PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma

Richardson, Paul G.; Schlossman, Robert; Alsina, Melissa; Weber, Donna M.; Coutre, Steven; Gasparetto, Cristina; Mukhopadhyay, Sutapa; Ondovik, Michael S.; Khan, Mahmudul; Paley, Carole; Lonial, Sagar

doi:10.1182/blood-2013-01-481325

Cited by 279 publications

(248 citation statements)

References 26 publications

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“…Groups of MRL/lpr mice 12-13 weeks old were treated daily with a reduced dose of panobinostat compared with preclinical studies with multiple myeloma 38 . Mice were monitored daily by a researcher masked to treatment groups and consistent with the recent panobinostat clinical trials 39 , no adverse effects were noted on the general wellbeing of mice. Furthermore, no significant changes were observed in the weights of animals throughout the treatment window ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As the reported side effects of long-term HDACi treatment in cancer patients have been demonstrated to be manageable 18,55 , and panobinostat treatment in multiple myeloma patients has been well tolerated with significant disease benefit 39 , this suggests that if the shortterm immunosuppression can be managed effectively, an HDACi-based therapy could be well tolerated in autoimmune disease patients. At the low doses anticipated in the treatment of autoimmune disease, potential B-cell-dependent immune suppression could be treated with treatment interruption or dose reduction.…”

Section: Discussionmentioning

confidence: 99%

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Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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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: 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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“…Panobinostat (LBH-589), a pan-HDAC inhibitor has been used in combination with Bortezomib in MM therapy 56,57 and has recently been approved by the FDA for its clinical use against MM. However, it is not clear which HDAC is commonly required for survival of genetically diverse groups of MMCLs.…”

Section: Nature Communications | Doimentioning

confidence: 99%

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

et al. 2015

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Although transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.

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PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma

Abstract: Key Points Panobinostat + bortezomib + dexamethasone recaptures responses in heavily pretreated, bortezomib-refractory multiple myeloma patients.

Cited by 279 publications

References 26 publications

Manipulation of B-cell responses with histone deacetylase inhibitors

Manipulation of B-cell responses with histone deacetylase 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)

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

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