The HDAC6 inhibitor ricolinostat was well tolerated in combination therapy for multiple myeloma.

  • Major finding: The HDAC6 inhibitor ricolinostat was well tolerated in combination therapy for multiple myeloma.

  • Concept: Selective HDAC6 inhibition may limit side effects linked to pan-HDAC inhibition and improve efficacy.

  • Impact: Ricolinostat plus lenalidomide and dexamethasone warrants further study in patients with multiple myeloma.

Histone deacetylase (HDAC) inhibitors have demonstrated activity against multiple myeloma. The pan-HDAC inhibitor panobinostat has been approved as part of a combination drug regimen for the treatment of multiple myeloma, but it is associated with serious toxicities. Thus, more tolerable HDAC inhibitors are desired. Selective HDAC6 inhibitors are attractive candidates, as multiple myeloma cells are sensitive to HDAC6 inhibition, and such agents target the aggresome protein degradation pathway without substantially affecting gene expression or cell-cycle progression and thus may have an improved safety profile compared with pan-HDAC inhibitors. In a multicenter phase Ib dose-escalation trial, Yee and colleagues evaluated the safety and preliminary activity of the selective HDAC6 inhibitor ricolinostat in combination with lenalidomide and dexamethasone in 38 patients with relapsed or refractory multiple myeloma. The primary outcomes were dose-limiting toxicities, maximum tolerated ricolinostat dose, and the recommended dose and schedule of ricolinostat for future phase II trials. Secondary outcomes included ricolinostat pharmacokinetics and pharmacodynamics in combination with lenalidomide and dexamethasone, and preliminary antitumor activity. Ricolinostat was well tolerated, with adverse events similar to what has been observed with lenalidomide and dexamethasone alone. Two patients experienced dose-limiting toxicities, but the maximum tolerated dose was not reached. Ricolinostat selectively inhibited HDAC6 with minimal inhibition of class I HDACs at the dose recommended for further trials, and coadministration of ricolinostat and lenalidomide did not significantly alter the pharmacokinetics of either drug. An overall response was observed in 55% of patients, and the median progression-free survival was 20.7 months. Altogether, these findings indicate that selective HDAC6 inhibition may be a strategy to avoid toxicity associated with pan-HDAC inhibitors and suggest that ricolinostat may safely enhance the antitumor activity of lenalidomide and dexamethasone in patients with multiple myeloma, supporting further clinical investigation of ricolinostat in larger clinical trials.

Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol 2016 Sep 16 [Epub ahead of print].

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