Are We Integrating Biologic Advances in Multiple Myeloma Into Clinical Practice?

Transcription

1 Are We Integrating Biologic Advances in Multiple Myeloma Into Clinical Practice? Minimal Residual Disease: A Measurable and Relevant Endpoint in Treatment Xavier Leleu Service d Hématologie et Thérapie cellulaire Hôpital de la Milètrie, CHU, Poitiers, France

2 MRD: A Measurable and Relevant Endpoint in Treatment Depth of response in Myeloma What is MRD Are all CR the same Techniques: NGF vs NGS Is it just about prolongation of PFS as a surrogate for OS Prognostic role of MRD MRD impacts OS MRD Rate and relevance in current treatment options and strategies MRD in NDMM MRD in RRMM MRD Including high risk MM Depth of MRD matters Work to do Conclusion

3 Treatment advances have increased the likelihood of achieving CR ORR VGPR CR

4 The prognostic impact to CR comes from MRD Multicentric, prospective study of 445 NDMM, post ASCT, 1/3 CR 147/295 NDMM (GEM2) in CR post ASCT. MRD by MFC at day 1 after ASCT. 69 NDMM, GEM2/GEM25/GEM51, MRD assessment 9 months after enrolment P<,1 Not reached vs 81 months 5-year OS rates 87% vs 59% Not reached vs 59 months Kapoor et al., JCO, 21 Paiva et al., Blood, 28 Lahuerta et al., JCO, 217

5 Minimal Residual Disease, MRD Diagnosis 1 12 CR 1 1 Immunophenotypic CR. CMF (Sensibilité de 1-4 à 1-8 selon le nombre de couleurs (2 à 1 couleurs)) MRD scr Negative MRD < 1 6 CR icr Molecular CR. ASO-PCR (Se 1-5 ), NGS mcr

6 MRD is about Prolongs PFS as a surrogate for OS Tumor dormancy, the ultimate objective for cure Paiva et al., Blood, 215

7 Overall effect of MRD on OS MRD-negative status was associated with significantly better OS overall (HR,.57; 95%CI, ; P <.1) Munshi et al. JAMA Oncol 217;3:28-35.

8 Effect of MRD status on OS in CR patients MRD-negative status was associated with significantly better OS in CR patients (HR,.47; 95%CI, ; P <.1) Munshi et al. JAMA Oncol 217;3:28-35.

9 IFM 28 Phase NDMM, VRD x 3 - Transplant - VRD x 2 - Rev 1 year After induction After ASCT After consolidation Completed Therapy n (%) n=31 n=31 n=31 n=31 Negative MRD 4/25 (16) 14/26 (54) 15/26 (58) 21/3 (7) scr + CR 7 (23) 14 (45) 15 (48) 18 (58) VGPR 18 (58) 21 (68) 26 (84) 26 (84) MRD at Roussel et al. JCO 214

10 MRD-negative rate (%) Progression free and alive (%) POLLUX: DRd vs Rd - MRD-negative rate Phase 3 multicenter, early RRMM PFS 5 DRd Rd 1 Rd MRD 4 p <.1 p <.1 8 DRd MRD 3 3% 6 DRd MRD + 23% p < Rd MRD + 1 8% 1% 2 5% 2% MRD- (1 4 ) MRD- (1 5 ) MRD- (1 6 ) Months Response-evaluable set. Assessed by next generation sequencing (NGS) in bone marrow. Avet-Loiseau H. Oral presentation at IMW 217. New Delhi, India.

11 MRD-negative patients POLLUX: MRD by Cytogenetic Risk Status (1 5 ) % surviving without progression 35 3 MRD-negative rates PFS in high-risk patients ** *** 1 DRd MRD negative 32 8 per risk group, % a DRd MRD positive Rd MRD positive 5 2 DRd n = 28 High risk Rd n = 37 Standard risk DRd Rd n = 133 n = Months In POLLUX, high-risk patients treated with daratumumab achieve MRD negativity and remain progression free **P =.9. ***P =.1. a Percentage of patients within a given risk group and treatment arm. Weisel K et al., ASCO 217 ClinicalTrials.gov Identifiers: NCT

