1. Frailty, salvage ASCT and AlloSCT: The 5 slide challenge! Prof Gordon Cook Section of Experimental Haematology University of Leeds

2. Frailty & Myeloma therapy Which Bond would you treat?

3. Age, frailty and survivorship http://seer.cancer.gov/faststats/ 1 http://myeloma.dk/download.php?f=e2007a29d8ceb162b50f632cbc369127

4. What patient factors effect treatment eligibility and outcome ?  Patient-related: − Age - Sensitivity to toxicity - Physical reserve - Efficacy declines with age − Co-morbidities - Multiple scoring systems Charlson Co-morbidity Index - Cardiac, respiratory, liver - Renal impairment ( eGFR <30 ml/min) − Performance Status - Karnovsky ≤ 70%  Disease-related: − Disease stage − Molecular risk stratification Kleber et al. Blood Cancer J (2011); 1 e35 Rosiñol L et al. Haematologica 2012;97:616-621 Bergsagel P L et al. Blood 2013;121:884-892 2

5. Frailty Assessment Performance Scores  PS does not differentiate between those who may be fit for intensive chemotherapy and those not  Needs to be refined to identify vulnerable patients  Inter-observer variability in PS  Standardised measurements of functional status may help inform us re treatment Comorbidity Assessments  Trials don’t consistently capture co- morbidity information  2 most commonly used scores are the Charleston Comorbidity Index (CCI) and the Haemopoietic Cell Transplantation Comorbidity Index (HCT-CI)  The higher the scores the shorter the survival  Screening for co-morbidity should be routine in older patients 3 Geriatric Assessment  Registry data used to retrospectively form a GA based on QOL questionnaire and co-morbidity assessment (HCT-CI)  Higher co-morbidity, reported difficulty with strenuous activity and pain were associated with mortality  Suggests simple targeted questions re physical functioning and specific symptoms can help id the vulnerable

6. Frailty scores and outcomes (EMN) Palumbo et al. 2015 Blood: 125 (3) 2068 - 2074. 4

7. Frailty Index-adjusted Therapy Non-adjusted 1:1 1:2 CRDaIRDa FIT C – 500mg D1 & D8 R – 25mg D1-21 D – 20mg I – 4mg weekly UNFIT FRAIL 1:2  CRDa  IRD a 1:2 CRDaIRDa 1:2  CRDa  IRDa TREAT TO MAXIMUM RESPONSE (6-8 cycles) FIT: C – 500mg D1 & D8, R – 25mg D1-21, D – 20mg/wk, I – 4mg/wk UNFIT: C – 350mg D1 & D8, R – 15mg D1-21, D – 10mg/wk, I – 3mg/wk FRAIL: C – 250mg D1 & D8, R – 10mg D1-21, D – 10mg/wk, I – 3mg/wk 1:1 RevlimidIxazomib/Revlimid MAINTENANCE INDUCTION Myeloma XIV – FITNESSTrial Design Transplant ineligible NDMM 5

8. Questions??

9. Salvage ASCT Is it worth it?

10. Background  Results to date all retrospective or single-centre with no RCT to assess the outcome of a second ASCT.  19 studies of salvage ASCT published form 1996-2013  Median TRM 4.1% (range 0-22%) with median ORR 64.3% (range 27.3%, 97.4%).  Median PFS of 12.3 mns with a median OS of 32.4 mns (range 8, 79.1) 1

11. Vol. 15, No. 8, p874–885. 2

12. Response Rate to Re-induction & randomized Treatment (Day+100) 39.3% 22.4% 16.5% 39.3% 22.4% sCR/CR P=0·012 (Fisher’s Exact test) Post-randomisation: ≥VGPR rate: 59·5% after salvage ASCT vs 47·1% after cyclophosphamide (OR 0·38, 95%CI 0·2,0·7; ordinal logistic regression P=0·0036) N=297 ORR – 79.2% N=85N=89 Cook et al, Lancet Oncology, 2014, Vol. 15, No. 8, p874–885 3

13. Time-to-progression (ITT) PD detected in 64% of ASCT patients & 80% in C-weekly. Median TTP (ITT) for ASCT is 19 mns (95% ci 16, 25) vs 11mns (95% ci 9, 12) for C-weekly (HR 0.36 (95% ci 0.25, 0.53); p<0.0001) TTP PFS Cook et al, Lancet Oncology, 2014, Vol. 15, No. 8, p874–885 NTC ASCT2 NTC ASCT2 4

14. RE-INDUCTION Ixazomib, Thalidomide & Dexamethasone RE-INDUCTION Ixazomib, Thalidomide & Dexamethasone ITD x2 cycles Time-to-Progression No Consolidation Ixazomib Maintenance No Maintenance 5 UK Myeloma Research Alliance Myeloma XII (ACCoRD study): Augmented Conditioning & Consolidation in Relapsed Disease

15. Questions??

16. Allogeneic SCT Is there still a role for consideration?

17. Why consider AlloSCT?  The lure of GvM raises the prospect of cure − Response to DLI − Link with GVHD (esp chronic GVHD) − Increased relapse with T-cell depletion  TRM rates decreased significantly in last 10 years  Deeper responses predict for durable responses, and with novel agents more patients will achieve deeper responses with limited impact on physiology  So why is use not more widespread? − Data so varied − Age at diagnosis − Comorbidities/PS − Cultural resistance in myeloma docs  So who should we consider? 1 Standard OS Current PFS (includes responses to salvage therapies) Standard EFS 0 0.25 0.5 0.75 1 012345678 Survival Years from transplant Bruno B, et al. Blood. 2009;113:3375-82.

18. J Clin Oncol. 2011;29:3016-22 2 PFS0S

19. Standard RiskHigh Risk 3 AlloSCT in High Risk disease Krishnan et al, Lancet Oncol. 2011;12(13) 1195-203 Roos-Weil et al Haematologica 2011

20. The way forward……?  As TRM falls over time, relapse becomes the biggest reason for treatment failure  Options: − Use a prior debulking ASCT vs intensity-modulated MAC to optimize pre-AlloSCT disease status − Use of anti-myeloma therapy post allograft − Use of optimized immunotherapy (novel agents + DLI, pre- emptive DLI) − limit the procedure to patients with sensitive disease − use the best conditioning with fludarabine/melphalan or low-dose TBI with or without fludarabine and with no T-cell depletion 4

21. The way forward……LenaRIC Trial overview ASCT pDLI 5 CI: Dr Mark Cook

22. Questions??