MRD Evaluation By PET/CT According to Deauville Criteria Combined with Multiparameter Flow Cytometry in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients Enrolled in the Phase II Randomized Forte Trial
Authors: Zamagni Elena , Nanni Cristina , Gay Francesca , Dozza Luca , Rota Scalabrini Delia , Omedé Paola , Ribolla Rossella , Galli Monica , Racca Manuela , Zambello Renato , Gamberi Barbara , Albano Domenico , Versari Annibale , Grasso Mariella , Troia Rossella , Spadano Tonino , Patriarca Francesca , Ruggeri Marina , Rensi Marco , Pascarella Anna , Zucchetta Pietro , Tacchetti Paola , Fanti Stefano , Boccadoro Mario , Cavo Michele , Oliva Stefania 
Published: November 2019

Background: 18F-FDG-PET/CT is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in multiple myeloma (MM) patients. A joined analysis of two prospective randomized trials in newly diagnosed transplant-eligible MM (NDTEMM) patients applied for the first time the Deauville Scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) and showed the liver background (DS < 4) to be the best cut-off to define PET negativity after therapy (Zamagni et al, ASH 2018). Multiparameter Flow cytometry (MFC) at the sensitivity level of 10-5 is one of the standardized methods to assess MRD in the BM (Kumar SK, Lancet Oncol 2016). In this analysis, we aimed at comparing MRD data by PET/TC assessment and MFC in the multicenter phase II randomized FORTE trial for NDTEMM patients.
Methods: NDTEMM patients ≤65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRD) induction - autologous stem cell transplantation (ASCT) intensification-KRd consolidation (arm A); KRd12 (arm B) and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT intensification-KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or lenalidomide plus carfilzomib. MRD evaluation was performed by 8-color second-generation flow cytometry (sensitivity 10-5) in patients who achieved at least VGPR before maintenance (Gay F, ASCO 2019). PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM) and the DS were applied both in the BM and FLs as previously described. Cramér's V coefficient was used to measure the concordance between PET/TC and MFC; Fisher or X2 tests were adopted, where appropriate, to evaluate the statistical significance, at the level of 0.05.
Results: 182 out of the 474 global patients enrolled in the trial had a matched PET/CT and MFC evaluation available and were included in the present analysis. Baseline characteristics of the patients were as follows: median age 57 years, ISS and R-ISS stage III 18% and 10%, respectively, high-risk cytogenetics (t(4;14) ± del(17p) ± t(14;16), detected by FISH) 26%, reflecting baseline clinical features of the entire FORTE population.
At B, 92% of the patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 11% presented extra-medullary lesions and nearly all the patients had increased BM uptake, with a median SUVmax of 3.3 [IQR: 2.8-4.3]. FS and BMS ≥4 were present in 87% and 59% of the patients, respectively. A higher FS at B was significantly correlated with ISS stage III (P= 0.04), while higher BMS with lower hemoglobin level (P= 0.002) and higher free light chain ratio (P= 0.004). At PM, PET/TC negativity according to DS < 4, was present in 78% in the FLs and 85% in the BM, respectively. No significant correlations between PET/CT negativity after therapy and baseline prognostic factors or PET/CT characteristics were found. 95% and 67.5% of the patients achieved ≥ VGPR and CR as best response, respectively, while 75% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS < 4 at PM (P= 0.013).
We analyzed the concordance between MRD results by the two techniques and Cramér's V coefficient measured a strong association, with a value of 0.76 (p<0.001). In particular, concordance between PET/CT BMS and MFC was 94% (80% both negative, 14% both positive) while 6% were PET/CT negative and MFC positive. FS and MFC were concordant in 63% of the cases (57% both negative, 6% both positive) while 20% were PET/CT negative and MFC positive and 17% showed residual FLs in the context of MFC negativity. The persistence of MFC positivity at PM was significantly related to a higher BMS and SUVmax at the same time-point.
Conclusion: In conclusion, the present analysis confirms the applicability and validity of DS criteria for the definition of PET/CT MRD outside the BM in an independent prospective series of NDTEMM patients. PET/CT negativity significantly correlated with the achievement of best CR. PET/CT and MFC at the sensitivity level of 10-5 showed a good concordance in the BM, while were also confirmed to be complementary outside (FLs). Future analyses will show the impact of PET/CT in comparison with BM MRD techniques on patient's outcomes.

Disclosures
Zamagni: Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau. Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Omedé:Janssen: Membership on an entity's Board of Directors or advisory committees. Galli:Janssen: Honoraria; Leadiant (Sigma-Tau): Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tacchetti:Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria; Oncopeptides: Honoraria, Speakers Bureau; BMS: Honoraria. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Oliva:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.