Ricolinostat Plus Lenalidomide–Dexamethasone ‘Tolerated’ By Multiple Myeloma Patients

A selective histone deacetylase 6 inhibitor appears to be tolerated in combination with lenalidomide plus dexamethasone for treatment-refractory multiple myeloma

medwireNews: Early trial results suggest that ricolinostat, an oral selective histone deacetylase (HDAC)6 inhibitor with reduced class I HDAC activity, may be feasible in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma.

The phase Ib study, published in The Lancet Oncology, included 38 patients who had received a median of two prior treatments but were naive to HDAC inhibitor therapy. The participants were given an escalating dose of ricolinostat in an oral solution from 40 to 240 mg given once daily or up to 160 mg twice daily, alongside lenalidomide 15–25 mg/day and dexamethasone 40 mg/week.

Two patients given the 160 mg twice daily dose of ricolinostat experienced dose-limiting toxicity, namely grade 3 syncope and grade 3 myalgia, report Noopur Raje, from Massachusetts General Hospital in Boston, USA, and co-authors.

But a maximum tolerated dose for the drug was not reached and the investigators determined that future phase II trials for ricolinostat in combination with lenalidomide 25 mg and dexamethasone 40 mg should be set at 160 mg once daily given on days 1 to 21 of a 28-day cycle.

Fatigue was the most common side effect with grade 1–2 events in 37% of patients and grade 3 in 18%. Diarrhoea was also common, with grade 1–2 and grade 3 effects reported in 39% and 5% of patients, respectively.

Neutropenia, anaemia and thrombocytopenia were the most common haematological side effects, with grade 1–2 events in 8%, 29% and 29%, respectively, and grade 3 events in 26%, 5% and 5%, respectively. Grade 4 neutropenia occurred in 8% of patients.

“Ricolinostat given with lenalidomide and dexamethasone showed encouraging preliminary activity in this relapsed or refractory population”, say the researchers.

The overall response rate was 55%, including a complete response in 5%, a very good partial response in 18% and a partial response in 26%, while minimal response, stable disease and progressive disease were reported for 8%, 18% and 18%, respectively.

This gave an overall clinical benefit rate of 63% and a disease control rate of 82%, the team reports, with a median progression-free survival (PFS) of 20.7 months.

And the overall response rate was 69% among the 26 patients whose tumours were not refractory to lenalidomide, 25% for the 12 patients refractory to lenalidomide and 40% for the five whose disease was refractory to lenalidomide and bortezomib.

“The addition of ricolinostat might enhance the activity of lenalidomide and dexamethasone, reflecting the cooperativity seen in vitro, and ricolinostat might salvage responses in patients who are refractory to lenalidomide”, Noopur Raje et al suggest.

Noting that addition of the pan-HDAC inhibitor panobinostat has extended PFS achieved with bortezomib and dexamethasone at the cost of serious toxicity, including diarrhoea and arrhythmia, the team writes that selective HDAC6 targeting and reduced class I HDAC inhibition with ricolinostat may be “an effective and better tolerated approach than is pan-HDAC inhibition.”

“Both the encouraging activity and safety profile of ricolinostat might be due to its unique mechanisms of synergy with immunomodulatory drugs”, the authors say, adding that the trial results “set the stage” for ACY-241, a second selective inhibitor of HDAC6 administered as a tablet that is now in phase 1b trial for use with pomalidomide and dexamethasone.

“Findings from these studies will better define the role of selective and pan-HDAC inhibition in treatment of multiple myeloma than at present”, the team concludes.

Reference

Yee AJ, Bensinger WI, Supko JG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol; Advance online publication 16 September 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30375-8

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