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Multiple Myeloma:2013 Update Genomies

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. Ongoing advances especially in elderly.

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Multiple Myeloma:2013 Update Genomies

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  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

  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

  6. Mayo Myeloma Pomalidomide/Dex Trials, 345 patients

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

  8. MM-003 Design: POM + LoDEX vs HiDEXRefractory MM Pts Who Have Failed BORT and LEN 28-day cycles (n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22 RANDOMIZATION 2:1 PD* orintolerable AE 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 Companion trialMM-003C POM 21/28 days PD* 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

  9. MM-003: Ongoing Evaluation of Response ITT Population As of Nov 9, 2012

  10. MM-003: Progression-Free SurvivalITT Population 1.0 0.8 0.6 HR = 0.45 P < .001 Proportion of Patients 0.4 0.2 0.0 0 4 8 12 16 Progression-Free Survival (months) Based on adjudicated data; IMWG criteria

  11. MM-003: Overall SurvivalITT Population 1.0 0.8 0.6 Proportion of Patients 0.4 HR = 0.53 P < .001 0.2 0.0 0 4 8 12 16 Overall Survival (months) • 29% of pts received POM after progression on HiDEX NE, not estimable

  12. 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

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

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

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

  16. Gene expression levels of Cereblon predict Overall Survival of Pomalidomide Treated Patients P=0.005 P=0.01 9.1 months versus 27 months

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

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

  19. EfficacyBest Confirmed Response (IMWG Criteria) • 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

  20. 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.

  21. Best Response across all cycles 6/27 or 22% response rate ≥MR

  22. Serum M-protein responses

  23. 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

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