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Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs

Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs. James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA. Treatment Choices. Anthracyclines Doxorubicin PLD . Thal. Carfilzomib. Bortezomib.

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Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs

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  1. Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA

  2. Treatment Choices • Anthracyclines • Doxorubicin • PLD Thal Carfilzomib Bortezomib Chemotherapy IMiDs Proteasome inhibitors Pom + + + + + + Len • Alkylating agents • Melphalan • Cyclophosphamide • Bendamustine Steroids Clarithromycin Dex + Methylpred Prednisone Clinical Trials Novel Combinations Investigational Drugs

  3. Individualize your choice for the myeloma patient based on: • How active is the patient? • Mobility? • Is potential neuropathy an issue? (e.g.- surgeon, pianist) • Responseand for how long? • Side effects and tolerability Work/ Lifestyle Prior Treatments • Diabetes mellitus (steroids) • Cardiac (Doxorubicin, PLD) • Neuropathy • (Thalidomide) • Renal, • Bone, • Marrow, • Subjective, • Rate of ProgressionGenetics? Disease characteristics Co-morbid conditions

  4. Principles of Treating Relapsed/Refractory Multiple Myeloma Be sure a patient has really progressed before changing therapy REPEAT MYELOMA LABS! Try to use drugs patient has not seen before HOWEVER, progression on one drug in combination does not mean that drug will not be effective w/ another agent e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD Even different drugs in the same class may be active so that bortezomib+melphalan failures may respond to other alkylating agents- cyclophosphamide or bendamustine LEN failures may respond to THAL and vice versa pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN the same combination may be effective again if the patient has not seen the combination in a long time

  5. Initial approval in multiple myeloma based on phase II data Only single agent to demonstrate a statistically significant survival advantage (APEX) Single Agent Bortezomib Relapsed/Refractory Multiple Myeloma PHASE II P = .0272 PHASE III *EBMT criteria

  6. Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1. Berenson et al., Brit J Haematol, in press

  7. Bendamustine & Bortezomib: Results • No DLT was observed at any dose level. • 50 mg/m2 (n = 5) • 70 mg/m2 (n = 4) • 90 mg/m2 (n = 5) • The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD • Overall response rate • Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR) • At MTD (90 mg/m2) 52% • Bortezomib-exposed (n=31) 42% • Alkylator-exposed (n=28) 46% Berenson et al., Brit J Haematol, in press

  8. Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial • R/R MM patients • N=29 • Regimen (28-day cycles) • B 75-100 mg/m2 d1 & 2 • L 5-10 mg qd d1-21 • Dex 40 mg PO weekly • MTD: B 75/ L 10/ D 40 • Results (only 25 considered evaluable for response) • ORR (> PR): 52% w/ 24% VGPR • MR 24% • PFS: 6.1 mo Lentzsch et al. Blood 2012

  9. Bortezomib + PLD vs. Bortezomib in Previously Treated MM BORT 1.3 mg/m2 PLD 30 mg/m2 1° Endpoint: TTP2° Endpoints: OS*, ORR N=646 (n=322) RANDOMI ZE q 3 weeks up to 8 cycles Days 1 4 8 11 q 3 weeks up to 8 cycles (n=324) *Not enough events to determine statistical significance in overall survival. ORR=overall response rate; OS=overall survival; TTP=time to progression. Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007

  10. Bortezomib ± PLD MMY-3001 Trial *By EBMT criteria Orlowski et al. J ClinOncol25:3892-901 (2007)

  11. More Frequent Dosing with PLD Improves Anti-Myeloma Effect in a SCID-hu MM Model Weekly Dosing1 Daily Dosing2 2Seventeen days post-implantation, mice received i.p. injection of PLD once daily for three consecutive days weekly. Human IgG was measured weekly in the mouse serum by ELISA. 1Twenty days post-implantation, mice received i.p. injection of PLD once weekly. Human IgG was measured weekly in the mouse serum by ELISA. Campbell et al. Br J Haematol 2006

  12. Bortezomib + PLD + Dexamethasone for Patients with Previously Untreated Myeloma:A Phase II Trial PLD: 5 mg/m2 IV infusion Dexamethasone 40 mg IV Bortezomib: 1.0 mg/m2 IV Cycle repeats Days 1 2 3 4 5 6 7 8 9 10 11 29 Berenson et al. Brit J Haematol, 2011

  13. DVD: Response Rates Berenson et al. Brit J Haematol, 2011

  14. Comparison of Adverse Events w/ Modified DVD vs Conventional Dosing Adverse Event Comparison Between DVD (Current Study) and Standard Dosing (Jakubowiak et al., Blood 2009).

  15. Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up1 • Endpoints: Primary:PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety • Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies • Study design: • Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against herpes zoster were required 15 Richardson PG et al. ASH 2010, abstract #3049

  16. Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up • Results: 62 pts evaluable for response • Median duration of ≥MR: 8.3 months • Median duration of ≥PR: 8.4 months • Safety: • Median cycles received: 11 (range 1–48) • Median treatment duration: 7.9 months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs 16 Richardson PG et al. ASH 2010, abstract #3049

  17. PLD: 4 mg/m2 IV infusion DVD-R (Bortezomib + PLD + Dexamethasone + Lenalidomide) for Patients with R/R MM: A Phase II Trial Dexamethasone 40 mg IV Bortezomib: 1.0 mg/m2 IV Cycle repeats Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29 Len 10 mg poqd d1-14 Berenson et al., Leukemia 2012

  18. DVD-R: Response Rate N=39 *Based on the modified Blade’ criteria Percent w/oProgression *Based on the modified Blade’ criteria *Based on the modified Blade’ criteria *Based on the modified Blade’ criteria

