1. 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

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

6. Prognosis
JCO 2015

9. Novel Drug Targets

10. Cancer Discovery 2013; 3:

11. Myeloma is clonally heterogenous

12. Slide Courtesy of Dr Rafael Fonseca12 12

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: )
IFM signature (Decaux O et al. J Clin Oncol 2008; 26: )
Centrosome Index (Chng WJ et al. Blood 2006; 107: ; Chng WJ et al. Blood 2008; 111: )
IL6-HMCL signature (Moreaux J et al. Haematologica 2011; 96: )
HZD Cell Death signature (Dickens NJ et al. Clin Cancer Res 2010; 16: )
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
Pre-treatment
Post-treatment
Host
Age
Albumin
Tumor Burden
Beta-2 microglobulin
PET-CT
Tumor Biology
Genetics
Response
Early Relapse

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 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

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. Education
Clinical Care
Research
Thank You - Questions 37