Multiple Myeloma in Session 2015: An Online Journal Club for Hematology/Oncology Fellows This program is supported by educational grants from Celgene Corporation and Onyx Pharmaceuticals.

PANORAMA1: Addition of Panobinostat to Bortezomib and Dexamethasone Improves PFS in Pts With Relapsed/Refractory MM Slideset on: San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206.

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Background: Panobinostat: oral nonselective HDAC inhibitor Shows synergistic anti-MM activity in combination with bortezomib and dexamethasone in preclinical studies[1,2] Higher activity in vitro compared to vorinostat[3] Received accelerated FDA approval in February 2015 in MM pts previously treated with ≥ 2 regimens including bortezomib and immunomodulatory agent PANORAMA1 evaluated efficacy of adding panobinostat to bortezomib and dexamethasone in RRMM[4] FDA, US Food and Drug Administration; HDAC, histone deacetylase; MM, multiple myeloma; RRMM, relapsed/refractory multiple myeloma. 1. Ocio EM, et al. Haematologica. 2010;95:794-803. 2. Catley L, et al. Blood. 2006;108:3441-3449. 3. Atadja P. Cancer Lett. 2009;280:233-241. 4. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: Study Design Randomized, multicenter, placebo-controlled, double-blind phase III trial Stratified by prior lines of therapy and prior bortezomib Phase I: Eight 3-wk cycles Phase II: Four 6-wk cycles Pts with symptomatic RRMM after 1-3 prior treatments (bortezomib-refractory excluded) (N = 768) Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2 Bortezomib 1.3 mg/m2 IV Days 1, 4 of Wks 1, 2 Dexamethasone 20 mg Days 1, 2, 4, 5 of Wks 1, 2 (n = 387) Placebo Days 1, 3, 5 of Wks 1,2 20 mg Days 1, 2, 4, 5 of Wks 1, 2 (n = 381) Panobinostat 20 mg Days 1, 3, 5 of Wks 1, 2, 4, 5 Bortezomib 1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5 Dexamethasone 20 mg Days 1, 2 of Wks 1, 2, 4, 5 ≥ SD IV, intravenous; RRMM, relapsed/refractory multiple myeloma; SD, stable disease. Placebo Days 1,3,5 of Wks 1, 2, 4, 5 Bortezomib 1.3 mg/m2 IV Day 1 of Wks 1, 2, 4, 5 Dexamethasone 20 mg Day 1 of Wks 1, 2, 4, 5 ≥ SD San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: Responses Response Panobinostat (n = 387) Placebo (n = 381) ORR*, % 60.7 54.6 CR 11 6 nCR 17 10 CR/nCR† 27.6 15.7 PR 33 39 MR SD 19 PD 5 8 Unknown 7 Median time to response, mos (range) 1.51 (1.41-14.91) 2.00 (1.61-2.79) Median duration of response, mos (range) 13.14 (11.76-14.92) 10.87 (9.23-11.76) Median time to progression/relapse/death from MM, mos (range) 12.71 (11.30-14.06) 8.54 (7.66-9.72) CR, complete response; MM, multiple myeloma; MR, molecular response; nCR, near complete response; PR, partial response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. *P = .09; †P = .00006 San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: PFS Significant improvement in PFS with addition of panobinostat to bortezomib and dexamethasone 100 Panobinostat, bortezomib, and dexamethasone Placebo, bortezomib, and dexamethasone 80 HR: 0.63 (95% CI: 0.52-0.76; P < .0001) 60 PFS (%) PFS, progression-free survival. 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Mos San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: PFS by Subgroups HR (95% CI) Sex Men/women 0.54 (0.41-0.70)/0.76 (0.51-1.00) Age Younger than 65 yrs of age/65 yrs of age or older 0.59 (0.46-0.76)/0.72 (0.53-0.96) Cytogenetic risk Normal/poor 0.88 (0.60-1.29)/0.47 (0.18-1.25) MM characteristics Relapsed only/relapsed + refractory 0.54 (0.39-0.75)/0.70 (0.56-0.89) Previous lines of therapy 1/2-3 0.66 (0.50-0.86)/0.64 (0.50-0.83) Previous bortezomib Yes/no 0.58 (0.44-0.77)/0.68 (0.53-0.87) Previous IMiD 0.54 (0.43-0.68)/0.78 (0.57-1.08) Previous IMiD + bortezomib 0.53 (0.37-0.76)/0.68 (0.55-0.85) IMiD, immunomodulatory agent; MM, multiple myeloma; PFS, progression-free survival. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: OS Data not yet mature Panobinostat, bortezomib, and dexamethasone Placebo, bortezomib, and dexamethasone 100 HR: 0.87 (95% CI: 0.69-1.10; P = .26) 80 60 OS (%) OS, overall survival. 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Mos San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: Safety AE, % Panobinostat (n = 381) Placebo (n = 377) Any grade 3/4 AE 96 82 Grade 3/4 nonhematologic AEs   Diarrhea 25 8 Asthenia or fatigue 24 12 Peripheral neuropathy 18 15 Pneumonia 13 11 Grade 3/4 hemorrhage 4 2 Grade 3/4 hematologic AEs (new or worsening) Thrombocytopenia 68 31 Lymphopenia 54 40 Neutropenia 35 Serious AE 60 42 Discontinuation due to treatment-related AE AE, adverse event. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: Strengths and Weaknesses Supports concept of improved efficacy from blocking aggresome–autophagy pathway Improved toxicity over vorinostat Weaknesses IV administration of bortezomib likely resulted in increased toxicity Study does not address optimal dose and schedule for panobinostat IV, intravenous. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

PANORAMA1: Conclusions Panobinostat + bortezomib and dexamethasone significantly improved PFS vs placebo, bortezomib, and dexamethasone in pts with RRMM Subgroup analyses suggest panobinostat effective in pts with poorer prognostic factors including relapsed/refractory disease, elderly, > 1 prior treatment, and poor cytogenetic risk factors Safety profile manageable, may improve with weekly subcutaneous bortezomib Investigators suggest panobinostat may be effective addition to treatment of relapsed or RRMM PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

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