panobinostat and Multiple-Myeloma

Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.. We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events.. Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6) and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7) and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8) and 4.6 (3.2-6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS.. Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.

Topics: Adverse Drug Reaction Reporting Systems; Cardiotoxicity; Humans; Multiple Myeloma; Panobinostat; Pharmacovigilance; United States; United States Food and Drug Administration

Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Deubiquitinating Enzymes; Drug Development; Drug Resistance; Histone Deacetylases; Humans; Ikaros Transcription Factor; Immunomodulating Agents; Models, Molecular; Morpholines; Multiple Myeloma; Phthalimides; Piperidones; Proteasome Inhibitors; Treatment Outcome; Ubiquitin-Protein Ligases

Despite the increasing number of treatment options available for multiple myeloma, relapse is still inevitable and there remains a critical unmet need for treatments for patients with late-stage, highly refractory disease. In this review, we discuss currently approved treatment options for heavily pretreated patients with relapsed and refractory multiple myeloma, with a focus on the optimal management of patients with MM refractory to lenalidomide, bortezomib, and in some cases, daratumumab or an anti-CD38 monoclonal antibody. Data from recent clinical trials of immunomodulatory agents (pomalidomide), proteasome inhibitors (PIs; carfilzomib and ixazomib), monoclonal antibodies (elotuzumab, daratumumab, and isatuximab), and other novel therapies (including panobinostat-based therapy) are summarized. We also provide potential therapeutic strategies for patients according to different treatment histories, and include case studies to illustrate the practical use of various treatment options in a clinical setting. Regimens containing pomalidomide, elotuzumab, next-generation PIs, panobinostat, or selinexor may provide effective treatment options in patients with triple-refractory disease. The choice of agents used, and combinations thereof should be individualized as well as strategically planned from early- to late-stage relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Proteasome Inhibitors

Oral oncolytic treatments (OOTs) have improved the prognosis of patients with multiple myeloma (MM). However, the effectiveness of these therapies is undermined by poor adherence. We aimed to characterize the real-world adherence to, and persistence with, OOTs for MM.. MEDLINE, EMBASE, and the International Pharmaceutical abstracts databases were searched for relevant observational studies published in English up to November 21, 2021. This was supplemented by manual searches of abstracts from the annual meetings of the American Society of Hematology, the American Society for Clinical Oncology, and the European Hematology Association as well as screening the references of included articles. Random-effects meta-analysis was performed.. Following screening of 11,557 articles, 19 studies involving 27,129 patients in 8 countries (France, the US, Germany, Italy, the UK, Brazil, South Korea, and Belgium) prescribed OOTs (lenalidomide, thalidomide, pomalidomide, panobinostat, ixazomib, and melphalan) for MM were included. The overall pooled proportion of adherent patients was 67.9% (95% confidence interval [CI]: 57.1%-77.8%). The pooled proportion of adherent patients was higher in self-reported questionnaire-based studies compared to those using prescription/dispensing data (81.6% vs. 61.0%; P-value for difference = .08). Across 5 studies involving 15,363 patients, a pooled proportion of 35.8% (95% CI: 22.0-50.9) discontinued treatment. Factors reported to be associated with nonadherence included increasing age, higher comorbidity, polypharmacy, and a lack of social support.. In patients with MM, adherence to and persistence with OOTs remains suboptimal. To achieve desired clinical outcomes, interventions to improve adherence and minimize discontinuation may be warranted.

Topics: Humans; Lenalidomide; Medication Adherence; Melphalan; Multiple Myeloma; Panobinostat; Pharmaceutical Preparations; Thalidomide

Relapsed and refractory multiple myeloma (RRMM) presents a therapeutic challenge due to the development of drug resistance. Panobinostat is an oral histone deacetylase inhibitor (HDACi) that affects multiple cellular pathways and has demonstrated the ability to resensitize refractory-multiple myeloma cells in preclinical studies, as well as in patients with RRMM in clinical trials. Synergy of panobinostat with a number of different classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies) has also been shown. Panobinostat is a promising HDACi for the treatment of multiple myeloma. Here, we present a comprehensive review of preclinical and clinical studies of panobinostat.

Topics: Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Panobinostat

Multiple myeloma (MM), which is derived from immunoglobulin-producing plasma cells, is treated using novel agents, such as proteasome inhibitors, immunomodulatory drugs (IMiDs), and anti-MM monoclonal antibodies, which have been developed based on preclinical findings. Although these treatments have improved MM prognosis, it still remains an incurable disease. Therefore, development of novel treatment strategies is warranted. Histone deacetylases (HDACs) are a group of deacetylating enzymes that catalyze the deacetylation of histone and non-histone proteins, leading to changes in gene expression and protein function and stability. Panobinostat, a pan-HDAC inhibitor, is now clinically available in combination with bortezomib and dexamethasone for the treatment of MM. To further improve treatment strategies for MM, HDACs are thought to have potential as next-generation therapeutics because HDAC isoform-selective inhibition, but not broad HDAC inhibition, is effective in MM cells. The roles of each HDAC isoform in MM are not yet precisely defined. To maintain or augment anti-MM effects without severe adverse reactions, preclinical and clinical studies are being undertaken to elucidate the impact of each HDAC isoform on MM and develop class- or isoform-selective HDAC inhibitors in combination with other therapeutics.

Topics: Bortezomib; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Multiple Myeloma; Panobinostat; Protein Isoforms

Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).

