubMed DOI

de Tute, R. M. et al. Minimal residual disease in the maintenance setting in myeloma: prognostic significance and impact of lenalidomide. Blood130, Abstract #904 [ASH 2017 59th Meeting] (2017).

Alonso R, et al. Prolonged lenalidomide maintenance therapy improves the depth of response in multiple myeloma. Blood Adv. 2020;4:2163–2171. doi: 10.1182/bloodadvances.2020001508. PubMed DOI PMC

Hahn TE, et al. Minimal residual disease (MRD) assessment before and after autologous hematopoietic cell transplantation (AutoHCT) and maintenance for multiple myeloma (MM): results of the prognostic immunophenotyping for myeloma response (PRIMeR) Study. Biol. Blood Marrow Transplant. 2019;25:S4–S6. doi: 10.1016/j.bbmt.2018.12.687. DOI

Paiva B, et al. Measurable residual disease by next-generation flow cytometry in multiple myeloma. J. Clin. Oncol. 2020;38:784–792. doi: 10.1200/JCO.19.01231. PubMed DOI

De Tute R, et al. Sequential minimal residual disease (MRD) monitoring: results from the UK Myeloma XI trial. Clin. Lymphoma Myeloma Leuk. 2019;19:e45–e46.. doi: 10.1016/j.clml.2019.09.069. DOI

Stadtmauer EA, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J. Clin. Oncol. 2019;37:589–597. doi: 10.1200/JCO.18.00685. PubMed DOI PMC

Moreau P, et al. Prospective evaluation of magnetic resonance imaging and [18F]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. J. Clin. Oncol. 2017;35:2911–2918. doi: 10.1200/JCO.2017.72.2975. PubMed DOI PMC

Rasche L, et al. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia. 2019;33:1713–1722. doi: 10.1038/s41375-018-0329-0. PubMed DOI PMC

Moreau P, et al. Evaluation of the prognostic value of positron emission tomography-computed tomography (PET-CT) at diagnosis and follow-up in transplant-eligible newly diagnosed multiple myeloma (te ndmm) patients treated in the phase 3 cassiopeia study: results of the cassiopet companion study. Blood. 2019;134:692–692. doi: 10.1182/blood-2019-123143. DOI

Madduri, D. et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-Cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Blood134, Abstract #577 [ASH 2019 61st Annual Meeting] (2019).

Munshi NC, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. J. Clin. Oncol. 2020;38:8503–8503. doi: 10.1200/JCO.2020.38.15_suppl.8503. DOI

Moreau P, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38. doi: 10.1016/S0140-6736(19)31240-1. PubMed DOI

Voorhees PM, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–945. doi: 10.1182/blood.2020005288. PubMed DOI PMC

Costa, L. J. et al. First clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): interim results of a phase 1 multicenter trial. Blood134, Abstract #143 [updated results presented at ASH 2019] (2019).

MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials