A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

ABSTRACT

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.

KEYWORDS:

• Multiple myeloma
• histone deacetylase inhibitors
• panobinostat
• vorinostat
• safety profile

Article highlights

• Histone deacetylase (HDAC) inhibition has been defined as a master switch that can influence multiple pathways simultaneously. HDAC inhibitors bind to the catalytic domains of HDACs, reducing their activity, which in turn inhibits myeloma cell survival and proliferation.

• HDAC and proteasome inhibitors have shown a synergistic inhibition of dual apoptotic activity on proteasome and aggresome pathways when used in combination. The mechanisms of action of both drugs are related with modifications in protein degradation pathways. Preclinical and clinical studies have demonstrated several mechanisms for synergy.

• Panobinostat, as the first FDA-approved histone deacetylase inhibitor anti-multiple myeloma drug, has made success in benefiting patients with relapse/refractory multiple myeloma. It has minimal single-agent activity but in combination setting, has been proven to have an improvement in PFS but not response rates. In addition, panobinostat carries a boxed warning for severe and fatal cardiac ischemic events, severe arrhythmias and ECG changes.

• Vorinostat is an oral nonselective class I and class II HDACi approved by FDA for the treatment of relapsed/refractory cutaneous T-cell lymphoma. In phase III trial, although promising results of vorinostat and bortezomib combination therapy has been reported, the early enthusiasm about vorinostat has turned into loss of interest. None of the new trials have established any significant improvement in clinical outcomes, but instead increased toxicity.

• To minimize toxicity seen with the use of pan-deacetylase inhibitors and to maintain efficacy, a more specific histone deacetylase-6 inhibitor known as ricolinostat had been under investigated in myeloma patients. But one aspect limiting further clinical development of ricolinostat is the challenge in deriving a solid dose formulation and a high exposure plateau and for this reason; it is not currently being further developed.

• The second-generation HIDAC inhibitor, quisinostat has been developed with an expectation of reducing AEs, achieving better, broader efficacy and/or overcoming bortezomib resistance. It has demonstrated high clinical activity in combination with bortezomib and dexamethasone even in patients resistant or not responsive to bortezomib treatment, and notably it causes grade 3 cardiac toxicities.

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Declaration of interest

M Beksac received honoraria for serving on the speakers’ bureau for Janssen-Cilag, Takeda, Calgene, Amgen, Bristol-Myers Squibb, and 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.

Reviewer disclosures

A reviewer of this manuscript was disclosed that they were an investigator (and lead author) on the clinical trial of ricolinostat alone and in combination with bortezomib. They have received research funding from Acetylon, the manufacturer of ricolinostat (since bought by Celgene), for laboratory research. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the Turkish Academy of Sciences:[Grant Number NA].