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Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma. Clin Cancer Res 2017 07 01;23(13):3307-3315 PMID: 28053023 PMCID: PMC5496796

Pubmed ID

28053023

Abstract

Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle. Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. .

Author List

Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowski R, Supko JG, Tamang D, Yang M, Jones SS, Wheeler C, Markelewicz RJ, Lonial S

Author

Parameswaran Hari MD Chief, Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-85021106014   42 Citations

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Bortezomib
Dexamethasone
Drug Resistance, Neoplasm
Female
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Male
Maximum Tolerated Dose
Middle Aged
Multiple Myeloma
Neoplasm Recurrence, Local
Pyrimidines
jenkins-FCD Prod-296 4db9d02597e0a2e889e230f853b641c12f1c3ee3