Vorinostat Overcomes Lenalidomide-Dexamethasone and Lenalidomide-Bortezomib-Dexamethasone Resistance In Relapsed/Refractory Multiple Myeloma

Abstract Abstract 3065 Introduction: Significant improvements have been made in the treatment of relapsed/refractory (RR) multiple myeloma (MM), although the disease remains incurable. Recently, a number of clinical trials have evaluated the efficacy of vorinostat (Zolinza®), an oral inhibitor of Class I and II histone deacetylases. Vorinostat has been evaluated as a single agent, showing minimal activity. In vitro studies demonstrated synergy between vorinostat and other pro-apoptotic agents. This led to Phase I and II trials of vorinostat in combination with both proteasome inhibitors and IMiDs. Based upon the positive phase I data, large, multinational phase II and III trials combining vorinostat (Z) and bortezomib (V) are ongoing. Previously presented Phase I data on the combination of lenalidomide (R), dexamethasone and vorinostat has been encouraging. To date, no large experience with this combination in patients previously found to be refractory to lenalidomide and dexamethasone (RD) has been reported. Here we report our single institution experience of 28 consecutive patients with RD refractory myeloma or VRD refractory myeloma treated with the RDZ or VRDZ respectively. Materials and Methods: This is a retrospective chart review of patients who received commercially available oral vorinostat 300 mg or 400 mg once daily (days 1–7 and days 15–21) and lenalidomide 10–25mg (days 1–21) in a 28-day cycle. Ten patients also received bortezomib 1.3 mg/m2 as an intravenous bolus on days 1, 4, 8, and 11. Subjects: All patients were refractory to prior RD. Most of the patients were relapsed and refractory not only to RD, but also to VRD. (Please refer to the table below.) All of the patients treated with VRDZ were R/R to prior VRD. 23/28 of these patients had previous autologous peripheral blood stem cell transplants (ASCT). 11 had two transplants, 1 had three and 5 had previous allogeneic transplants. The median prior lines of therapy were 4 (2-10) and median prior regimens was 5 (2-11). Results: An overall response rate (ORR) of 43% was noted. This included 8 partial responses (PRs) and 4 very good partial responses (VGPRs) or better. An additional 5 showed minimal responses (MRs) and 8 showed stable disease (SD). The overall clinical benefit rate (including MRs and SD) was 89%. The duration of response ranged from two months to 23+ months. The most common toxicities were GI, mostly diarrhea and cramping. Cytopenias were also experienced, but were not different from those expected for this population treated with lenalidomide-based therapy alone. We will report on additional patients, more complete toxicity data, event-free (EFS) and overall survival (OS), as well as a limited subgroup analysis. Conclusions: These results suggest that this convenient oral regimen of vorinostat combined with lenalidomide and dexamethasone is well tolerated in patients with heavily pretreated, RD relapsed/refractory MM. These results further demonstrate the ability of vorinostat to overcome resistance to RD and VRD. Disclosures: Siegel: Celgene: Advisory board, Speakers Bureau; Merck: Advisory board; Millennium: Advisory Board, Speakers Bureau. Off Label Use: vorinostat for multiple myeloma. Bilotti:Celgene: Advisory Board, Speakers Bureau; Merck: Honoraria; Millennium: Advisory Board, Speakers Bureau. McNeill:Celgene: Advisory Board, Speakers Bureau; Millennium: Advisory Board, Speakers Bureau. Graef:Merck Research Laboratories: Employment. Vesole:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau.

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Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood-2019-126972 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5582-5582

Author(s):

Florian Lignet ◽

Christina Esdar ◽

Manja Friese-Hamim ◽

Andreas Becker ◽

Elise Drouin ◽

...

