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. 2023 Jun 9:60:102017.
doi: 10.1016/j.eclinm.2023.102017. eCollection 2023 Jun.

Impact of minimal residual disease standardised assessment by FDG-PET/CT in transplant-eligible patients with newly diagnosed multiple myeloma enrolled in the imaging sub-study of the FORTE trial

Elena Zamagni  1   2 , Stefania Oliva  3 , Francesca Gay  3   4 , Andrea Capra  4 , Delia Rota-Scalabrini  5 , Mattia D'Agostino  3   4 , Angelo Belotti  6 , Monica Galli  7 , Manuela Racca  8 , Renato Zambello  9 , Barbara Gamberi  10 , Domenico Albano  11 , Luca Bertamini  3   4 , Annibale Versari  12 , Mariella Grasso  13 , Nicola Sgherza  14 , Claudia Priola  4 , Francesca Fioritoni  15 , Francesca Patriarca  16 , Gabriella De Cicco  1   2 , Tania Villanova  4 , Anna Pascarella  17 , Pietro Zucchetta  18 , Paola Tacchetti  1 , Stefano Fanti  19 , Katia Mancuso  1   2 , Simona Barbato  1   2 , Mario Boccadoro  4 , Pellegrino Musto  14   20 , Michele Cavo  1   2 , Cristina Nanni  19
Affiliations

Impact of minimal residual disease standardised assessment by FDG-PET/CT in transplant-eligible patients with newly diagnosed multiple myeloma enrolled in the imaging sub-study of the FORTE trial

Elena Zamagni et al. EClinicalMedicine. .

Abstract

Background: 18F-FDG-PET/CT is the current standard technique to define minimal residual disease (MRD) outside the bone marrow (BM) in multiple myeloma (MM), recently standardised applying the Deauville scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) and defining the complete metabolic response (CMR) as uptake below the liver background (DS <4).

Methods: In this analysis, we aimed at confirming the role of CMR, and complementarity with BM multiparameter flow cytometry (MFC) at 10-5, in an independent cohort of newly diagnosed transplant-eligible MM patients previously enrolled in the phase II randomised FORTE trial. 109 of the 474 global patients enrolled in the trial between February 23, 2015, and April 5, 2017, who had paired PET/CT (performed at baseline [B] and preceding maintenance therapy [PM]) and MFC evaluation, were included in this analysis.

Findings: At B, 93% of patients had focal lesions within the bones (FS ≥4 in 89%) and 99% increased BM uptake (BMS ≥4 in 61%). At PM, CMR was achieved in 63% of patients, which was a strong predictor for prolonged PFS in univariate analysis at landmark time PM (HR 0.40, P = 0.0065) and in Cox multivariate analysis (HR 0.31, P = 0.0023). Regarding OS, a trend in favour of CMR was present in univariate (HR 0.44, P = 0.094), and Cox multivariate model (HR 0.17, P = 0.0037). Patients achieving both PET/CT CMR and MFC negativity at PM showed significantly extended PFS in univariate (HR 0.45, P = 0.020) and multivariate analysis (HR 0.41, P = 0.015).

Interpretation: We herein confirm the applicability and validity of DS criteria to define CMR and its prognostic relevance and complementarity with MFC at the BM level.

Funding: Amgen, Celgene/Bristol Myers Squibb, Italian Ministry of Health (RC-2022-2773423).

Keywords: Complete metabolic response (CMR); FDG-PET/CT; Minimal residual disease (MRD); Multiparameter flow cytometry (MFC); Newly diagnosed multiple myeloma (NDMM).

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Conflict of interest statement

EZ receives honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda. SO has received honoraria from Amgen, Celgene/Bristol Myers Squibb, and Janssen; has served on the advisory boards for Adaptive Biotechnologies, Janssen, Amgen, and Takeda. FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. MD has received honoraria for lectures from GlaxoSmithKline, Sanofi, and Janssen; has served on the advisory boards for GlaxoSmithKline, Sanofi, and Bristol Myers Squibb. AB has served on the advisory board for Amgen, Janssen, Takeda, Celgene, GlaxoSmithKline. MGa has received honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda, GlaxoSmithKline. RZ has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, GlaxoSmithKline, and Pfizer. BG has received honoraria from Amgen, Bristol Myers Squibb, Janssen, and Takeda; has served on the advisory boards for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda. AV received honoraria from Novartis, Advanced Accelerator Applications and GE Healthcare. FP receives honoraria and travel accommodation support from Celgene, Janssen, Takeda and has served on the advisory boards for Celgene BMS, Janssen, Amgen, GlaxoSmithKline. PT has received honoraria from Janssen, Celgene, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, GlaxoSmithKline, and Pfizer; has served on the data safety monitoring boards or advisory boards for Janssen, Celgene, Bristol Myers Squibb, and Amgen. KM has received honoraria from Celgene, Takeda, Amgen, Sanofi, Janssen. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. PM has received honoraria from and/or served on scientific boards for AbbVie, Alexion, Amgen, AstraZeneca, Astellas, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, GlaxoSmithKline, Incyte, Janssen, Jazz, Novartis, Pfizer, Roche, Sanofi, and Takeda. MC has received honoraria from Janssen, Celgene, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Takeda, AbbVie, Sanofi, Pfizer, and Adaptive Biotechnologies; has served on the advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Amgen, GlaxoSmithKline, and Pfizer; has served on the speakers’ bureaus for Janssen, Celgene, and Sanofi. CN has been PET revisor for Keosys-Sanofi. The other authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Progression-free survival (a) and overall survival (b) according to pre-maintenance PET/CT complete metabolic response Abbreviations. CI, Confidence interval; CMR, Complete metabolic response; HR, Hazard ratio; Neg, Negativity; P, P-value; PET/CT, positron emission tomography/computed tomography; PFS, Progression-free survival; Pos, Positivity.
Fig. 2
Fig. 2
Forest plots for PET/CT pre maintenance for PFS (a) and OS (b). ∗High-risk cytogenetics were defined in accordance with the International Myeloma Working Group (IMWG) criteria: presence of t (4; 14) and/or t (14; 16) and/or del (17p). Abbreviations. ASCT, Autologous stem-cell transplantation; CI, Confidence interval; HR, Hazard ratio; IMWG, International myeloma working group; ISS, International staging system stage; ITT, Intention to treat; MRD, Minimal residual disease; KCd, carfilzomib-cyclophosphamide-dexamethasone; MEL200, melphalan at 200 mg/m2; KCd plus ASCT, 4 KCd induction cycles, MEL200-ASCT, 4 KCd consolidation cycles; KRd, carfilzomib-lenalidomide-dexamethasone; KRd12, 12 KRd cycles without ASCT; KRd plus ASCT, 4 KRd induction cycles, MEL200-ASCT, 4 KRd consolidation cycles; OS, Overall survival; P, P-value; PET/CT, positron emission tomography/computed tomography; PFS, Progression-free survival; R1, first randomisation (induction-intensification-consolidation treatment).
Fig. 3
Fig. 3
Progression-free survival (a) and overall survival (b) according to pre-maintenance PET/CT complete metabolic response and multiparameter flow cytometry negativity Abbreviations. ∧, and; CI, Confidence interval; HR, Hazard ratio; MFC, Multiparameter flow cytometry; MRD, Minimal residual disease; Neg, Negativity; P, P-value; PET/CT, Positron emission tomography/computed tomography; PFS, Progression-free survival; Pos, Positivity.
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