1. Multiple Myeloma:2013 Update Genomies
A. Keith Stewart MB.ChB., MBA
Anna Maria and Vasek Polak Professor of
Cancer Research
Dean for Research Mayo Clinic in Arizona
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida 1

2. Ongoing advances especially in elderly

3. Survival in Myeloma

4. 376 pre clinical studies, 117 single-agent trials, 9 FDA approved drugs

5. All Approved Drugs Best Reported Response of at Least 20%
Melphalan
Dexamethasone
Thalidomide
Fotemustine
Pomalidomide
Carfilzomib
Bortezomib
Lenalidomide
Prednisone
Interferon
Idarubicin
Paclitaxel
Cyclophosphamide
Bendamustine
Teniposide
Doxorubicin

9. Mayo Myeloma Pomalidomide/Dex Trials, 345 patients
Cohort
Group
Dose
mg/day N
Accrual dates 1
Relapsed
< 4 prior reg
2, 28/28 60
Nov Aug 2008 2
Len refractory 34
Nov April 2009 3
Bortez/Len refractory 35
May Nov 2009 4
4, 28/28
Nov April 2010 5
<4 prior reg 61
May 2010 – Nov 2010 6
4, 21/28
120
April 2011 – March 2012

10. Change in the measurable parameter from baseline (serum, urine, FLC)

11. Follow-Up for OS and SPM Until 5 Years Post Enrollment
MM-003 Design: POM + LoDEX vs HiDEX Refractory MM Pts Who Have Failed BORT and LEN
(n = 302)
POM: 4 mg/day D1-21 +
LoDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1, 8, 15, 22
RANDOMIZATION 2:1
Follow-Up for OS and SPM Until 5 Years Post Enrollment
(n = 153)
HiDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1-4, 9-12, 17-20
28-day cycles
PD* or intolerable AE
PD*
Companion trial MM-003C
POM 21/28 days
Thromboprophylaxis was indicated for those receiving POM or with DVT history
Stratification
Age (≤ 75 vs > 75 yrs)
Number of prior Tx ( 2 vs > 2)
Disease population
*Progression of disease was independently adjudicated in real-time

12. MM-003: Ongoing Evaluation of Response ITT Population
POM + LoDEX
HiDEX
Response, %
IRAC
Randomized ≥ 6 months
(n = 204)
(n = 99)
P value
ORR (≥ PR) 24 3
< .001
VGPR —
≥ MR 38 7
≥ SD 79 55
Median DOR*, m (95% CI)
10.1
(6.2 – 12.1) NE
As of Nov 9, 2012

13. MM-003: Progression-Free Survival ITT Population4 8 12 16
0.0
0.2
0.4
0.6
0.8
1.0
Median PFS
POM + LoDEX (n = 302)
3.6 months
HiDEX (n = 153)
1.8 months
HR = 0.45
P < .001
Proportion of Patients
Based on adjudicated data; IMWG criteria
Progression-Free Survival (months)

14. MM-003: Overall Survival ITT Population
Median OS (95% CI)
POM + LoDEX (n = 302)
Not Reached (11.1-NE)
HiDEX (n = 153)
7.8 months ( )
1.0
0.8
0.6
Proportion of Patients
0.4
HR = 0.53
P < .001
0.2
0.0 4 8 12 16
Overall Survival (months)
29% of pts received POM after progression on HiDEX
NE, not estimable

15. Conclusions POM + LoDEX significantly improved PFS and OS vs HiDEX
Median PFS: 3.6 vs 1.8 months
HR = 0.45; P < .001
Median OS: not reached vs 7.8 months
HR = 0.53; P < .001
Equal benefit in pts refractory to both LEN and BORT
In these heavily pre-treated pts, POM + LoDEX was generally well tolerated
POM + LoDEX should be considered as a new treatment option for these pts

16. Molecular Structure of Thalidomide, Lenalidomide, and Pomalidomide
15–25 mg/d
Myelosuppression
Skin rash
DVT
Pomalidomide
2–4 mg/d N O H
NH2 2
Thalidomide
100–200 mg/d
Neuropathy
Constipation
Sedation
DVT

17. Cereblon knockdown confers complete
Lenalidomide and Pomalidomide resistance In Myeloma
Lenalidomide
Pomalidomide
Cereblon knockdown
Control

18. Gene expression levels of Cereblon predict response to Pomalidomide
33%
19% 0%
CRBN % of mean MM
N =
N =
N =

19. Gene expression levels of Cereblon predict Overall Survival of Pomalidomide Treated Patients
9.1 months versus 27 months

20. All Approved Drugs Average Response of at Least 15%
MLN9708 GSK ARRY520

21. All Approved Drugs Average Response of at Least 15%
No single agent activity
Elotuzumab
Panabinostat
Vorinostat
Perifosine
Siltuximab (anti-IL6)
MLN9708 GSK ARRY \

22. Efficacy Best Confirmed Response (IMWG Criteria)
Elotuzumab 10 mg/kg
Elotuzumab 20 mg/kg
Total
Patients, n 36 37 73
ORR (≥PR), n (%)
33 (92)
27 (73)
60 (82)
CR/stringent CR, n (%)
5 (14)
4 (11)
9 (12)
VGPR, n (%)
14 (39)
12 (32)
26 (36)
PR, n (%)
11 (30)
25 (34)
No confirmed response, n (%)
3 (8)
10 (27)
13 (18)
Median time to response, months (range): 1 ( )
Median time to best response, months (range): 2.2 ( )
CR = complete response; IMWG = International Myeloma Working Group; PR = partial response; VGPR = very good partial response 22

23. Dinaciclib (SCH727965)
Dinaciclib is a novel, potent, small molecule inhibitor of cyclin dependent kinases (cdk).
It inhibits cdk1, cdk2, cdk5 and cdk9 with 50% inhibitory concentrations (IC50) of 4nM, 1nM, 1nM and 4nM respectively.
Cyclin D/CDK4 complexes are inhibited with an IC50 of 100nM.

24. Best Response across all cycles
30 mg/m2
(N=3)
40 mg/m2
(N=6)
All 50 mg/m2
(N=18)
All
(N=27)
VGPR 1 2 PR MR SD 4 8 13 PD 6 NA
6/27 or 22% response rate ≥MR

25. Serum M-protein responses

26. Conclusions Doing better overall - drug combinatons given for longer
High risk disease a major problem
MOA of Lenalidomide better understood
New Agents
Pomalidomide
Carfilzomib
Other investigational