Keyword(s):

Multiple Myeloma ◽

Research And Development ◽

Phase I ◽

Dose Escalation ◽

Single Agent ◽

Proteasome Inhibitors ◽

Refractory Multiple Myeloma ◽

Oral Application ◽

Development Institute ◽

Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

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Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma

Cancers ◽

10.3390/cancers11070990 ◽

2019 ◽

Vol 11 (7) ◽

pp. 990 ◽

Cited By ~ 13

Author(s):

Giada Juli ◽

Manuela Oliverio ◽

Dina Bellizzi ◽

Maria Eugenia Gallo Cantafio ◽

Katia Grillone ◽

...

Keyword(s):

Multiple Myeloma ◽

Histone Deacetylases ◽

Mononuclear Cells ◽

Single Agent ◽

In Vitro Models ◽

Biologically Active ◽

Down Regulation ◽

Peripheral Blood Mononuclear ◽

Natural Agents

Olive oil contains different biologically active polyphenols, among which oleacein, the most abundant secoiridoid, has recently emerged for its beneficial properties in various disease contexts. By using in vitro models of human multiple myeloma (MM), we here investigated the anti-tumor potential of oleacein and the underlying bio-molecular sequelae. Within a low micromolar range, oleacein reduced the viability of MM primary samples and cell lines even in the presence of bone marrow stromal cells (BMSCs), while sparing healthy peripheral blood mononuclear cells. We also demonstrated that oleacein inhibited MM cell clonogenicity, prompted cell cycle blockade and triggered apoptosis. We evaluated the epigenetic impact of oleacein on MM cells, and observed dose-dependent accumulation of both acetylated histones and α-tubulin, along with down-regulation of several class I/II histone deacetylases (HDACs) both at the mRNA and protein level, providing evidence of the HDAC inhibitory activity of this compound; conversely, no effect on global DNA methylation was found. Mechanistically, HDACs inhibition by oleacein was associated with down-regulation of Sp1, the major transactivator of HDACs promoter, via Caspase 8 activation. Of potential translational significance, oleacein synergistically enhanced the in vitro anti-MM activity of the proteasome inhibitor carfilzomib. Altogether, these results indicate that oleacein is endowed with HDAC inhibitory properties, which associate with significant anti-MM activity both as single agent or in combination with carfilzomib. These findings may pave the way to novel potential anti-MM epi-therapeutic approaches based on natural agents.

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PTH- PTHR1 Axis Control on Anti-Myeloma Effect of Proteasome Inhibitors

Blood ◽

10.1182/blood.v116.21.5017.5017 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5017-5017

Author(s):

Maurizio Zangari ◽

Fang Xiao ◽

Ye Yang ◽

Hongwei Xu ◽

Guido J. Tricot ◽

...

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Single Agent ◽

Proteasome Inhibitors ◽

In Vitro Study ◽

Inhibitory Effect ◽

Tumor Burden ◽

Control Group

Abstract Abstract 5017 Multiple myeloma (MM) is a plasma cell malignancy with high osteolytic capacity and impaired bone formation. Our recent studies have demonstrated that PTH serum increases are associated with Bortezomib responses in multiple myeloma patients, indicating a possible role of PTH in anti myeloma effect of Bortezomib. We first tested the 5TGM1 cell line for sensitivity to bortezomib, PTH, and [TYR34]bPTH-(7-34) bovine (a specific PTHR1 inhibitor) in various combinations. In an in vitro study, 5TGM1 cells were sensitive to cytotoxicity of bortezomib and PTH in a dose dependent fashion. TYR compound was found to have no effect as single agent on 5TGM1 cell survival, but was able to partially block the inhibitory effect of bortezomib on cell growth (Figure 1). In an in vivo study using the 5TGM1 C 57BL/KaLwRijmice, we tested PTH-PTHR1 axis on bortezomib anti-myeloma activity. As shown in Figure 1, mice survival was positively affected by bortezomib administration (P = 0.04), and the combination of PTH + bortezomib showed a trend to further improve survival (P = 0.09). Interestingly, the concomitant use of [TYR] compound with bortezomib completely abrogated the efficacy of the proteasome inhibitor on survival. Tumor burden assessed by M-protein levels decreased consistently in mice treated with bortezomib alone, PTH alone, or a combination of PTH + bortezomib compared with the control group treated with PBS (P = 0.003, P = 0.05, P = 0.01 respectively). Importantly the tumor burden in the mice treated with bortezomib was significantly lower than in mice treated with bortezomib plus the PTH inhibitor (TYR), again indicating that the PTHR inhibitor abrogates the effect of Bortezomib on tumor growth. Similar results were obtained using the same systems for other commercially available proteasome inhibitors. Thus, we conclude that the PTH- PTHR1 pathway appears essential for proteasome inhibition activity in myeloma. Our observations may lead to novel treatment approaches in myeloma. Disclosures: No relevant conflicts of interest to declare.

