Education Clinical Care Research 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) 1 1

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

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

Companion Diagnostics in MM Landgren and Morgan CCR 2014

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

Prognosis JCO 2015

Novel Drug Targets

Cancer Discovery 2013; 3: 862-869

Myeloma is clonally heterogenous

Slide Courtesy of Dr Rafael Fonseca 12 12

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

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

Revised ISS Palumbo et al JCO 2015

Evolution of Prognostic System ISS FISH + GEP +

Combination of ISS with GEP Kuiper et al. Blood 2015

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)

Combination of Signature Chng et al, Leukemia 2016

Chng et al, Leukemia 2016

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

Summary of Prognostic Factors Pre-treatment Post-treatment Host Age Albumin Tumor Burden Beta-2 microglobulin PET-CT Tumor Biology Genetics Response Early Relapse

Can novel agents modulate risk?

Weinhold et al Leukemia 2015

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

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

Ixazomib - Tourmaline Moreau ASH 2015 ORR, % ≥VGPR, % ≥CR, % Median PFS, months IRd Placebo-Rd HR All patients 78.3* 71.5 48.1* 39 11.7* 6.6 20.6 14.7 0.742* Standard-risk patients 80 73 51 44 12 7 15.6 0.640* All high-risk patients 79* 60 45* 21 12* 2 21.4 9.7 0.543 Patients with del(17p)† 72 48 15 11* 0.596 Patients with t(4;14) alone 89 76 53 28 14 4 18.5 12.0 0.645 Moreau ASH 2015

Carfilzomib - Endeavour Chng ASH 2015

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

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

Education Clinical Care Research Thank You - Questions 37