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

Ongoing advances especially in elderly

Survival in Myeloma

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

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

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 2007 - Aug 2008 2 Len refractory 34 Nov 2008 - April 2009 3 Bortez/Len refractory 35 May 2009 - Nov 2009 4 4, 28/28 Nov 2009 - April 2010 5 <4 prior reg 61 May 2010 – Nov 2010 6 4, 21/28 120 April 2011 – March 2012

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

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) 20 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) 20 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

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

MM-003: Progression-Free Survival ITT Population 4 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)

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 (5.4-9.2) 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

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

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

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

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

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

All Approved Drugs Average Response of at Least 15% MLN9708 GSK0183 ARRY520

All Approved Drugs Average Response of at Least 15% No single agent activity Elotuzumab Panabinostat Vorinostat Perifosine Siltuximab (anti-IL6) MLN9708 GSK0183 ARRY520 \

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 (0.7-5.8) Median time to best response, months (range): 2.2 (0.7-17.5) CR = complete response; IMWG = International Myeloma Working Group; PR = partial response; VGPR = very good partial response 22

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.

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

Serum M-protein responses

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