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Phase I Study of AR-42 in Relapsed Multiple Myeloma and Lymphoma.

Blood ◽

10.1182/blood.v120.21.2955.2955 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2955-2955 ◽

Cited By ~ 2

Author(s):

Craig C. Hofmeister ◽

Zhongfa Liu ◽

Mindy A Bowers ◽

Pierluigi Porcu ◽

Joseph M. Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Phase I ◽

Dose Escalation ◽

Cell Lymphoma ◽

Single Agent ◽

Class I ◽

Qtc Prolongation ◽

Grade 3

Abstract Abstract 2955 Introduction: Deacetylase (DAC) inhibitors show promise as anti-neoplastic agents, the approved drugs are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have suboptimal activity or unacceptable toxicities. AR-42 is a class I/II DAC-I designed at OSU that demonstrates a 20,000-fold improvement in DAC inhibitory potency relative to the parent molecule (IC50=16 nM) with greater antiproliferative effects than Vorinostat in vitro and in vivo (Kulp et al, Clin Cancer Res, 2006 and Lucas et al, PLoS One, 2010). Methods: OSU 09102 (NCI 9119) is a first-in-man single agent, cohorts-of-3 phase I dose escalation study in adult patients with relapsed CLL, lymphoma (NHL), or multiple myeloma (MM) with normal kidney and liver function. Patients received AR-42 orally M-W-F in cycles of 28 days (3 weeks of 3-times-per-week dosing followed by a 7-day break). Moderate cell count suppression was allowed with an absolute neutrophil cutoff of 1000/μL, platelets 3 50,000/μL and hemoglobin 3 10 g/dL. In the first stage of dose escalation, each dose level increased by 100% until the first grade 2, drug-related toxicity was observed. Subsequent dose increases will be approximately 33% increase with accrual in cohorts of 3 patients. For pharmacokinetic analysis, plasma was obtained at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 24, and 48 hours after dosing on day 1 and day 19 (only up to 24 h), and then kept at –80°C until analysis. Results: We enrolled 3 patients at 20 mg (MM, MM, NHL), 3 patients at 40 mg (MM) with a transition to a slower dose escalation due to a grade 2 thrombocytopenia. Three more patients were enrolled at 40 mg (MM, MM, T-cell NHL), then 7 patients at 50 mg (MM × 4, follicular × 1, T-cell NHL × 2). One myeloma patient was enrolled at 70 mg. In the 40 mg cohort, related toxicities include 2 grade 3 and 2 grade 2 thrombocytopenia, 1 grade 3 neutropenia, 1 grade 2 vomiting, and 2 grade 1 QTc prolongation. In the 50 mg cohort 1 grade 4 and 3 grade 3 thrombocytopenia, 2 grade 3 neutropenia, 4 grade 2 fatigue, 2 grade 2 muscle spasm, 1 grade 2 blurred vision/dizziness, 3 grade 1 QTc prolongation, and 3 grade 1 nausea. Accrual was temporarily halted for a safety analysis Mar-2012 focused on the 50 mg cohort toxicities – one grade 4 thrombocytopenia considered a DLT, one patient found dead on cycle 2 day 10 without prior evidence of QTc prolongation, and one patient with reproducible dizziness and blurry vision. AR-42 was detected 15 mins after dose in 12 of 17 patients, suggesting rapid absorption. The time to reach the peak concentration in plasma (Tmax) varied from 1.5 hours to 4 hours. The Cmax (see chart) and AUC of AR-42 was not increased proportionally with doses, suggesting that the PK of AR-42 is not linear in the 20–50 mg range. Conclusion: The Cmax achieved at the 40 mg and 50 mg dose levels is adequate for HDAC inhibition in vitro and minor clinical responses were observed in myeloma and T-cell lymphoma as a single agent in the 40 mg cohort (see monoclonal proteins chart), hence 40 mg TIW 3-weeks-on and 1-week-off was declared the MTD. Complete pharmacokinetic, toxicity, and results from brief fatigue inventory will be presented at the meeting. AR-42 does not have the severe fatigue and gastrointestinal side effects of other broad DAC inhibitors and may be suitable for combination phase Ib trials in T-cell lymphoma and myeloma. Disclosures: No relevant conflicts of interest to declare.

