Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma

Abstract

Purpose 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. Experimental Design We conducted a phase 1/2 trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase 2 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. Results 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 non-selective 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. Conclusions At the recommended phase 2 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.

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

“…Again, many of the literature reports need to be carefully interpreted due to the use of high molarities and non-selective compounds, such as ACY-241. 56 Synergistic effects combining Tubacin or Tubastatin A and Bortezomib/Carfilzomib when used against multiple myeloma, breast cancer and ovarian cancer, were only present at high molarities. 27,[51][52][53] One of the most studied combinatory therapies concerning HDAC6i, is their use with proteasome inhibitors, such as Bortezomib and Carfilzomib, for the treatment of multiple myeloma.…”

“…23,54,55 In fact, it was shown that Ricolinostat, at a clinically relevant dose of 160 mg (twice daily), in combination with Bortezomib in patients, elevated the level of acetylated histones in peripheral blood lymphocytes taken 1 h after the first Ricolinostat dose. 56 Synergistic effects combining Tubacin or Tubastatin A and Bortezomib/Carfilzomib when used against multiple myeloma, breast cancer and ovarian cancer, were only present at high molarities. 55,[57][58][59] All together, these results call for caution when claiming synergy between HDAC6i and proteasome inhibitors.…”

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma)

“…Comparison of our VBDD results to other HDACi trials was favorable, while AEs were well manageable (Table 1A). 3,4,12,13,[16][17][18][19][20][21] With a median follow-up of 30.8 months, median PFS and OS were 9.6 and 33.8 months, respectively (Fig.1E+F). Maintenance with VD or VTD was performed in eight and four patients, respectively.…”

“…Two, ricolinostat and ACY-241, are currently being tested in clinical trials to optimize HDACi combinations. 20,21 Within the armamentarium for RRMM, our HDACi-quadruplet seems to be also a cost-effective treatment option: we have calculated therapy costs at our center of VBDD vs. Dara-Rd or Dara-VD which for the latter are 5-and 4-fold higher, respectively. Moreover, our data re-assessed the role of HDACi as a well- …”

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

“…As a single agent, ACY-1215 was well-tolerated in a phase I dose-escalation study [19,204]. ACY-1215 was combined with BTZ-DEX in a phase Ib trial by Vogl et al in 57 RRMM patients (two-thirds were BTZ-refractory), who had received a median of 4 prior regimens (range, 2–13), using the following dosing schedule: ACY-1215 40–240 mg/d or 160 mg BID on days 1–5 and 8–12; BTZ 1–1.3 mg/m 2 IV or SQ on days 1, 4, 8, and 11; and DEX 20 mg on the day of and the day after BTZ of 21 days cycle [205]. Treatment-emergent AEs were mainly G1–2, but common G3–4 AEs included thrombocytopenia, anemia, fatigue, hypokalemia, hyperglycemia, diarrhea, elevated liver enzymes and hyponatremia.…”