UK MRA Myeloma XII Relapsed Intensive Study CI: Prof Gordon Cook

Transcription

1 UK Myeloma Research Alliance Myeloma XII study (ACCoRD): Augmented Conditioning & Consolidation in Relapsed Disease UK MRA Myeloma XII Relapsed Intensive Study CI: Prof Gordon Cook Sponsor ID: Pending EudraCT Number: Pending

2 (2014) Vol. 15, No. 8, p ISRCTN Sponsor ID: HM05/7287 EudraCT Number:

3 SO, WHERE DOES THIS PLACE ASCT IN THE CURRENT ERA?

4 ASPIRE: Phase III, randomised, open-label trial in patients with RRMM (1 3 prior lines of therapy) N=792 Randomisation 1:1 Carfilzomib + lenalidomide + dexamethasone (KRd) Carfilzomib: 27mg/m 2* on days 1, 2, 8, 9, 15 and 16 (cycles 1 12); days 1, 2, 15 and 16 (cycles 13 18) Lenalidomide: 25mg on days 1 21 Dexamethasone: 40mg on days 1, 8, 15 and day cycles until withdrawal of consent, disease progression, or unacceptable toxicity; carfilzomib discontinued after 18 cycles Lenalidomide + dexamethasone (Rd) Lenalidomide: 25mg days 1 21, q28 days Dexamethasone: 40mg on days 1, 8, 15 and 22 Stratification: Β2-microglobin level: <2.5mg/L vs 2.5mg/L Prior therapy with bortezomib: yes vs. no Prior therapy with lenalidomide: yes vs. no Primary endpoint Progression-free survival Key secondary endpoints Overall survival Health-related quality of life Overall response rate Safety Progression-free survival Stewart AK, et al. N Engl J Med 2015;372:

5 TOURMALINE-MM1: Phase III, double-blind, randomised, placebo-controlled trial in patients with RRMM (1 3 prior lines of therapy) N=722 Randomisation 1:1 Ixazomib + lenalidomide + dexamethasone (IRd) Ixazomib: 4 mg on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1 21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Repeat every 28 days until progression, or unacceptable toxicity Placebo + lenalidomide + dexamethasone (Rd) Placebo: on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1 21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Stratification: Prior therapy: 1 vs. 2 or 3 ISS: I or II vs. III Proteasome inhibitor exposure: yes vs. no Primary endpoint Key secondary endpoints Progression-free survival Overall survival Overall survival in patients with del(17p) Response and progression (defined by International Myeloma Working Group 2011 criteria) assessed by an Independent Review Committee blinded to both treatment and investigator assessment. Moreau P, et al. Blood 2015; 126(23): abstract 727.

6 ELOQUENT-2: Phase III, randomised, open-label trial in patients with RRMM (1 3 prior lines of therapy) N=646 Randomisation 1:1 Elotuzumab + lenalidomide + dexamethasone (ERd) Elotuzumab: 10mg/kg days 1, 8, 15 and 22 on cycles 1 and 2; on days 1 and 15 thereafter Lenalidomide: 25mg on days 1 21, q28 days Dexamethasone: 40mg on days 1, 8, 15 and 22 Repeat every 28 days until withdrawal of consent, disease progression, or unacceptable toxicity Lenalidomide + dexamethasone (Rd) Lenalidomide: 25mg on days 1 21, q28 days Dexamethasone: 40mg on days 1, 8, 15 and 22 Stratification: Β2-microglobin level: <2.5mg/L vs. 2.5mg/L Number of previous therapies: 1, 2 or 3 Previous immunomodulatory drug therapy: none vs. thalidomide only or other Co-primary endpoint Progression-free survival and overall response rate Key secondary endpoints Overall survival Severity of pain or interference with daily life Exploratory endpoints Time to tumour response Health-related quality of life Duration of response Safety Lonial S, et al. N Engl J Med 2015; 373:

7 Myeloma X in context Rx Duration n FU (mns) PFS OS ASPIRE 1 KRd Rd NR NR ENDEAVOR 2 KD VD TOURMALINE 3 IRd Rd NR NR ELOQUENT 2 4 ERd Rd MYELOMA X 5,6 PAD/NTC PAD/sASCT Stewart AK, et al. N Engl J Med 2015;372: Dimopoulos M, et al. Lancet Oncology 2016, 17, 27 3.Moreau M, N Engl J Med 2016, 374, Lonial S, et al. N Engl J Med 2015; 373: Cook G Lancet Oncology, 2014 Vol. 15, No. 8, p Cook et al, The Lancet Haematology, 2016 (in press)

