Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing

Stefania Oliva; Elisa Genuardi; Laura Paris; Mattia D'Agostino; Jennifer Rogers; Delia Rota-Scalabrini; Allison P Jacob; Francesca Patriarca; Mario Luppi; Paola Bertazzoni; Cristina Velluti; Andrea Capra; Elona Saraci; Marco Rossi; Alessandro Allegra; Roberto Mina; Massimo Gentile; Ilan R Kirsch; Angelo Belotti; Michele Cavo; Benedetto Bruno; Pellegrino Musto; Mario Boccadoro; Elena Zamagni; Francesca Gay

doi:10.1016/j.eclinm.2023.102016

Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing

EClinicalMedicine. 2023 Jun 9:60:102016. doi: 10.1016/j.eclinm.2023.102016. eCollection 2023 Jun.

Authors

Stefania Oliva¹, Elisa Genuardi², Laura Paris³, Mattia D'Agostino^{1

2}, Jennifer Rogers⁴, Delia Rota-Scalabrini⁵, Allison P Jacob⁶, Francesca Patriarca⁷, Mario Luppi⁸, Paola Bertazzoni⁹, Cristina Velluti², Andrea Capra², Elona Saraci², Marco Rossi¹⁰, Alessandro Allegra¹¹, Roberto Mina^{1

2}, Massimo Gentile¹², Ilan R Kirsch⁶, Angelo Belotti¹³, Michele Cavo^{14

15}, Benedetto Bruno^{1

2}, Pellegrino Musto^{16

17}, Mario Boccadoro², Elena Zamagni^{14

15}, Francesca Gay^{1

2}

Affiliations

¹ Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
² Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
³ Division of Hematology, ASST Papa Giovanni XXIII, Bergamo, Italy.
⁴ Multiple Myeloma Research Foundation (MMRF), Norwalk, CT, USA.
⁵ Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO - IRCCS, Torino, Italy.
⁶ Adaptive Biotechnologies, Seattle, WA, USA.
⁷ Hematologic Clinic and Transplant Center, University Hospital of Central Friuli, DAME, University of Udine, Udine, Italy.
⁸ Dipartimento di Scienze Mediche e Chirurgiche Materno Infantili e dell'Adulto, UNIMORE, UOC Ematologia, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
⁹ ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.
¹⁰ SOC Ematologia, Department of Oncology/Hematology, Azienda Ospedaliera Pugliese-Ciaccio and Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
¹¹ Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Messina, Italy.
¹² UOC Ematologia, AO Cosenza, Cosenza, Italy.
¹³ Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy.
¹⁴ IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.
¹⁵ Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.
¹⁶ Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University School of Medicine, Bari, Italy.
¹⁷ Hematology and Stem Cell Transplantation Unit, AOU Consorziale Policlinico, Bari, Italy.

Abstract

Background: Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients.

Methods: MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored.

Findings: Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10^-5 and 83% at the 10^-6 cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p < 0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10^-5), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p = 0.046) and NGS (56% vs 30%, p = 0.046).

Interpretation: The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome.

Funding: Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation.

Keywords: Autologous stem-cell transplantation (ASCT); Minimal residual disease (MRD); Multiparameter flow cytometry (MFC); Newly diagnosed multiple myeloma (NDMM); Next-generation sequencing (NGS).