Minimal residual disease assessment by multiparameter flow cytometry in transplant-eligible myeloma in the EMN02/HOVON 95 MM trial

Stefania Oliva*, Davine Hofste op Bruinink, Lucie Rihova, Mattia D’Agostino, Lucia Pantani, Andrea Capra, Bronno van der Holt, Rossella Troia, Maria Teresa Petrucci, Tania Villanova, Pavla Vsianska, Romana Jugooa, Claudia Brandt-Hagens, Milena Gilestro, Massimo Offidani, Rossella Ribolla, Monica Galli, Roman Hajek, Francesca Gay, Michele CavoPaola Omedé, Vincent H.J. van der Velden, Mario Boccadoro, Pieter Sonneveld

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number106
JournalBlood Cancer Journal
Volume11
Issue number6
DOIs
Publication statusPublished - 3 Jun 2021

Bibliographical note

Funding Information:
This work was supported by Ministry of Health of the Czech Republic, grant Nr. 17-30089A.

Funding Information:
S.O. has received honoraria from Amgen, Celgene, and Janssen; has served on the advisory boards for Adaptive Biotechnologies, Janssen, Amgen, and Takeda. M.D. has received honoraria for lectures from Sanofi; has served on the advisory board for GSK. L.P. has received honoraria from Celgene, Janssen, Amgen, Takeda. M.T.P. has received honoraria from and served on the advisory board for Celgene, Janssen-Cilag; Bristol-Myers-Squibb. Takeda, Amgen, Sanofi, GSK. M.O. has received honoraria from and served on the advisory board for Amgen, Bristol-Myers-Squibb, Celgene, Janssen, Takeda. R.R. has served on the advisory board for Janssen. M.G. has received honoraria from Bristol-Myers-Squibb, Celgene, Janssen, Takeda. R.H. has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. F.G. has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol-Myers Squibb, AbbVie, and GSK; has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol-Myers Squibb, AbbVie, GSK, Roche, Adaptive Biotechnologies, and Oncopeptides. M.C. has received honoraria from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Takeda, AbbVie, Sanofi, and Adaptive Biotechnologies, and is a member of speakers’ bureaus for Janssen and Celgene. V. H.J.v.d.V. has Laboratory Service Agreements with Pfizer, Janssen, Novartis/ Navigate, BD Biosciences; and is the inventor of the EuroFlow-owned patents PCT/ NL2010/050332 and PCT/NL2013/0505420. M.B. has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GSK; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma. P.S. received honoraria from and research funding from Amgen, Celgene, Janssen, SkylineDx, and Takeda. All the other authors have no conflicts of interest.

Publisher Copyright:
© 2021, The Author(s).

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