  19. DVD-R Study: Adverse Events • Grade 3 adverse events included: • 6 reversible neutropenia, 4 reversible anemia, 4 pneumonia, • 1 dyspnea, 3 reversible thrombocytopenia, • 1 reversible peripheral neuropathy, 1 mental confusion, • 1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to moxifloxacin, • 1 dysphagia, 1 syncope, 1 respiratory distress. • Grade 4 adverse events included: • 1 reversible thrombocytopenia & 1 anemia • No cases of stomatitis or hand-foot syndrome reported! • Treatment-emergent peripheral neuropathy (25%): • Grade 1: n=8 (20%) • Grade 2: n=1 (2.5%) • Grade 3: n=1 (2.5%) Percent w/oProgression

  20. Retreatment w/ IMiDs for MM Patients • Retrospective study in 140 pts treated firstline w/ • THAL/DEX- 58% • LEN/DEX- 42% • Retreatment w/ a regimen containing • THAL- 24% • LEN- 76% • # of treatments before retreatment - median of 2 (range 1-6) • 89% received IMiD w/ DEX • 113 considered evaluable for response • 44% > PR • MR not reported Madan et al. Blood 2011

  21. PX-171-003: Study Overview Study expanded to registration trial Phase 2 Study Population PX-171-003-A1 (N=266) PX-171-003-A0 (N=46) • Progressive disease required at study entry • Relapsed from ≥2 prior lines of therapy • Must include bortezomib • Must include thalidomide or lenalidomide • Refractory to last regimen Carfilzomibfor Injection* days 1,2,8,9,15,16 (28-day cycles) Maximum 12 cycles Dosing regimen, premedication, and hydration were defined in 003-A0 *Cycle 1, 20 mg/m2 Cycle 2 and beyond, 27 mg/m2 • Primary endpoint: Overall response rate • Assessed by an Independent Review Committee, using International Myeloma Working Group criteria Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation).

  22. PX-171-003-A1 (N=266): Disease characteristics

  23. PX-171-003-A1: Response *As assessed by the Independent Response Review Committee

  24. Carfilzomib in MM Patients Following 1-3 Prior Therapies Bortezomib-treated 004, Phase II Bortezomib-naïve Carfilzomib Cohort 1 20 mg/m2 Relapsed / Refractory Multiple Myeloma 1-3 Prior Therapies N = 165 1:1 Carfilzomib Cohort 2 20 mg/m2→27 mg/m2 Bortezomib-naïve Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

  25. Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.

  26. Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM MM: 1-3 Prior Therapies N = 52 1o Endpoint ORR 2o Endpoint DOR, TTP, OS, PFS, Safety Carfilzomib Lenalidomide Low-dose dex Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.

  27. Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial response; PR, partial response. Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.

  28. A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing Bortezomib-Containing Regimens • Nontraditional intrapatient Phase I/II trial • Eligibility: Progressive disease while on bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen • Carfilzomib replaces bortezomib in combination with: • Alkylating agent • Anthracycline • Glucocorticosteroid • IMiD

  29. Study Design (cont’d) Study treatment Carfilzomib starting at 20 mg/m2 for the 1st cycle increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and 4, respectively if no DLT is observed DLT considered > Grade 2 administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only) Maximum # of cycles- 8

  30. Results

  31. Efficacy (N=24)

  32. Summary Intrapatient Phase I/II trial of MM patients refractory to bortezomib combination therapy with and without IMiDs Treatment with same regimen w/ carfilzomib (CAR) replacing bortezomib CAR escalated from 20 to 27, 36, and 45 mg/m2 during cycles 1-4; maximum of 8 cycles MTD for one regimen (CY+CAR) reached at the maximum dose of CAR (45 mg/m2) with no DLT Well tolerated Clinical benefit rate 75% including 8% CR, 17% VGPR, 29% PR, & 21% MR Responses observed with all drugs!

  33. A Phase I/II Trial of Weekly Carfilzomib in Combination With IV Dexamethasone for R/R Multiple Myeloma • Phase I/II, open-label, multi-center trial investigating weekly carfilzomib + dexamethasone in R/R MM patients • Phase I: • 28-day cycle • Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15 • Dexamethasone IV at 40 mg days 1, 8, 15, & 22 • Phase II: • Carfilzomib at MTD on days 1, 8 & 15 • Dexamethasone IV at 40 mg days 1, 8, 15, & 22 • Enrollment: second cohort (56 mg/m2) currently being treated!

  34. HDAC Inhibitor Vorinostat & Bortezomib for R/R MM: VANTAGE 088: Phase III Trial Bortezomib + Vorinostat Multiple Myeloma 1-3 Prior Therapies N = 637 R Bortezomib + Placebo ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival. Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.

  35. Vorinostat, Lenalidomide & Dexamethasone for R/R MM Vorinostat (300 or 400 mg, 1x daily) Lenalidomide (10, 20, 25 mg daily) Dexamethasone (40 mg weekly) Relapsed / Refractory MM N = 28 1:1 • Serious AE • Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever • Grade 3 DVT in 2 patients • No treatment-related deaths Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.

  36. Novel Combinations of Approved Drugs Greatly Expand the Therapeutic Options for R/R Myeloma Patients! • Approved drugs • Novel combinations • Modifications of dose and schedule • Improve efficacy • Better tolerability • Many new drugs in development • Similar targets • Proteasome inhibitors- carfilzomib (FDA-approved!) • IMiDs- pomalidomide • New classes of agents • HDAC inhibitors- vorinostat, panobinostat • Monoclonal antibodies • Anti-CS-1- elotuzumab • Anti-CD40- dacetuzumab • MTOR inhibitors- temsirolimus • PI3K inhibitors- perifosine

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