Update on a Phase III Study of Panobinostat with Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: PANORAMA 1,
Authors: San-Miguel Jesús F. , de Moraes Hungria Vânia Tietsche , Yoon Sung-Soo , Wiktor-Jedrzejczak Wieslaw , Elghandour Ashraf , Siritanaratkul Noppadol , Dimopoulos Meletios Athanasios , Corradini Paolo , Nakorn Thanyaphong Na , Shelekhova Tatiana , Günther Andreas , Yong Kwee , Schlossman Robert , Wroclawska-Swacha Monika , Weber Hans-Jochen , Bourquelot Priscille , Hou Jian , Einsele Hermann , Lee Jae Hoon , Moreau Philippe , Lonial Sagar , Richardson Paul G. 
Published: October 2019

Abstract
Abstract 3976

Background:
The outcomes of patients with multiple myeloma (MM) have significantly improved in recent years mainly because of the availability of 2 novel classes of drugs: immunomodulatory drugs (IMiDs; thalidomide and lenalidomide) and proteasome inhibitors (bortezomib). However, a subset of MM patients is refractory to these agents, and responding patients often relapse or progress. Therefore, novel salvage treatments are needed. Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that has demonstrated synergy in combination with bortezomib in preclinical MM studies. This synergy is thought to occur through inhibition of protein metabolism via targeting of the aggresome and proteasome pathways. Significant clinical activity, including complete responses, was observed in a phase Ib study of panobinostat + bortezomib in patients with relapsed or relapsed and refractory MM (San-Miguel et al, EHA 2011, abstract 0314). In addition, responses were observed in patients with bortezomib-refractory MM. Based on these preliminary data, a phase II and III clinical study program of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed or refractory MM was initiated—PANobinostat ORAl in Multiple myelomA (PANORAMA). PANORAMA 1 is an international, randomized, double-blind, phase III study of panobinostat (or placebo) + bortezomib + dexamethasone. PANORAMA 2 is a single-arm, open-label, phase II study in bortezomib-refractory patients conducted in the United States. Preliminary response data from PANORAMA 2 were available in 20 patients, and met the predefined threshold allowing, together with early tolerability data, continuation and completion of study enrollment (Schlossman et al, EHA 2011, abstract 0900). Here we present the preliminary demographic and blinded safety results of the phase III study (PANORAMA 1) in patients with relapsed MM.

Methods:
A total of 672 patients with relapsed or relapsed and refractory MM (1–3 prior lines of therapy) will be enrolled to the trial. Patients with prior bortezomib-based therapy are eligible; however, patients with bortezomib-refractory MM (not achieving at least a minimal response or progressed on or within 60 days of the last bortezomib-containing regimen) are excluded from this trial. PANORAMA 1 comprises 2 treatment phases. Treatment phase 1 consists of eight 3-week cycles of panobinostat (oral 20 mg) or placebo administered thrice weekly and bortezomib (intravenous 1.3 mg/m2) administered twice weekly, each for 2 of 3 weeks. Dexamethasone (oral 20 mg) is administered on the days of and after bortezomib dosing. If clinical benefit is observed, patients proceed to treatment phase 2, which consists of four 6-week cycles with a modified (once-weekly) bortezomib schedule. The primary endpoint is progression-free survival, and the key secondary endpoint is overall survival.

Results:
Blinded data from 273 enrolled patients in a planned safety analysis are available (data cutoff 31 January 2011). Median age was 64 years (range 32–79 years), and 45% of patients were ≥ 65 years of age. Approximately half of the patients (51%) had received 1 prior line of therapy, whereas 49% received 2–3 prior lines of therapy. Most patients (60%) had also received prior stem cell transplantation. Previous treatment included thalidomide (35%), bortezomib (32%), and lenalidomide (14%). Preliminary pooled safety data (blinded) were available in 267 patients who received 1 dose of treatment. The most commonly affected organ class was the gastrointestinal system (all grade, 59% vs grade 3/4, 15.4%), of which diarrhea was most common (all grade, 36% vs grade 3/4, 10%). Other common AEs (all grade vs grade 3/4) were thrombocytopenia (41% vs 29%), anemia (24% vs 10%), fatigue (24% vs 9%), and neutropenia (12% vs 8%). Peripheral neuropathy of any grade was observed in 19% of patients, with grade 3/4 observed in 3% of patients.

Conclusions:
Panobinostat in combination with bortezomib has shown clinical activity in relapsed and refractory MM patients. Preliminary analysis of pooled safety data (blinded) from the first 267 patients treated in PANORAMA 1 demonstrated no new or unexpected AEs. Updated demographics and safety data for approximately 500 patients will be presented. The results of PANORAMA 1 and PANORAMA 2 will help determine the potential role of panobinostat in the treatment of patients with relapsed and refractory MM.

Disclosures:
San-Miguel: Celgene: 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; Millennium: 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. Yoon:Celgene: Consultancy; NK Bio: Consultancy. Wiktor-Jedrzejczak:Janssen-Cilag Polska: Honoraria; Novartis: Research Funding. Siritanaratkul:Novartis: Research Funding. Dimopoulos:Novartis: Consultancy, Honoraria. Corradini:Celgene: Honoraria; Genzyme: Honoraria. Günther:Novartis: Consultancy, Research Funding; Celgene: Consultancy. Yong:Janssen-Cilag UK: Honoraria. Wroclawska-Swacha:Novartis: Employment. Weber:Novartis: Employment, Equity Ownership. Bourquelot:Novartis: Employment, Equity Ownership. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Einsele:Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy. Moreau:Novartis: Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; 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; BMS: Membership on an entity's Board of Directors or advisory committees.