Efficacy and Safety Based on Duration of Treatment of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma in the Phase 3 Panorama 1 Study
Authors: San Miguel Jesus , Hungria Vania TM , Yoon Sung-Soo , Beksac Meral , Dimopoulos Meletios A. , Elghandour Ashraf , Jedrzejczak Wieslaw Wiktor , Guenther Andreas , Na Nakorn Thanyaphong , Siritanaratkul Noppadol , Schlossman Robert L , Hou Jian , Moreau Philippe , Lonial Sagar , Lee Jae-Hoon , Einsele Hermann , Salwender Hans , Sopala Monika , Redhu Suman , Paul Sofia , Corrado Claudia , Binlich Florence , Richardson Paul G. 
Published: October 2019

Abstract
Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including protein metabolism and epigenetics. In a randomized phase 3 clinical trial in patients (pts) with relapsed or relapsed and refractory MM (PANORAMA 1), the addition of PAN to bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically relevant and statistically significant increase in progression-free survival (PFS) of ≈ 4 months compared to placebo plus BTZ and Dex (Pbo-BTZ-Dex). PAN-BTZ-Dex was associated with a higher rate of adverse events (AEs) compared to Pbo-BTZ-Dex; however, a comparable number of pts completed the full duration of treatment on both treatment arms. Thus, we sought to determine the effect of treatment duration on the safety and efficacy of PAN-BTZ-Dex.
Methods: The PANORAMA 1 trial consisted of two treatment phases (TP1 and TP2) with a maximum of 12 cycles total. In TP1 (eight 3-wk cycles), pts were randomized to receive oral PAN (20 mg) or Pbo administered three times a wk for the first 2 wks, and intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 with Dex (20 mg) administered orally on the days of and after BTZ. Pts demonstrating clinical benefit could proceed to TP2 (four 6-wk cycles), in which PAN was administered on a similar schedule but BTZ was administered once-wkly (days 1, 8, 22 and 29) with Dex administered on the days of and after BTZ. This analysis focused on safety and efficacy specifically associated with the two treatment phases. For efficacy outcomes (PFS and near complete response/complete response [nCR/CR] rate), pt groups were delineated by those who received treatment > 8 cycles (completed TP1, 24 weeks) and all 12 cycles (completed TP2, 48 weeks). Median PFS was calculated based on time averaged dose (cumulative dose in a time interval divided by the planned number of dosing days) of PAN received to determine the potential role of dose adjustments/interruptions on efficacy. PFS was analyzed by Kaplan-Meier estimates. A safety analysis was conducted of AEs for TP1/TP2 for pts who completed TP2. Due to interdependencies among outcomes, further investigations of these data are needed.
Results: Among the pts enrolled in the PAN-BTZ-Dex arm (N = 387), 169 (44%) completed TP1 and 102 (26.4%) completed TP2. Overall, pts who received a longer duration of treatment with PAN-BTZ-Dex demonstrated a longer PFS (Figure). Median PFS for pts who received PAN-BTZ-Dex and completed TP1 was 14.65 months (95% CI, 12.94, 16.85) and 17.64 months (95% CI, 15.90, 20.07) for those who completed TP2. In addition, nCR/CR rate was 52.9% for pts who completed TP2. Overall, the rates of commonly observed grade 3/4 AEs (≥ 20%) in the PAN-BTZ-Dex arm were thrombocytopenia (TCP, 57.0%), diarrhea (25.5%), and asthenia/fatigue (23.9%). Safety analysis for pts who completed TP2 demonstrated the higher rate of AEs in TP1 vs TP2 (excluding AEs that continued from TP1). For pts in the PAN-BTZ-Dex arm who completed treatment (n = 102), the rates of grade 3/4 events in TP1 and TP2 for common AEs were TCP (47.1% and 5.9%), diarrhea (25.5% and 8.8%), and asthenia/fatigue (19.6% and 5.9%). For pts in the Pbo-BTZ-Dex arm who completed treatment (n = 102), the rates for TP1 and TP2 were TCP (10.8% and 1.0%), diarrhea (5.9% and 0%), and asthenia/fatigue (7.8% and 0%). About half the pts (218/387; 56.3%) in the PAN-BTZ-Dex arm did not enter TP2 (112/218; 51.4% discontinued to due AEs). Analysis of time averaged dose of safety set pts on the PAN-BTZ-Dex arm demonstrated a median PFS of 12.71 (95% CI, 10.58, 14.19) months for pts who received >15-20 mg of PAN and 10.90 months (95% CI, 8.08, 12.71) for >10-15 mg.
Conclusions: These data highlight the PFS and nCR/CR rate among pts able to complete TP2 with PAN-BTZ-Dex. Furthermore, for pts who completed the entire treatment regimen, the incidence of new/worsening AEs in TP2 where BTZ was administered on a once weekly schedule was decreased. Pts who received a lower time averaged dose due to dose adjustments/interruption of PAN had a similar median PFS to pts who received a time averaged dose closer to the planned dose. Together, these data support the hypothesis that optimal management of AEs for pts receiving PAN-BTZ-Dex via dose adjustments including BTZ and/or concomitant medications, particularly earlier during their course of therapy, could increase treatment duration and maintain outcomes.
Figure 1 Figure 1.

Disclosures
San Miguel: Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Jedrzejczak:Amgen, Novartis : Consultancy, Research Funding. Guenther:Novartis: Consultancy, Research Funding. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Sopala:Novartis Pharma AG: Employment. Redhu:Novartis : Employment. Paul:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment. Richardson:Takeda: Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.