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In Vitro and In Vivo Efficacy of a Novel Orally Bioavailable Beta-Catenin Inhibitor-BC2059- As Monotherapy or in Combination with Proteasome Inhibitors in Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.1816.1816 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1816-1816

Author(s):

Ioanna Savvidou ◽

Tiffany T. Khong ◽

Stephen K. Horrigan ◽

Andrew Spencer

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Single Agent ◽

Proteasome Inhibitors ◽

Canonical Pathway ◽

Beta Catenin ◽

Dependent Manner ◽

Canonical Wnt

Abstract Background: The currently available treatment options are unlikely to be curative for the majority of Multiple Myeloma (MM) patients, emphasizing a continuing role for the introduction of investigational agents that overcome drug resistance. The canonical Wnt/β-catenin signalling pathway has been found to be dysregulated in MM, and its activation is associated with advanced stage MM, providing a rationale to evaluate the novel β-catenin inhibitor BC2059 in mono- and combination therapy with proteasome inhibitors in vitro and in vivo. Methods and Results: We evaluated the activation status of the canonical Wnt pathway in 12 genetically heterogeneous Human Myeloma Cell Lines (HMCL) by assessing the expression of β-catenin protein in the nuclear compartment (active form). This showed that nuclear β-catenin was present in all HMCL tested and absent in plasma cells derived from a healthy donor. Moreover, additional stimulation of the canonical pathway with rhWnt3a was shown to be pro-proliferative, in contrast, no proliferation was seen with activation of the non canonical pathway following treatment with rhWnt5a. BC2059 (50nM to 500nM) induced apoptosis of all 12 HMCL and was able to inhibit the proliferation of all HMCL tested in a dose and time dependent manner assessed by MTS assay and viable enumeration with trypan blue (IC50: 53nM to 247nM). Mimicking the bone marrow (BM) microenvironment by co-culturing HMCL with the immortalised human stromal cell line HS-5, BC2059 was able to overcome the protective effect of HS-5 (for example KMS18 at IC90=220nM had no stromal pro-survival effect). Similarly, BC2059 was able to abolish the pro-proliferative effect of rh-Wnt3a or conditioned media derived from MM patients' BM when used at doses >100nM or 50nM, respectively. BC2059 facilitated the degradation of β-catenin protein in the nuclear cellular compartment ( >50% decrease of nuclear β-catenin in KMS18 treated with 1.5xIC50 when compared with untreated cells), furthermore, using a reporter assay we showed that BC2059 inhibited TCF/LEF transcriptional activity in a dose-dependent manner and decreased the transcription of axin2, a down-stream target gene of β-catenin - 78% reduction in KMS18 cells treated with 1.5x IC50 when compared to untreated controls. BC2059-induced HMCL cell death was associated with activation of both the intrinsic and extrinsic caspase-dependent apoptotic pathways, as shown by the accumulation of the activated forms of caspases 8, 9 and 3 following BC2059 treatment. However, inhibition of the caspase-pathway by the addition of caspase inhibitors (pan-caspase inhibitor Z-VAD, and caspase-3 inhibitor Z-DEVD) could not abolish the pro-necrotic effect of BC2059 or BC2059 plus bortezomib, suggesting a possible role for autophagy-induced cell death. As β-catenin undergoes proteasome-mediated destruction and has been found to increase following bortezomib treatment, we evaluated the effect of combining BC2059 with Bortezomib. The combination was synergistic for 6/8 HMCL tested (e.g. for LP1 CI:0.64-0.55, where CI<1.1=synergism). We also evaluated the effect of the combination of BC2059 with next generation proteasome inhibitors (carfilzomib and marizomib) where it was shown to have synergistic and/or additive effects (e.g. for carfilzomib LP1 CI:0.33-0.99). Single agent BC2059 effectively killed primary MM tumour cells from relapsed/refractory MM patients (n=13) and the combination with bortezomib was synergistic (n=2) with no effect on healthy peripheral blood mononuclear cells (n=4). Finally, BC2059 (10mg/kg) prolonged survival of xenografted NSG mice compared to untreated controls with no major side effects in Wnt/β-catenin dependent tissues (GI track and haematopoiesis). Conclusion: We have demonstrated that BC2059 at nano-molar concentrations has a strong anti-MM effect both in vitro and in vivo and synergises with proteasome inhibitors. These data strongly support the clinical evaluation of BC2059 for the treatment of MM. Disclosures Horrigan: BetaCat Pharmaceuticals: Employment.

