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Scottsdale, Arizona

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Optimal Use of Newly Approved Agents – Carfilzomib and Pomalidomide Lymphoma-Myeloma Symposium October 2013. Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona. Disclosures.

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Scottsdale, Arizona

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  1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Optimal Use of Newly Approved Agents – Carfilzomib and PomalidomideLymphoma-Myeloma SymposiumOctober 2013 Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

  2. Disclosures • I do not have any relevant financial relationships with any commercial interests.

  3. Objectives • Review recent and critical data on the use of carfilzomib and pomalidomide • Provide practical advice as to the optimal use of these agents in clinical practice

  4. Treatment sequence SCT VD/VRD Thal/Dex VD Rev/Dex CyBorD VTD VRD Nothing Thalidomide? Bortezomib? Lenalidomide Bortezomib Lenalidomide Thalidomide Carfilzomib Pomalidomide NEW Maintenance Front line treatment Relapsed Consolidation Induction Post consolidation Rescue SCT VAD DEX Nothing Prednisone Thalidomide Few options OLD

  5. Carfilzomib: A Novel Agent Designed to Promote Selective and Sustained Proteasome Inhibition Tetrapeptide Epoxyketone 5 Adapted from: Kuhn DJ, et al. Blood. 2007;110:3281-3290. • Carfilzomib is a next-generation, selective proteasome inhibitor • Potent and sustained target suppression • Improved antitumor activity • Minimal off-target activity with low neurotoxicity

  6. Neuropathy Was Infrequent and Not Dose LimitingPooled data from single-agent studies (003 / 004 / 005) N=505 Did not experience peripheral neuropathy Grade 1/2 PN (13.4%) Grade 3 PN (1.2%) *Includes the terms peripheral neuropathy, neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy 6 Adapted from: Singhal S, et al. ASH 2010. Abstract 1954 (poster presentation). • Peripheral neuropathy occurred infrequently across all single-agent studies* • Only 6 patients (1.2%) experienced a Grade 3 PN event • No Grade 4 PN events • Only 1 patient had drug discontinued for PN (study 004; BTZ-treated arm)

  7. Carfilzomib Single-Agent Activity ORR 55% CBR 62% 7

  8. Responses in Bortezomib-Refractory Immunomodulator-Exposed Patients (Response-Evaluable Population, N=257) DOR (≥ PR) and (≥ MR) = 8.3 mo 34.6% 35 CBR = 34% 30 26.8% ORR = 24% Percentage of Patients 25 18.7% 20 15 10.1% 10 5.1% 5 0.4% 0 CR* (n=1) VGPR (n=13) PR (n=48) MR (n=26) SD (n=89) PD (n=69) 8

  9. Phase III ASPIRE Trial • Carfilzomib 27 mg/m2 IV Day 1, 2, 8, 9, 15, 16 (20 mg/m2 on Days 1, 2 of Cycle 1) • Lenalidomide 25 mg PO Days 1–21 • Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 • Randomized 1:1 • N = 700 • Stratification • Prior bortezomib • Prior lenalidomide • β2m Cycle = 28 days • Lenalidomide 25 mg Days 1–21 • Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 Cycle = 28 days Primary End Point: PFS β2m = beta-2-microglobulin. US NIH, 2011. 9

  10. Carfilzomib - Upfront 1. Carfilzomib-Lenalidomide Dexamethasone (CRD) in newly diagnosed 2. Cyclophosphamide – Carfilzomib – Thalidomide – Dex (CYCLONE) in newly diagnosed

  11. Treatment Schema Lenalidomide (off protocol) CRd Induction CRd Maintenance Transplant-eligible and --ineligible patients LEN Cycles 25+ CRd Cycles 9–24 CRd Cycles 5–8 CRd Cycles 1–4 Transplant-eligible Until disease progression or unacceptable toxicity ≥PR ASCT Stem cell collection • Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteriawith nCR • Cycles 1–8 • CFZ Days 1–2, 8–9, 15–16 at assigned doses1 • 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 • After Cycle 4, pts could undergo stem cell collection and then continue CRd with the option to proceed to ASCT 1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631. ASCO 2012 Slides courtesy of Dr. Jakubowiak