8 MRD in context of adverse cytogenetics Frontline Rawstron et al, J Clin Oncol ;31(20): st Relapse Cook et al, ASH 2013

9 HOW DO WE IMPROVE ON MMX?

10 Bortezomib sensitizes myeloma cells to DNAdamaging agents % survival Control PS Mitsiades N et al. Blood. 2003;101(6): ; Baumann et al, Leuk Res, 2008, 32,

11 Bortezomib enhanced conditioning Bor-HDM vs HDM (Case-matched) %Patients treated Bor-HDM p=0.001 p=0.038 N=46 N=115 IFM Bor-HDM Roussel et al, Blood 2010, 115, IFM Bord-induction CR VGPR

12 Role of consolidation post-asct McCarthy & Hahn, Hematology, 2013,

13 Lenalidomide & bortezomib/ lenalidomide-based consolidation Study details IFM Len consolidation (2 mos) Maintenance randomization: Len vs placebo n=572 Response data VGPR 58% 69% < p IFM VRD induction ASCT VRD consolidation (2 cycles) Len maintenance n=31 Preconsolidation Postconsolidation Postinduction Post- ASCT Postconsolidation scr 17% 36% 39% CR 6% 6% 9% VGPR 39% 26% 36% Consolidation: upgraded response in 26% 1 Attal et al. N Engl J Med 2012;366(19): Roussel et al. ASH 2011 (Abstract 1872), poster presentation

14 Research Questions ACCoRD: Augmented Conditioning & Consolidation in Relapsed Disease If the depth of response relates to its durability, then: Q Can augmentation of transplant conditioning regimen improve the depth of response and response durability in the salvage setting after a prior ASCT? Q Can post-asct consolidation/maintenance improve the response durability post-asct?

15 Relapse after a prior ASCT RE-INDUCTION Ixazomib, Thalidomide & Dexamethasone ASCT Con Melphalan 200mg/m 2 ASCT Aug Melphalan 200mg/m 2 + Ixazomib ITD x2 cycles No Consolidation Ixazomib Maintenance No Maintenance Time-to-Progression

16 Ixazomib-augmented ASCT schedule D-4 D-3 D-2 D-1 D0 Melphalan (iv) 100mg/m 2 100mg/m 2 Ixazomib (PO) 4mg 4mg

17 Objectives Primary Objective : R 1 (ASCT Con vs ASCT Aug ): VGPR rate R 2 (ITD Con /Ixa main vs No therapy): Profession-free survival (PFS) Secondary Objectives: R 1 : Overall Response Rate, MRD negative rate & conversion after ITD consolidation, Engraftment kinetics, Safety & Tolerability, Quality of Life R 2 : Overall Response Rate, MRD negative rate, Time-to-progression (TTP), TTNT, PFS2, OS, Safety & Tolerability, Quality of Life Total Recruitment Target: 360 first relapse patients Expected FPFV: Q2 2016

18 Exploratory Translational Research Biomarker prognosis determination: ifish versus NGS-based risk stratification. MRD detection: comparative analysis of MPF and NGS-based molecular analysis. Proteasome inhibitor susceptibility biomarker discovery. Immuno-genomic biomarker discovery Immune Diversity Genotyping Immune senescence Immune Response Signature

19 UK MRA Myeloma XII Trial TMG Clinical Investigators: Dr Cathy Williams, Nottingham City Hospitals, UK Prof Kwee Yong, UCH, London, UK Prof Jamie Cavenagh, Barts & The London NHS Trust, UK Dr John Snowden, Royal Hallamshire Hospital, Sheffield, UK Dr John Ashcroft, Mid-Yorks Trust, Wakefield, UK Dr Mark Cook, University Hospitals Birmingham NHS Trust, UK Central Immunology Analysis Prof Mark Drayson, Uni. of Birmingham, UK Central MRD Monitoring Dr Roger Owen, HMDS, Leeds, UK Statistical support Prof Julia Brown, CTRU, Uni. Of Leeds, UK Mr David Cairns, CTRU, Uni. of Leeds, UK Trial Co-ordination Ms Anna Hockaday, CTRU, Uni. of Leeds, UK