Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes

Abstract

Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.

Keywords:

• bortezomib
• deacetylase inhibitors
• multiple myeloma
• panobinostat
• relapsed and refractory multiple myeloma

Key Issues

• Panobinostat, a potent pan-DAC inhibitor, elicits antimyeloma activity through a dual mechanism of epigenetic modulation of protein expression and inhibition of aggresome-mediated protein degradation.

• The dual mechanism of action of panobinostat promotes complementary and synergistic activity with a number of agents including the PI bortezomib.

• No significant drug–drug interactions are noted with panobinostat exposure and clearance is largely intact in patients with renal impairment.

• In Phase 1 and 2 studies, the combination of panobinostat with bortezomib and dexamethasone led to clinical benefit in patients with relapsed and refractory MM, including in bortezomib-refractory patients.

• The Phase 3 PANORAMA 1 trial, which evaluated panobinostat or placebo in combination with bortezomib/dexamethasone, met its primary endpoint: a significant increase in median PFS for patients in the panobinostat arm of the trial vs those in the placebo arm (12 vs 8.1 months; p < 0.0001), which was maintained across all subgroups analyzed.

• Grade 3/4 thrombocytopenia and diarrhea were common with PAN-BTZ-Dex but led to limited patient discontinuation.

• Proactive management strategies and potential dose/administration optimization of panobinostat and bortezomib should improve tolerability.

• Panobinostat recently became the first agent with a novel mechanism of action to be approved by the US FDA and EMA for myeloma in over a decade upon receiving accelerated approval for the treatment of relapsed or relapsed and refractory patients who have received ≥2 prior lines of therapy including bortezomib and an IMiD.

Financial & competing interests disclosure

P Richardson is on advisory committees for Novartis, Takeda and Johnson and Johnson. R Harvey is on advisory committees for Onyx and Millennium. J Laubach has received research funding from Novartis, Celgene, Millennium and Onyx. P Moreau is on advisory committees for Novartis, Takeda, Janssen, Millennium and Onyx. S Lonial has provided consultancy for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx and Sanofi. J San-Miguel is on advisory committees for Janssen, Bristol-Myers Squibb, Merck Sharpe & Dohme, Millennium, Celgene, Novartis and Onyx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and performed by Michael Demars of Articulate Science and funded by Novartis Pharmaceuticals.