In-depth look at specific data-sets; which ones meet requirements? Individual data owners /cooperative groups

Transcription

1 In-depth look at specific data-sets; which ones meet requirements? Individual data owners /cooperative groups

2 Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) in transplant eligible patients with newly diagnosed multiple myeloma (MM): results from the EMN02/HO95 phase 3 trial

3 Methods MM patients enrolled in the RV-MM-COOP-0556 (EMN02/HO95 MM; NCT ) Newly diagnosed 65 years MRD assessement in patients achieving suspected CR before lenalidomide maintenance N: 706 N: 459 N: VCD CTX + PBSC harvest R1 HDM1-2 N: 506 R2 2 VRD N: VMP No cons Lenalidomide maintenance CR: complete response; N: number of patients ; V, bortezomib; C, cyclophosphamide; D, dexamethasone; CTX: cyclophosphamide 2-3g/mq, PBSC: peripheral stem cell collection, HDM: high dose melphalan 200mg/mq, R, lenalidomide; M, melphalan; P, prednisone; Cons: consolidation, Maint: maintenanc; Cavo M et al. ASH 2016; Abstract 673. Sonneveld P. et al. ASH 2016; Abstract 292 Pre Maint Maint Maint Maint Maint EVERY 6 MONTHS UNTIL CLINICAL RELAPSE

4 Methods MM patients enrolled in the RV-MM-COOP-0556 (EMN02/HO95 MM; NCT ) Newly diagnosed 65 years MRD assessement in patients achieving suspected CR before lenalidomide maintenance N: 706 N: 459 N: VCD CTX + PBSC harvest R1 HDM1-2 N: 506 R2 2 VRD N: VMP No cons Lenalidomide maintenance CR: complete response, N: number of patients ; V, bortezomib; C, cyclophosphamide; D, dexamethasone; CTX: cyclophosphamide 2-3g/mq, PBSC: peripheral stem cell collection, HDM: high dose melphalan 200mg/mq, R, lenalidomide; M, melphalan; P, prednisone; Cons: consolidation, Maint: maintenanc; Cavo M et al. ASH 2016; Abstract 673. Sonneveld P. et al. ASH 2016; Abstract 292 Pre Maint Maint Maint Maint Maint EVERY 6 MONTHS UNTIL CLINICAL RELAPSE

5 Methods Sample logistics in the EMNO2 MRD study Samples were centralized in 3 laboratories from 10 countries 2 workshops: 1) Orlando, (ASH) December ) Rotterdam, May 2016 Brno, Czech republic Rotterdam, The Netherlands Turin, Italy

6 Tube 1: Tube 2: Methods - Sampling: bone marrow - Processation: within hours - Preparation: Bulk-lysis protocol (EuroFlow) -Data acquisition: 2 x 10 6 leucocytes or 1 x 10 4 plasma cells - Cut-off for MRD positivity: 20 clonal plasma cells - Maximal sensitivity: 1 x 10-5 Brno, Czech republic Rotterdam, The Netherlands Turin, Italy van Dongen JJ et al. Leukemia Sep;26(9): Kalina T et al. Leukemia Sep;26(9):

7 Results Quality checks were done among the 3 European laboratories to compare sensitivity and to show correlation between protocols Hofste op Bruinink D et al. ASH 2016; Poster 2072

8 Age Median, yrs Range (IQR) ISS stage at diagnosis, N (%) I II III FISH RISK, N (%) Standard High Missing Random A, N (%) HDM1-2 VMP Random B, N (%) VRD no consolidation off Results Patient characteristics (n = 316) (44) 120 (38) 57 (18) 186 (52) 70 (22) 60 (19) 199 (63) 117 (37) 160 (51) 144 (46) 12 (3) IQR: interquartile range, ISS: International Staging System, FISH : fluorescence in situ hybridization, standard risk : del17 and t(4;14) and t(14; 16) negative, High risk: del17 and/or t(4;14) and/or t(14; 16) positive

9 Results MRD status at pre-maintenance Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation >1 year of Lenalidomide % 24% MRD positive Pre maintenance MRD positive MRD negative % of patients % 52% LEN maintenance 6-12 months

