Improved Safety with the Use of Subcutaneous Bortezomib in Combination with Panobinostat and Dexamethasone: Preliminary Data from a Panobinostat Global Expanded Treatment Protocol
Authors: Guenther Andreas , Mügge Lars-Olof , Haenel Mathias , Schjesvold Fredrik H. , Lechner Daniel , Yaser Sameer , Hebart Holger , Gisslinger Heinz , Greil Richard , Gunsilius Eberhard , Goerner Martin , Weisel Katja , Dürig Jan , Elemary Mohamed , Wolleschak Denise , Klein Stefan A. , Munder Markus , Kiani Alexander , Nahi Hareth , Junghanss Christian , Campello-Iddison Valerie , Deniau Ythier , Feng Xiaoshu , Einsele Hermann 
Published: November 2019

Abstract
Introduction:
Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availability to patients with relapsed/refractory MM who have received ≥ 2 prior lines of therapy but for whom satisfactory treatment alternatives are not available.
Methods:
Panobinostat-ETP is a multicenter, open-label, ETP study of PAN+BTZ+Dex in adult patients with MM relapsed and/or refractory to ≥ 2 prior lines of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN 20 mg (days 1, 3, 5, 8, 10, and 12) plus intravenous or subcutaneous BTZ 1.3 mg/m2 (days 1, 4, 8, and 11) for eight 21-day cycles. Patients with ≥ stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex 20 mg was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed prior to TP2 as a dose reduction strategy.
Results:
A total of 49 patients with a median age of 67 years (range, 45-85 years) were enrolled in the study. Patients were heavily pretreated; 73.5% received ≥ 3 prior lines of therapy. Most patients (n = 43 [87.8%]) received subcutaneous BTZ, while 3 (6.1%) received intravenous BTZ, and another 3 (6.1%) received both. The median duration of treatment with PAN+BTZ+Dex was 67 days (range, 12-305 days). The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (51.0%), anemia (12.2%), and neutropenia (10.2%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were diarrhea (14.3%), fatigue (8.2%), infection (6.1%), and nausea (6.1%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (51.0%), constipation (16.3%), and nausea (16.3%). Interestingly, in the patients receiving subcutaneous BTZ, the rates of grade 3/4 diarrhea (11.6%), thrombocytopenia (48.8%), anemia (14.0%), and neutropenia (11.6%) were lower than those seen with intravenous BTZ administration in the phase 3 PANORAMA 1 trial (25%, 57%, 16.8%, and 24.1%, respectively). Two patients died while on treatment; one due to disease progression and the other due to infection. Common serious AEs included diarrhea (12.2%) and thrombocytopenia, atrial fibrillation, infection, pneumonia, and syncope (all 6.1%); serious AEs of atrial fibrillation and syncope were higher than in PANORAMA 1 (1.0% and 1.3%, respectively). AEs led to PAN, BTZ, and Dex dose adjustment in 36.7%, 42.9%, and 16.3% of patients, respectively; the most common AE leading to dose adjustment or temporary interruption was thrombocytopenia (all-grade, 30.6%; grade 3/4, 28.6%). Efficacy data will be reported after sufficient follow-up.
Conclusions:
Overall, the safety results from panobinostat-ETP, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1, with only a slight increase in atrial fibrillation, potentially because of the older population. In the subgroup of patients receiving subcutaneous BTZ, rates of diarrhea and hematologic toxicities, AEs of interest with PAN+BTZ+Dex therapy, appear to be reduced compared with PANORAMA 1 data with intravenous BTZ administration; however, because of the small size of this study, these results should be interpreted with caution. Further clinical experience with the use of subcutaneous BTZ in this combination will help to determine the potential impact of the route of BTZ administration on tolerability.

Disclosures
Guenther: Takeda: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers-Suibb: Honoraria. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lechner:Novartis: Honoraria. Gisslinger:Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria. Greil:Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen: Consultancy, Honoraria; Bristol Myer-Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Munder:Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria. Kiani:Novartis: Consultancy, Honoraria, Speakers Bureau. Campello-Iddison:Novartis: Employment, Equity Ownership. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.