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Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00728-y ◽

2021 ◽

Author(s):

Yu-bo Zhou ◽

Yang-ming Zhang ◽

Hong-hui Huang ◽

Li-jing Shen ◽

Xiao-feng Han ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Targets ◽

Single Agent ◽

Hdac Inhibitors ◽

Preclinical Study ◽

Parp Cleavage ◽

Rpmi 8226 ◽

Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

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Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.3522 ◽

2015 ◽

Vol 33 (7) ◽

pp. 732-739 ◽

Cited By ~ 58

Author(s):

Kyriakos P. Papadopoulos ◽

David S. Siegel ◽

David H. Vesole ◽

Peter Lee ◽

Steven T. Rosen ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Concentration ◽

Phase I ◽

Phase I Study ◽

Low Dose ◽

Single Agent ◽

Phase Iii ◽

Maximum Plasma ◽

Irreversible Inhibitor ◽

Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

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Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Blood ◽

10.1182/blood-2007-08-105601 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1654-1664 ◽

Cited By ~ 138

Author(s):

Dharminder Chauhan ◽

Ajita Singh ◽

Mohan Brahmandam ◽

Klaus Podar ◽

Teru Hideshima ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitors ◽

Xenograft Model ◽

Er Stress Response ◽

Synergistic Cytotoxicity ◽

Proteolytic Activities ◽

Dose Combination ◽

Inhibition Of Tumor Growth

AbstractOur recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib–induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-κB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib–treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.

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Relapsed Multiple Myeloma

Hematology ◽

10.1182/asheducation-2010.1.303 ◽

2010 ◽

Vol 2010 (1) ◽

pp. 303-309 ◽

Cited By ~ 29

Author(s):

Sagar Lonial

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Phase 1 ◽

Treatment Options ◽

Single Agent ◽

Great Promise ◽

New Agents ◽

Ongoing Work ◽

The Many

Abstract Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

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Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.1347 ◽

2010 ◽

Vol 28 (18) ◽

pp. 3015-3022 ◽

Cited By ~ 128

Author(s):

Wei-Gang Tong ◽

Rong Chen ◽

William Plunkett ◽

David Siegel ◽

Rajni Sinha ◽

...

Keyword(s):

Multiple Myeloma ◽

Chronic Lymphocytic Leukemia ◽

Phase I ◽

Clinical Efficacy ◽

Stable Disease ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

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