Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma

Abstract

Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.

Keywords:

• bortezomib
• deacetylase inhibitors
• multiple myeloma
• panobinostat
• treatment of relapsed and refractory disease

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Erratum

Financial & competing interests and disclosure

PG Richardson: advisory committees for Novartis, Takeda and Johnson & Johnson; JP Laubach: research funding from Novartis, Celgene, Millennium and Onyx; S Lonial: consultancy for Millennium, Celgene, Novartis, Bristol-Myers Squibb, Onyx and Sanofi; P Moreau: advisory committees for Novartis, Takeda, Janssen, Millennium and Onyx; MA Dimopoulos: honoraria from Novartis, Celgene, Onyx and Janssen; M Beksac: advisory committees for Celgene, Amgen, Novartis, Bristol-Myers Squibb and Millennium; M Alsina: advisory committee for Millennium; JFS-M: member of advisory committee for Janssen, Bristol-Myers Squibb, Merck Sharpe & Dohme, Millennium, Celgene, Novartis and Onyx. S Tanik and W Fazzone provided writing assistance funded by Novartis. 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.

Key issues

• Panobinostat is a potent pan-deacetylase inhibitor that elicits anti-myeloma activity primarily through epigenetic modulation of gene expression and inhibition of pathways involved in protein metabolism.

• Panobinostat demonstrated synergistic activity when combined with bortezomib and dexamethasone in in vitro and in in vivo models of multiple myeloma (MM).

• In Phase I and II studies, the combination of panobinostat with bortezomib and dexamethasone led to durable responses in patients with relapsed and refractory MM, including in bortezomib-refractory patients.

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

• Patients on the panobinostat arm of the PANORAMA 1 trial also demonstrated an increase in higher-quality responses (≥ near-complete response), duration of response and time to response.

• Common grade 3/4 laboratory abnormalities and AEs for patients who received panobinostat in PANORAMA 1 were thrombocytopenia (67%), lymphopenia (53%), diarrhea (26%), asthenia/fatigue (24%) and peripheral neuropathy (18%).

• Panobinostat is the first agent with a novel mechanism of action in more than a decade to demonstrate benefit for patients with MM.

• Panobinostat is currently FDA approved for use in combination with bortezomib and dexamethasone in patients who received at least two prior regimens including bortezomib and an immunomodulatory drug.