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Director, Myeloma Section Professor, Depts. of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator,

Moving Carfilzomib into the Front-line Setting in Multiple Myeloma : An Irreversible Trend? Discussion of Abstracts 8009, 8010, and 8011 Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Professor, Depts. of Lymphoma/Myeloma & Experimental Therapeutics

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Director, Myeloma Section Professor, Depts. of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator,

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  1. Moving Carfilzomib into the Front-line Setting in Multiple Myeloma : An Irreversible Trend?Discussion of Abstracts 8009, 8010, and 8011Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Professor, Depts. of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

  2. Disclosures • I will include discussion of investigational/ off-label use of carfilzomib for myeloma PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  3. Carfilzomib Background • Tetrapeptide epoxyketone • Binds the b5 & b5i subunits irreversibly • Overcame bort resistance1 • Well tolerated in phase I2 • Active alone, and in a number of combinations3 in relapsed and/or refractory MM 1Kuhn et al. Blood 110:3281, 2007. 2O’Connor et al. Clin Cancer Res. 15:7085, 2009. Alsina et al. Submitted. 3Vij et al. Blood May 3, E-pub. Siegel et al. Submitted PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  4. CMP Study Overview 20 27 36 • CMP for 9 cycles of 6 weeks each • C 20 mg/m2 iv day 1, 2 cycle 1; then 36 (MTD) • M 9 mg/m2 po daily on days 1-4 • P 60 mg/m2 po daily on days 1-4 0 DLT 0 DLT 6 patients 6 patients 6 patients 1 DLT 1 DLT 1 DLT ≥ 2 DLT * ≥ 2 DLT * ≥ 2 DLT * Up to 27mg/m² Up to 36mg/m² MTD = 27 MTD = 36 MTD = 20 MTD = 20 PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  5. CMP vs. Other Options • Comparisons dangerous at this stage • Small cohort and no randomization/stratification • 8 patients with ≤3 cycles excluded from ORR • No information about median age, ISS stage, cytogenetic profiles, and GEP risk • Different study designs, with other trials (MPT, MPR, VMP) incorporating a maintenance phase • Authors do state that 89% ORR is very promising compared to best MPT (76%), MPR (80%), Rd (85%) PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  6. CMP vs. VMP: Response Rate • ORR 89% for CMP in this phase I/II • 1 CR, 14 VGPR, 16 PR, 1 MR, 2 SD, 1 PD • Comparison made to VISTA1 (ORR 71%) • Better benchmark is VMP phase I/II2, which had ORR 89% • 17 CR, 6 nCR (VGPR), 24 PR, 0 MR, 6 SD • Duration of CMP longer (54 vs. 49 weeks) • More doses of C given than V (72 vs. 57) 1San Miguel et al. NEJM 359:906, 2008. 2Mateos et al. Blood 108:2165, 2006. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  7. CMP vs. VMP: Response Duration • OS • CMP: 93.9% @ 12-month median follow-up • VMP1: 90% @ 16-months • EFS • CMP: 80.7% @ 12-month median follow-up • VMP1: 83% @ 16-months 1Mateos et al. Blood 108:2165, 2006. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  8. CMP vs. VMP: Toxicity Grade ≥3 • CMP • Infection (15%); DVT, Afib (6% each); renal impairment, pericardial effusion, fatigue, cardiac failure, toxic death (3% each) • Only 1 peripheral neuropathy (PN) at grade 1 • VMP1 • Thrombocytopenia (51%), neutropenia (43%), PN (17%), diarrhea (16%), infection (16%) • 16 (27%) patients received G-CSF support 1Mateos et al. Blood 108:2165, 2006. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  9. CYCLONE Study Overview • Rationale • Build on international standard CTD • Add new PI with less neuropathy to front-line • Save lenalidomide & bortezomib (?) for relapse 1 vs. 1Disclosure: I own no stock in Time Warner. