Analysis of Outcomes Based on Response in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma Treated with Panobinostat or Placebo in Combination with Bortezomib and Dexamethasone in the Panorama 1 Trial: Updated Analysis Based on Prior Treatment
Authors: San Miguel Jesús F , Hungria Vânia TM , Yoon Sung-Soo , Beksac Meral , Dimopoulos Meletios A. , Elghandour Ashraf , Jedrzejczak Wieslaw W. , Guenther Andreas , Nakorn Thanyaphong Na , Siritanaratkul Noppadol , Schlossman Robert L. , Hou Jian , Moreau Philippe , Lonial Sagar , Lee Jae Hoon , Einsele Hermann , Sopala Monika , Bengoudifa Bourras-Rezki , Corrado Claudia , Binlich Florence , Richardson Paul G. 
Published: October 2019

Abstract
Introduction: Panobinostat (PAN), a potent pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median progression-free survival (PFS) of patients (pts) with relapsed or relapsed and refractory multiple myeloma (MM) in a phase 3 trial. In the PANORAMA 1 trial, the addition of PAN to treatment with bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a significant increase in high-quality responses (near-complete response/complete response [nCR/CR]; 27.6%) vs treatment with placebo (Pbo), BTZ, and Dex (15.7%; P = .00006). Pts in the PAN-BTZ-Dex arm also had a significantly prolonged median PFS of 12.0 months vs 8.1 months in pts treated with Pbo-BTZ-Dex (hazard ratio [HR], 0.63; P < .0001). Further, subgroup analysis showed that the PFS benefit was maintained in pts with previous exposure to BTZ and immunomodulatory drugs (IMiDs; 10.6 vs 5.8 months; HR, 0.52). These results supported the recent US FDA approval of PAN in combination with BTZ and Dex for the treatment of pts with relapsed or relapsed and refractory MM who have received ≥ 2 prior regimens including BTZ and an IMiD. Here, we present a detailed analysis of the effect of response on clinical outcomes in a subpopulation of PANORAMA 1 pts with prior exposure to BTZ and IMiDs.
Methods: Response outcomes were analyzed for the subgroup of PANORAMA 1 pts with prior exposure to BTZ and IMiDs based on modified European Society for Blood and Marrow Transplantation criteria, including nCR/CR and partial response (PR). A landmark analysis at 12, 18, and 24 weeks was performed using a Cox regression model to assess the median PFS in pts who achieved nCR/CR and PR.
Results: Among pts with prior exposure to BTZ and IMiDs, the nCR/CR rate was higher in the PAN-BTZ-Dex arm (22.3% [95% CI, 14.4-32.1]) vs the Pbo-BTZ-Dex arm (9.9% [95% CI, 4.2-16.6]). In the PAN-BTZ-Dex arm, the landmark analysis at 12 weeks demonstrated a median PFS of 13.7 months in pts achieving nCR/CR vs 8.1 months in pts achieving PR (HR, 0.34 [95% CI, 0.12-0.96]). Similarly, pts achieving nCR/CR in the Pbo-BTZ-Dex arm had a median PFS of 12.2 vs 7.8 months for pts achieving a PR (HR, 0.74 [95% CI, 0.27-2.01]). Landmark analysis at 18 weeks demonstrated a median PFS of 15.8 months for pts with nCR/CR vs 10.3 months for pts with a PR in the PAN arm (HR, 0.30 [95% CI, 0.12-0.75]) and 14.1 vs 9.0 months (HR, 0.76 [95% CI, 0.29-1.98]) in the Pbo arm for pts with nCR/CR and PR, respectively. The 24 week landmark assessment revealed a median PFS in the PAN arm of 15.8 months for pts with nCR/CR vs 13.7 months for pts with PR (HR, 0.32 [95% CI, 0.14-0.74]) and, in the Pbo arm, a median PFS of 12.2 months for pts with nCR/CR vs 11.2 months in pts with PR (HR, 0.93 [95% CI, 0.36-2.43]).
Conclusions: Treatment with PAN-BTZ-Dex is associated with a > 2-fold increase in the rate of nCR/CR in pts with relapsed or relapsed and refractory MM compared with control arm. Among study pts who had received prior treatment with BTZ + IMiDs, those who achieved nCR/CR after treatment with PAN-BTZ-Dex demonstrated a prolonged PFS compared to pts who achieved PR.These data highlight the importance of achieving deep responses with PAN-BTZ-Dex in this subpopulation, suggesting that the achievement of such responses may be linked to improved clinical outcomes.

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. Beksac:Janssen-Cilag: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Dimopoulos:Onyx: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Jedrzejczak:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onconova: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Einsele:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Binlich:Novartis: Employment. Richardson:Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: 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; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.