Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial

Brown, Sarah; Pawlyn, Charlotte; Tillotson, Avie-Lee; Sherratt, Debbie; Flanagan, Louise; Low, Eric; Morgan, Gareth J.; Williams, Cathy; Kaiser, Martin; Davies, Faith E.; Jenner, Matthew

doi:10.1016/j.clml.2020.11.019

Cited by 17 publications

(13 citation statements)

References 31 publications

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“…Along this line, a number of studies showed efficacy of combinations of bortezomib or pevonedistat with other drugs. Examples include combination of bortezomib with vorinostat and dexamethasone in relapsed multiple myeloma [NCT01720875 ( 34 )]. Pevonedistat was found to synergize with EGFR pathway inhibition, leading to tumor regression, in CRC xenograft models ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient

et al. 2023

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High-grade mucinous colorectal cancer (HGM CRC) is particularly aggressive, prone to metastasis and treatment resistance, frequently accompanied by “signet ring” cancer cells. A sizeable fraction of HGM CRCs (20-40%) arises in the context of the Lynch Syndrome, an autosomal hereditary syndrome that predisposes to microsatellite instable (MSI) CRC. Development of patient-derived preclinical models for this challenging subtype of colorectal cancer represents an unmet need in oncology. We describe here successful propagation of preclinical models from a case of early-onset, MSI-positive metastatic colorectal cancer in a male Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to immunotherapy. Surgical material from a debulking operation was implanted in NOD/SCID mice, successfully yielding one patient-derived xenograft (PDX). PDX explants were subsequently used to generate 2D and 3D cell cultures. Histologically, all models resembled the tumor of origin, displaying a high-grade mucinous phenotype with signet ring cells. For preclinical exploration of alternative treatments, in light of recent findings, we considered inhibition of the proteasome by bortezomib and of the related NEDD8 pathway by pevonedistat. Indeed, sensitivity to bortezomib was observed in mucinous adenocarcinoma of the lung, and we previously found that HGM CRC is preferentially sensitive to pevonedistat in models with low or absent expression of cadherin 17 (CDH17), a differentiation marker. We therefore performed IHC on the tumor and models, and observed no CDH17 expression, suggesting sensitivity to pevonedistat. Both bortezomib and pevonedistat showed strong activity on 2D cells at 72 hours and on 3D organoids at 7 days, thus providing valid options for in vivo testing. Accordingly, three PDX cohorts were treated for four weeks, respectively with vehicle, bortezomib and pevonedistat. Both drugs significantly reduced tumor growth, as compared to the vehicle group. Interestingly, while bortezomib was more effective in vitro, pevonedistat was more effective in vivo. Drug efficacy was further substantiated by a reduction of cellularity and of Ki67-positive cells in the treated tumors. These results highlight proteasome and NEDD8 inhibition as potentially effective therapeutic approaches against Lynch syndrome-associated HGM CRC, also when the disease is refractory to all available treatment options.

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Section: Discussionmentioning

confidence: 99%

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient

et al. 2023

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“…In the MUKfour trial, toxicity was also a factor limiting the utility of a vorinostat, bortezomib and dexamethasone combination in relapsed myeloma. 14 There is a fine balance between clinical efficacy and increased toxicity especially when using drugs during the maintenance setting where tolerability and quality of life are crucial. These considerations not only apply to the use of HDAC inhibitors but have also been noted in other settings, such as the addition of clarithromycin to lenalidomide and dexamethasone for newly diagnosed patients, 15 where although higher response rates were seen an inferior PFS was noted due to intolerability.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the Myeloma XI study, and a small study reporting only as recruitment to Myeloma XI 13 concluded, significant toxicity was seen with HDAC inhibition and was associated with compromised delivery of the lenalidomide‐vorinostat combination. In the MUKfour trial, toxicity was also a factor limiting the utility of a vorinostat, bortezomib and dexamethasone combination in relapsed myeloma 14 …”

Section: Discussionmentioning

confidence: 99%

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from ‘Myeloma XI’, a multicentre, open‐label, randomised, phase III trial

et al. 2022

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Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28day cycle) with treatment continuing until unacceptable toxicity or progressive lenalidomide, maintenance combinations, myeloma, vorinostat

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“…Based on promising in vitro activity alone and in combination [122,[143][144][145], vorinostat, a pan-HDAC inhibitor approved for the treatment of cutaneous T-cell lymphoma, was also studied in MM patients. Studies on vorinostat have included combination therapy with bortezomib [146,147] in relapsed and refractory patients; combinations with bortezomib, lenalidomide and dexamethasone in newly diagnosed MM patients [138] and maintenance treatment in combinations with lenalidomide [148] or bortezomib [149]. Overall, despite showing some degree of responses, with ORR ranging from 96% to 56% according to the different population of patients included in the studies, these trials confirmed an increased toxicity of pan-HDAC inhibitors, and vorinostat has, so far, not been approved for MM treatment.…”

Section: Therapeutic Strategies Addressing Aberrant Epigenetics In Multiple Myelomamentioning

confidence: 99%

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications

Schütt

Nägler

Schenk

et al. 2021

Cancers

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Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.

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Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial

Cited by 17 publications

References 31 publications

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from ‘Myeloma XI’, a multicentre, open‐label, randomised, phase III trial

Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications

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