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  10. CYCLONE Outcomes • ORR 96% in phase II after 4 cycles • 7 CR, 11 VGPR, 5 PR, 1 MR; 75% ≥VGPR • 24 responses/27 patients reported (VGPR 67%) • ECOG 0 in 74%, ISS I in 43% • No information about molecular risk • Need long-term follow-up (median 8.2 months) • Additional dose levels being explored with carfilzomib at >20 mg/m2 PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  11. CYCLONE Efficacy Comparators • CTD • Transplant eligible patients • ORR 82.5%, CR 13%, ≥VGPR 43% (n=555)1 • Transplant ineligible patients • ORR 63.8%, CR 13.1%, ≥VGPR 30% (n=426)2 • CyBorD • Mixed patients (x 4 cycles) • ORR 88%, CR/nCR 46%, ≥VGPR 61% (n=33)3 1Morgan et al. Haematologica 97:442, 2012. 2Morgan et al. Blood 118:1231, 2011. 3Reeder et al. Leukemia 23:1337, 2009. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  12. Efficacy Comparators II • VMPT • Transplant ineligible patients (also + VT maint.) • ORR 89%, CR 38%, ≥VGPR 67% (n=250)1 • VDCmod vs. VDCR • Mixed population (x 4 cycles) • ORR 100% vs. 88% (n=17 vs. n=48) • CR 47% vs. 25%; VGPR 53% vs. 58%2 • If 4 drugs are not better than 3, why not use CarCyDex and eliminate Thal altogether? 1Palumbo et al. J Clin Oncol 28:5101, 2010. 2Kumar et al. Blood 119:4375, 2012. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  13. CRd Study Overview Lenalidomide (off protocol) CRd Induction CRd Maintenance • Cycles 1–8 • CFZ Days 1–2, 8–9, 15–16 at assigned doses • LEN 25 mg Days 1–21 • DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8 • Cycles 9–24 • CFZ on Days 1–2 and 15–16 only • CFZ, LEN, DEX at last best tolerated doses Transplant-eligible and -ineligible patients LEN Cycles 25+ CRd Cycles 9–24 CRd Cycles 5–8 CRd Cycles 1–4 Until disease progression or unacceptable toxicity Tran spl ant-eligible ≥PR ASCT Stem cell collection PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  14. Efficacy & Durability Best Response Patients (%) PFS 97% @ 12 months PFS 92% @ 24 months N= 53; median 12 cycles (range 1–25) PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  15. Efficacy Comparators • RVD • ORR 100%, ≥VGPR 67%1 • PFS @ 18 mos. was 75% (median of 10 cycles vs. ? for CRd) • 8 cycles CRd is more therapy than 8 of RVd • 32 weeks vs. 24 weeks • CRd has more proteasome inhibitor doses (48 vs. 32) • CRd has more lenalidomide (168 days vs. 112 days) • CRd has less dexamethasone (960 mg vs. 1280 mg) 1Richardson et al. Blood 116:679, 2010. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  16. Comparators II • CRd • High rate of sCR (CR + normal serum free light chains) of 61% after 8+ cycles • As sCR is a relatively new parameter, it has not been reported in RVd1 • sCR may not have better outcome than CR2 • 20/22 patients (91%) with suspected CR had no MRD by flow immunophenotyping • Immunophenotypic CR associated with prolongation of TTP and EFS compared to less rigorous CR 1Richardson et al. Blood 116:679, 2010. 2Paiva et al. J Clin Oncol. 29:1627, 2011. PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  17. Conclusions • Up-front combinations with carfilzomib are showing attractive response rates • Depth of response (CR, sCR) seems improved in some studies, though longer f/u is needed • Tolerability may be improved, especially with less neuropathy, but data from comparisons are needed with sc ± weekly bortezomib PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

  18. Future Directions • Phase III studies needed to determine role of these attractive regimens in our arma-mentarium for newly diagnosed patients • Trials must be performed in a risk-adapted fashion given large difference in outcomes for patients with standard vs. high risk • ECOG E1A11: RVd vs. CRd for standard • SWOG S1211: RVd vs. RVd/Elo for high risk PRESENTED BY: Robert Z. Orlowski, Ph.D., M.D.

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