12 Patients without progression (%) Depth of MRD matters Phase 3 multicenter, IFM/DFCI 29, NDMM Randomize 1. MRD at post-maintenance RVDx3 RVDx3.9.8 <1-6 CY (3g/m2) MOBILIZATION Goal: 5 x1 6 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x1 6 cells/kg Melphalan 2mg/m 2 * + ASCT RVD x P-value (trend) : p<.1 [1-6;1-5[ [1-5;1-4[ >=1-4.2 RVD x 2 Revlimid 12 mos Revlimid 12 mos N at risk (events) <1-6 [1-6 ;1-5 [ [1-5 ;1-4 [ [1-4 ;1-3 [ () 86 () 86 () 86 () 86 (5) 77 (3) 61 (5) 36 () 1 29 () 29 () 29 () 29 () 28 (5) 22 (3) 16 (4) 4 (1) 1 23 () 23 () 23 () 23 (1) 22 (3) 19 (2) 14 (5) 3 () 2 4 () 4 () 4 () 4 (6) 33 (9) 23 (6) 15 (4) 4 (1) 2 3 Months since randomization Avet-Loiseau H. Oral presentation at IMW 217. New Delhi, India.

13 Patients (%) Role of treatment IFM 29 trial P<.1 25 positive MRD-Transplant positive MRD-RVD negative MRD_Transp negative MRD_RVD N at risk positive MRD-Transplant positive MRD-RVD negative MRD_Transp negative MRD_RVD Time since MRD assessment

14 Patients (%) Role cytogenetics IFM 29 trial P<.1 25 pos.mrd-high Risk pos.mrd-stdard Risk neg.mrd-high Risk neg.mrd-stdard Risk N at risk pos.mrd-high Risk pos.mrd-stdard Risk neg.mrd-high Risk neg.mrd-stdard Risk Time since MRD assessment

15 Work to do (1), MRD and Clonal selection 31% Lenalidomide/ dexamethasone 64% 64% 21% Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc % 72% Diagnosis ~2N Plasmacytoid Phenotype % 66% Remissio n ~2N Relapse 1 ~2N Plasmacytoid Phenotype 37% Relapse 2 ~2N Relapse 3 ~2N 19% 58% Bortezomib SGN-4 17% 78% Lymphoid Phenotype 34% 95% Plasma cell leukaemia ~3N 96 % % % Relapse 4 ~3N Lymphoid phenotype 63% 71% Melphalan/prednisone/ bortezomib (MPV) Keats et al., Blood, 212 Morgan et al., Oral communication

16 Patients without progression (%) Work to do (2) MRD and Best timing 1..9 MRD at pre-maintenance for MRD neg (FCM) Negative (<1-6) 1..9 MRD at post-maintenance for MRD neg (FCM) Negative (<1-6) Positive.7.6 Positive P-value : p=.2.4 P-value : p= N at risk (events) MRD neg (<1-6 ) MRD positive () 79 () 79 (2) 77 (2) 75 (4) 68 (3) 51 (2) 3 () 8 84 () 84 (1) 83 (5) 78 (3) 74 (13) 59 (5) 41 (6) 17 (2) 6 3 Months since randomization N at risk (events) MRD neg (<1-6 ) MRD positive () 69 () 69 () 69 () 69 (4) 63 (2) 5 (4) 29 () 9 42 () 42 () 42 () 42 (3) 38 (7) 31 (4) 21 (5) 5 (1) 1 3 Months since randomization Avet-Loiseau H. Oral presentation at IMW 217. New Delhi, India.

17 Work to do (3) MRD and MGUS like profile Paiva et al., Leukemia, 213

18 Work to do (4) MRD study Various ways to study the BM, BM sampling, PET CT. Thal/dex followed by tandem ASCT IFM 29/DFCI - Imajem Switch PET CT - Switch PET CT + p=.424 Months Zamagni et al, Blood 211 Moreau et al, Oral communication

19 Work to do (5) MRD and treatment decision Attal M IFM - Confidential IFM 218 MRD1 MRD2 Standard Risk PI + ImidsD- MoAB x6 - R HDT1 + PI + ImidsD-MoAB X4 PI + ImidsD-MoAB x7 R Maint A Maint B PI + ImidsD- MoAB x6 + HDT1 + PI + ImidsD- MoAB* x6 *diff PI, Imids,.. + HDT2 - R R Maint C Maint D Maint A Maint B High Risk PI + ImidsD- MoAB x6 HDT1 + PI + ImidsD- MoAB* x6 *diff PI, Imids,.. HDT2 Maint C or D

20 Minimal Residual Disease Assessment: Not Relevant for Clinical Practice Yet Sagar Lonial, MD Chair and Professor Department of Hematology and Medical Oncology Chief Medical Officer, Winship Cancer Institute Emory University School of Medicine

