Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial

Yee, Andrew J.; Bensinger, William I.; Supko, Jeffrey G.; Voorhees, Peter M.; Berdeja, Jesús G.; Richardson, Paul G.; Libby, Edward N.; Wallace, Ellen; Birrer, Nicole; Burke, Jack D.; Tamang, David; Yang, Min; Jones, Simon; Wheeler, Catherine; Markelewicz, Robert J.; Raje, Noopur

doi:10.1016/s1470-2045(16)30375-8

Cited by 170 publications

(144 citation statements)

References 28 publications

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“…6 In MM, PD-L1 expression directly correlates with progression of disease, with highest levels in patients with relapsed/refractory MM. 7,8 Here we utilized an orally bioavalable HDAC6 selective inhibitor ACY-241, currently in clinical trials 9 , to examine whether the combination of ACY-241 with anti-PD-L1 antibody enhances anti-MM immunity in the MM BM microenvironment.…”

Section: Letter To the Editormentioning

confidence: 99%

Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

et al. 2017

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Section: Letter To the Editormentioning

confidence: 99%

Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

et al. 2017

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“…Therefore, efforts have been made to develop HDAC6 inhibitors with enhanced specificity (106). One such inhibitor, Ricolinostat (ACY-1215) demonstrated some antitumor activity in combination therapy (107). Beyond Ricolinostat’s primary target HDAC6, IKZF1/3 and MYC were downregulated (103).…”

Section: Drugs Targeting Histone Acetylationmentioning

confidence: 99%

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

Dupéré-Richér

Licht

2017

Current Opinion in Hematology

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Purpose of review Next generation sequencing and large scale analysis of patient specimens has created a more complete picture of Multiple Myeloma (MM) revealing that epigenetic deregulation is a prominent factor in MM pathogenesis. Recent findings Over half of MM patients have mutations in genes encoding epigenetic modifier enzymes. The DNA methylation profile of MM is related to the stage of the disease and certain classes of mutations in epigenetic modifiers are more prevalent upon disease relapse, suggesting a role in disease progression. Many small molecules targeting regulators of epigenetic machinery have been developed and clinical trials are underway for some of these in MM. Summary Recent findings suggest that epigenetic targeting drugs could be an important strategy to cure MM. Combining these agents along with other strategies to affect the MM cell such as IMIDs and proteasome inhibitors may enhance efficacy of combination regimens in MM.

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“…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.…”

mentioning

confidence: 97%

“…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- …”

mentioning

confidence: 99%

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)

et al. 2018

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Engelhardt. 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). Haematologica. 2018; 103:xxx doi:10.3324/haematol.2018.189969 Publisher's Disclaimer. Vorinostat is an oral class I/II HDACi and has been investigated with bortezomib in a randomized phase III trial for RRMM patients: this VANTAGE088 study reported a median PFS of 7.6 vs. 6.8 months for (Table 1A). The synergism of vorinostat and bortezomib is depicted in Fig.S1A. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.All patients suffered from relapsed (n=23) or RRMM (n=10). The median age was 62 years, which was comparable or more advanced to others (Table 1B). In line with our earlier description of age and stage migration, 8 we here observed more elderly, unfit and advanced MM stages. [8][9][10] The Revised Myeloma Comorbidity Index (R-MCI) was 4, thus patients were by definition intermediate-fit. In line, their Charlson Comorbidity Index (CCI) was 2 vs. 1 in our control patients (Table 1C). For comparison, Palumbo et al.described their elderly clinical trial cohort with a CCI of 0. 11Our pretreatment with PIs, IMiDs and autologous stem cell transplantation (ASCT) was similar to others. 5,12,13 The number of prior lines was 3: virtually all (91%) had received ASCT, bortezomib (88%) and IMiDs (42%). The median bone marrow (BM) infiltration was 40%, iFISH showed HR in 18% and unfavorable cytogenetics (CG) in 52% (Table 1A+B). The VBDD data were presented as of 12/2016 with at least one year follow-up of the last patient being treated. NA being approved in Europe since 2016, 3 such as daratumumab (Dara), elotuzumab, carfilzomib or ixazomib, had not been available for RRMM patients outside clinical trials at that time.14 With three patients having been treated in each dose level (DL) 0 and +1, without any DLT during the first cycle, the remaining 27 proceeded to DL+2. Common hematologic side effects (AEs) included anemia and thrombocytopenia. Non-hematological AEs included infections, amongst others three cases of sepsis, three with pneumonia, and one each with esophageal candidiasis, colitis and herpes zoster reactivation.Others included one case of syncope and cerebral seizure in a patient with seizure history (Table 2).Cardiotoxicity was not observ...

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Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial

Cited by 170 publications

References 28 publications

Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

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)

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