  12. Responses Initial Response Best Response Change from baseline 51% 67% 81% Patients (%) N= 53; median 12 cycles (range 1–25) ASCO 2012 Slides courtesy of Dr. Jakubowiak

  13. Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma #445J. Mikhael, C. Reeder, E. Libby, L. Costa, A. Mayo, L. Bergsagel, F. Buadi, N. Pirooz, J. Lubben, AC. Dueck, AK. Stewart Scottsdale, Arizona Jacksonville, Florida Rochester, Minnesota

  14. Newly Diagnosed: CYCLONE Phase I/II Carfilzomib Cyclophosphamide Thalidomide Dexamethasone Newly Diagnosed MM Response PFS Toxicity Stem cell harvest

  15. Overall Response 96% Results Levels 0 and 1 – Response n=27 CR VGPR 26% PR • CR 7 • VGPR 13 • PR 6 • MR 1 MR ≥ VGPR 74% 48% 22% 4%

  16. Carfilzomib - Practical • Highly effective and very well tolerated • Beware of tumor lysis hence dosing schedule • Cardiac issue present but mostly mitigated by fluid management • Issues of weekly dosing being explored • Lack of neuropathy very attractive • Upfront uses increasing

  17. Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide Structurally similar, but functionally different both qualitatively and quantitatively

  18. Myeloma Pomalidomide Summary Median 3 prior regimens Median 4-6 prior regimens 18

  19. Pomalidomide in 350 Relapsed Patients: Change in the Measurable Parameter From Baseline 19

  20. 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 *Progression of disease was independently adjudicated in real-time Dimopoulos Blood 2012, 120(21): LBA-6 Stratification • Age (≤ 75 vs. > 75 yrs) • Number of prior Tx ( 2 vs. > 2) • Disease population

  21. MM-003: Key Eligibility Criteria Dimopoulos Blood 2012, 120(21): LBA-6 • All pts had to be refractory to last therapy • At least 2 prior therapies • ≥ 2 consecutive cycles of LEN and BORT (alone or in combination) • Adequate prior alkylator therapy (SCT or ≥ 6 cycles or PD following ≥ 2 cycles) • All pts must have failed LEN and BORT • Pt progressed on or within 60 days • Pt with PR must have progressed within 6 months • Intolerant to BORT • Refractory or relapsed and refractory disease • Primary refractory: never achieved > PD to any therapy • Relapsed and refractory: relapsed after having achieved ≥ SD for ≥ 2 cycles of Tx to at least one prior regimen and then developed PD ≤ 60 days of completing their last therapy

  22. MM-003: Patient Disposition* RANDOMIZATION 2:1(N = 455) POM + LoDEX(n = 302) HiDEX(n = 153) Discontinued 55%PD: 35%AE: 7%Death: 6%Withdrawal: 2%Lost to follow-up: 1%Other: 4% Discontinued 75% PD: 49%AE: 6% Death: 10%Withdrawal: 3%Lost to follow-up: 1%Other: 6% PD 29% Pts received POM after PD on HiDEX 45% Ongoing Tx 25% Ongoing Tx *As of final PFS analysis, Sept 7, 2012. Dimopoulos Blood 2012, 120(21): LBA-6

  23. MM-003: Progression-Free Survival ITT 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) Dimopoulos Blood 2012, 120(21): LBA-6 Based on adjudicated data; IMWG criteria

  24. 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 Dimopoulos Blood 2012, 120(21): LBA-6 NE, not estimable

  25. MM-003: Ongoing Evaluation of Response ITT Population As of Nov 9, 2012 Dimopoulos Blood 2012, 120(21): LBA-6 PFS of ≥ MR in POM + LoDEX: 8.5 months Response based on IMWG criteria, except for MR (based on EBMT criteria) * KM median, patients with ≥ PR only NE, not estimated due to too few responders

  26. Pomalidomide - Practical • Similar to lenalidomide with slightly less myelotoxicity and fatigue • Dosing range 2-4mg • Thromboprophylaxis necessary • Feasible in combination

  27. Selecting Therapy • Both are highly active agents • Class switch a consideration • Useful even when progressing on same class agent • Convenience and toxicity is important • Most MM patients will ultimately see both drugs

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