21 There are patients with old drugs and old tests that do well.. Functional cure? Martinez-Lopez et al, Blood 211

22 Impact of MRD: Meta-analysis Are these the same patients? Munshi et al, JAMA Oncol. 217;3(1):28-35.

23 Getting to Minimal Residual Disease (MRD): New Definitions for CR S.S. Patient CR Disease burden Newly diagnosed MRD Stringent CR Flow CR NGS CR 1 1-6?Cur e?. Antibodi es Genomi c Based Tx

24 Patients without progression (%) How you measure MRD impacts the results MRD at pre-maintenance MRD at post-maintenance <1-6.8 < P-value (trend) : p<.1 [1-6;1-5[ [1-5;1-4[ >= P-value (trend) : p<.1 [1-6;1-5[ [1-5;1-4[ >=1-4.2 N at risk (events) <1-6 [1-6 ;1-5 [ [1-5 ;1-4 [ [1-4 ;1-3 [ () 87 () 87 (2) 85 (2) 83 (6) 74 (4) 54 (3) 31 () 8 31 () 31 (1) 3 (2) 28 () 27 (4) 22 (1) 17 (2) 8 (1) 4 49 () 49 (2) 47 (2) 45 (2) 43 (7) 34 (4) 22 (6) 8 () 2 79 () 79 (9) 7 (11) 59 (9) 5 (11) 38 (6) 28 (9) 6 (3) 3 Months since randomization N at risk (events) <1-6 [1-6 ;1-5 [ [1-5 ;1-4 [ [1-4 ;1-3 [ () 86 () 86 () 86 () 86 (5) 77 (3) 61 (5) 36 () 1 29 () 29 () 29 () 29 () 28 (5) 22 (3) 16 (4) 4 (1) 1 23 () 23 () 23 () 23 (1) 22 (3) 19 (2) 14 (5) 3 () 2 4 () 4 () 4 () 4 (6) 33 (9) 23 (6) 15 (4) 4 (1) 2 3 Months since randomization Avet-Loiseau et al, ASH 215

25 Lahuerta et al, JCO 217 MRD testing is not a surrogate for Cure

26 PFS (%) OS (%) MRC Myeloma IX: PFS and OS Do Not Plateau MRD negativity at Day 1 post-asct was associated with improved PFS (P<.1) and OS (P=.183) PFS OS Median PFS MRD 28.6 months MRD months Months 96 since MRD assessment Numbers at risk: MRD MRD Months 96 since MRD assessment MRD status at Day 1 post-asct: MRD n=247; MRD+ n=15 1. Rawstron AC, et al. J Clin Oncol) Median OS MRD 8.6 months MRD+ 59. months Numbers at risk: MRD MRD

27 Avet-Loiseau et al, ASH Cannot use MRD to decide who gets a transplant MRD at post-maintenance 2/3 of these patients were from HDT, 1/3 from delayed HDT P-value (trend) : p<.1 <1-6 [1-6;1-5[ [1-5;1-4[ >=1-4.2 N at risk (events) <1-6 [1-6 ;1-5 [ [1-5 ;1-4 [ [1-4 ;1-3 [ () 86 () 86 () 86 () 86 (5) 77 (3) 61 (5) 36 () 1 29 () 29 () 29 () 29 () 28 (5) 22 (3) 16 (4) 4 (1) 1 23 () 23 () 23 () 23 (1) 22 (3) 19 (2) 14 (5) 3 () 2 4 () 4 () 4 () 4 (6) 33 (9) 23 (6) 15 (4) 4 (1) 2 3 Months since randomization

28 Lahuerta et al, JCO 217 MRD changes post transplant do not impact OS

29 Conclusion YES. Minimal Residual Disease is A Measurable and Relevant Endpoint in Treatment Is manageable in most countries Has demonstrated a prognostic role, PFS and OS You already have implemented depth of response in your practice for treatment decision - You decide a treatment strategy based on known depth of response - You optimize a treatment scheme to improve depth of response, ASCT, consolidation, maintenance Time for the next step, MRD-based treatment choice decision making

30 Summary (Fallacies) of MRD testing MRD is a surrogate for cure If you are MRD negative, you can stop treatment If you are MRD positive after transplant, you need to change from standard treatment MRD is the only predictor of good long term outcomes If you convert from MRD negative to MRD positive, you need to change therapy MRD assessment in the marrow is enough to

31 What can MRD testing be used for Comparing across clinical trials Assessing efficacy of new treatment approaches Prognosis But not for current clinical decision making There are too many unknowns that will be addressed by ongoing trials

32 Never give up! Thank you for your attention