Integrating NGS Approaches into Patient Care: Managing High-Risk Disease in Transplant Eligible Patients

1. Research Clinical Care Education Integrating NGS approaches into patient care: How I manage high-risk disease at presentation in a transplant eligible patient Prof Chng Wee Joo Director National University Cancer Institute, Singapore (NCIS) National University Health System (NUHS) Deputy Director Cancer Science Institute, Singapore (CSI) National University of Singapore (NUS)

2. Disclosure • Employment – NA • Stock Ownership – NA • Honoraria – Janssen, Novartis, Celgene, Roche • Research Funding – Roche, Celgene • Advisory Board – Janssen, Novartis, Celgene, Roche

3. Outline • Clinical Utility of NGS • How do we identify high risk MM • Implication on Treatment

4. Companion Diagnostics in MM Landgren and Morgan CCR 2014

5. Lohr et al. Cancer Cell 2014; 25: 91-101 Key Pathways RAS/MAPK NFKB DNA Damage Epigenetic

6. Prognosis JCO 2015

9. Novel Drug Targets

10. Cancer Discovery 2013; 3: 862-869

11. Myeloma is clonally heterogenous

12. Slide Courtesy of Dr Rafael Fonseca

13. Gaps for NGS • Driver vs passenger • Lack of standardisation (Depth, panel, algorithm) • How to handle mutations of unknown significance • How to prioritize mutations

14. How to identify the High-Risk Patients Definition: Median survival of 2 years (Chng et al Leukemia 2015)

15. Revised ISS Palumbo et al JCO 2015

16. Evolution of Prognostic System ISS + FISH + GEP

17. Combination of ISS with GEP Kuiper et al. Blood 2015

18. Prognostic Signatures • UAMS 70-gene signature (Shaughnessy JD et al. Blood 2007; 109: 2276-2284) • IFM signature (Decaux O et al. J Clin Oncol 2008; 26: 4798-805) • Centrosome Index (Chng WJ et al. Blood 2006; 107: 3669-3675; Chng WJ et al. Blood 2008; 111: 1603-1609) • IL6-HMCL signature (Moreaux J et al. Haematologica 2011; 96: 574-82) • HZD Cell Death signature (Dickens NJ et al. Clin Cancer Res 2010; 16: 1856-64) • CINGEC signature (Chung TH et al. PLoS ONE 2013; 8: e66361)

19. Combination of Signature Chng et al, Leukemia 2016

20. Chng et al, Leukemia 2016

21. ISS-MUT Factors ISS CNSA – t(4;14), 17p(del), MYC Translocation, 1q+ Mut - TP53, ZFHX4, CCND1, ATM and ATR Group 1 – ISS I or II, no CNSA or Mut Group 2 – ISS III, no CNSA or Mut or ISS I/II/III + 1 CNSA/Mut Group 3 – 2 CNSA or Mut, regards of ISS

22. Summary of Prognostic Factors

23. Can novel agents modulate risk?

24. Weinhold et al Leukemia 2015

29. Shaughnesy et al. Br J Haematol 2009; 147:347-351

32. What About the Newer Agents Pomalidomide Dimopoulos et al. Haematologica 2015

33. Ixazomib - Tourmaline Moreau ASH 2015

34. Carfilzomib - Endeavour Chng ASH 2015

35. What have we learn • Velcade especially benefit t(4;14) patients • Inclusion of Velcade (and hence prolonged use) in different phases of treatment is important in high-risk disease • The use of double autologous transplant seem to also be an important factor. • Revlimid seem to have a more moderate and less consistent effect on high-risk disease • Thalidomide maintenance contra-indicated in 17p13 deletion • Newer Imids and PI may be more effective

36. Conclusion • No current routine role for NGS in clinic yet • We should adopt standardized risk categories • Revised ISS should be current gold standard • GEP and post-treatment MRD/Imaging await further studies • No evidence for the routine application of risk-adapted therapy • Best evidence is use of Velcade for patients with t(4;14) • Should incorporate risk stratification into design of clinical trials • Test hypothesis in high-risk patients e.g. Velcade maintenance, double transplant, allo-SCT, Use of novel PI and Imids upfront

37. Research • Clinical Care • Education • Thank You - Questions