3-drug Regimen With Ricolinostat Active, Safe in Multiple Myeloma
HDAC inhibition improves efficacy of proteasome inhibitors in multiple myeloma but toxicity is an issue.
Selective inhibition of HDAC6 with ricolinostat in combination with bortezomib and dexamethasone appears active and safe in patients with relapsed or refractory multiple myeloma, according to a study published in the journal Clinical Cancer Research.1
Previous research has demonstrated HDAC inhibition improves the efficacy of proteasome inhibitors in multiple myeloma but adds significant toxicity. Because preclinical models suggest that HDAC6 is responsible for the observed synergy between HDAC inhibitors and proteasome inhibitors, researchers sought to evaluate the safety and preliminary efficacy of the HDAC6-selective inhibitor ricolinostat in combination with standard proteasome inhibitor therapy.
For the multicenter, open-label, phase 1/2 study (ClinicalTrials.gov Identifier: NCT01323751), investigators enrolled 72 patients with relapsed or refractory multiple myeloma who had received at least 2 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug.
Of those, 15 patients received oral ricolinostat monotherapy and 57 patients received ricolinostat in combination with bortezomib and dexamethasone.
Results showed although single-agent ricolinostat therapy was not associated with significant toxicity, no patients achieved a minor or partial response. Six patients had stable disease for a median of 11 weeks.
In the combination cohort, 160 mg daily of ricolinostat was well tolerated, with less severe constitutional, gastrointestinal, and hematologic toxicities compared with reported data on nonselective HDAC inhibitors. The most common treatment-emergent adverse events were thrombocytopenia, anemia, diarrhea, hypertension, fatigue, hyperglycemia, renal insufficiency, nausea, hypophosphatemia, and hyponatremia.
Investigators observed significant gastrointestinal toxicity in patients who were treated with twice daily dosing of ricolinostat.
Researchers found that 37% of patients in the combination cohort who received daily ricolinostat at a dose of 160 or 240 mg achieved a partial response or better. Among those with bortezomib-refractory disease, the response rate was 14%.
Therefore, researchers recommend that ricolinostat at a dose of 160 mg daily on days 1 to 5 and days 8 to 12 of each 21-day cycle be evaluated in combination with bortezomib and dexamethasone in the phase 2 portion.
Ongoing trials are also assessing the combination of ricolinostat with lenalidomide and dexamethasone or with pomalidomide and dexamethasone in this population.