10 Results MRD status during maintenance Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation >1 year of Lenalidomide 100 4% months MRD positive Pre maintenance % of patients % 52% 6-12 months 0 LEN maintenance MRD negative

11 Results Progression free Survival: Median Follow-Up from MRD enrollement of 33 Months yr PFS 77% Progression-free survival N = 316 MRD negative MRD positive Median PFS NR 38 months 52% 0.00 HR (95% CI) P value 0.33 ( ) < Numbers at risk MRD Negative MRD Positive Months

12 Results PFS by Random 1 VCD-ASCT vs VCD-VMP 1.00 Progression-free survival (%) Time (months) Number at risk ASCT VMP ASCT VMP ASCT VMP PFS median, mos NR 42.5 PFS at 3 yrs, % Cavo M et al. ASH 2016; Abstract 673. Cavo M et al. ASCO 2017; Abstract

13 Results Indipendence from treatment MRD for ARM A MRD for ARM B Progression-free survival Progression-free survival Numbers at risk MRD Negative MRD Positive MRD negative MRD positive P= Months MRD negative MRD positive P= Months

14 Results Landmark analysis at 1 year of len maintenance VCD-int- ± cons Lenalidomide Continuous Therapy yr PFS Progression-free survival MRD negative MRD positive 92% 65% 0.00 P< Months Preliminary results: Longer follow-up needed Int: intensification; Cons: consolidation 85% were persistent MRD negative (first negativity pre-maintenance)

15 Results Multivariable Cox analysis for PFS HR (95% CI) p value MRD Negative vs Positive 0.33 ( ) < ISS II vs III 0.71 ( ) I vs III 0.39 ( ) Citogenetic Risk Standard vs High 0.34 ( ) < Age >60 vs ( ) Sex Female vs Male 1.27 ( ) Lower risk of progression/death Higher risk of progression/death * Adjusted for random therapies

16 Results Subgroup analyses for PFS HR (95% CI) Interaction-p Overall 0.33 ( ) ISS I 0.51 ( ) II 0.39 ( ) III 0.07 ( ) Citogenetic Risk Standard 0.64 ( ) High 0.11 ( ) Age ( ) > ( ) Sex Female 0.27 ( ) Male 0.38 ( ) Lower risk for MRD - * Adjusted for random therapies

17 Results Subgroup analyses for PFS: High Risk patients and MRD FISH HIGH RISK ISS III Progression-free survival yr PFS 79% 27% FISH High-MRD Neg FISH High-MRD pos Progression-free survival % 33% 2-yr PFS ISS III-MRD pos ISS III-MRD Neg Months Months Del17p : 25 patients; 8/9 MRD + relapsed, 5/16 (31%) MRD- relapsed t (4; 14): 41 patients; 5/6 MRD + relapsed, 10/35 (28) MRD - relapsed t (14; 16): 10 patients, all MRD - at pre-maintenance

18 Conclusions MRD by MFC is a strong prognostic factor in MM patients receiving intensification with novel agents or transplant During Lenalidomide maintenance 48% of MRD positive patients with at least one evaluation after 1 year of therapy became MRD-negative The achievement of MRD negativity suggest the importance of deep response in high-risk MM patients defined by FISH abnormalities and ISS stage

19 Acknowledgments Divisione di Ematologia 1 Azienda Ospedaliero Universitaria Citta della Salute e della Scienza, Torino, Italy. Prof. Mario Boccadoro Prof. Antonio Palumbo Dr. Sara Bringhen Dr. Alessandra Larocca Dr. Francesca Gay Dr. Mariella Genuardi Babak Myeloma Group, Masaryk University, Brno, Czech Republic Prof. Roman Hajek Transplant Unit, nurses, patients and all participating centers Data Managing Staff Department of Hematology, Erasmus Universisty Medical Center, Rotterdam, Netherlands Prof. Pieter Sonneveld Dr. Davine Hofste op Bruinink Cytofluorimetric laboratories: Turin: Paola Omedé, Milena Gilestro, Vittorio Muccio, Elona Saraci Rotterdam: Vincent Van der Velden Brno: Lucie Říhová Statisticians: Stefano Spada and Bronno Van der Holt

20 EMN-02 MRD Workshop. Rotterdam, The Netherlands May 2016 Thank you!