Topics: Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Drug Synergism; Energy Metabolism; Female; Humans; Isoquinolines; Leukemia, Plasma Cell; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Multiple Myeloma; Panobinostat; Retrospective Studies

Multiple myeloma is a plasma cell neoplasm that has seen impressive improvements in outcomes in recent years with combination therapies, such as proteasome inhibitors and immunomodulatory drugs. Histone deacetylase inhibition is an additional unique mechanism of action with established biological relevance in multiple myeloma. Panobinostat is the first histone deacetylase inhibitor indicated for the treatment of relapsed/refractory multiple myeloma in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. While the addition of panobinostat to bortezomib and dexamethasone has demonstrated response and progression-free survival benefits, the incidence and severity of adverse events associated with it can create a challenge for clinicians and patients. Specifically, diarrhea, myelosuppression, an increased risk for infectious complications, cardiotoxicity, and nausea/vomiting may be seen with use. The frequency and grade of adverse event occurrence may differ between doses and schedule of panobinostat as well as with different companion therapies and routes. Herein we discuss the incidence, severity, and practical management of adverse events associated with panobinostat in the treatment of relapsed/refractory multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Incidence; Multiple Myeloma; Panobinostat

Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.. A literature search on 'HDAC inhibitors' and 'multiple myeloma' was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.. First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.

Topics: Animals; Antineoplastic Agents; Depsipeptides; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Multiple Myeloma; Panobinostat; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biological Availability; Bortezomib; Dexamethasone; Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Panobinostat

Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the histone deacetylase inhibitor panobinostat, but also new targeted agents are under active investigation (e.g. signal transduction modulators, kinesin spindle protein inhibitors, and inhibitors of NF-kB, MAPK, AKT). We here describe a new paradigm for the treatment of relapsed multiple myeloma. The final goal should be finding a balance among efficacy, toxicity, and cost and, at the end of the road, achieving long-lasting control of the disease and eventually even cure in a subset of patients.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Multiple Myeloma; Panobinostat; Proteasome Inhibitors; Recurrence

Farydak was approved in the European Union in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). The addition of panobinostat to bortezomib and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression-free survival compared with bortezomib and dexamethasone, and an additional therapeutic option with a new mechanism of action was considered valuable. Although the toxicity associated with panobinostat combination was significant, at the time of the marketing authorization of panobinostat, it was considered that it was acceptable and that it should be left to the clinician and the patient to decide whether the panobinostat combination is the preferred treatment option or not.

Topics: Antineoplastic Agents; Female; Humans; Male; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat

Recent advances in treatment have extended the survival of patients with multiple myeloma. This improvement in itself poses challenges because of the length of time that patients live with myeloma, its physical complications, and toxicities of treatment. Thus, improvements in maintaining quality of life are essential, and part of this challenge involves learning how to optimally use new therapeutic agents. Panobinostat is the first histone deacetylase inhibitor approved for the treatment of multiple myeloma. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory multiple myeloma who have received ≥ 2 previous regimens, including bortezomib and an immunomodulatory drug. In this review multiple myeloma-related symptoms and adverse events resulting from treatments for multiple myeloma are discussed, with a focus on adverse events related to histone deacetylase inhibitors and histone deacetylase inhibitor combinations. The contribution of myeloma to these adverse events is discussed as well as how these AEs can best be managed.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Molecular Targeted Therapy; Multiple Myeloma; Panobinostat; Risk Factors; Treatment Outcome

The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Bortezomib; Dexamethasone; Glycine; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Multiple Myeloma; Oligopeptides; Panobinostat; Proteasome Inhibitors; Recurrence; Thalidomide

Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib. In our current review of these studies, all the novel therapies resulted in an improvement in progression-free survival for high-risk patients, but none of the trials provided clear statistical evidence that they overcame high-risk status. Moreover, there are several limitations in the currently available data. For example, the patient's Revised International Staging System score is generally not reported, and even when it is reported, it is usually at the time of initial diagnosis rather than at the time of study entry. Furthermore, the methodology used to determine risk suffers from technologic issues. Finally, the clonal and allele burden and concurrent molecular abnormalities can affect risk status and prognosis. To determine the optimal therapy for high-risk patients, future clinical trials should provide standardized risk assessments for all patients in addition to hazard ratios for Kaplan-Meier survival curves of high-risk patients vs those of standard-risk patients to determine if high-risk status has truly been overcome by a novel agent.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron Compounds; Disease-Free Survival; Glycine; Humans; Hydroxamic Acids; Indoles; Kaplan-Meier Estimate; Multiple Myeloma; Oligopeptides; Panobinostat; Prognosis

Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Management; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome

Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Dexamethasone; Drug Discovery; Drug Resistance, Neoplasm; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Molecular Targeted Therapy; Multiple Myeloma; Panobinostat; Recurrence

Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy or a combination of low-dose dexamethasone and pomaildomide may be proposed. Panobinostat is the first histone deacetylase (HDAC) inhibitor to be authorised in the European Union for use in this indication. A randomised, double-blind, placebo-controlled trial evaluated panobinostat in 768 patients with relapsed or refractory multiple myeloma who were also receiving bortezomib + dexamethasone. Panobinostat did not prolong survival. The median time to myeloma progression, relapse, or death was prolonged by about 3 months with the panobinostat-containing combination, and by a median of about 8 months in the subgroup of patients who had received at least two lines of chemotherapy including bortezomib and an "immunomodulatory" drug. There was no statistically significant increase in survival, however. In this trial, adverse events led one in six patients to discontinue panobinostat and resulted in numerous hospital admissions. The proportion of patients who died from causes unrelated to myeloma was 6.8% in the panobinostat group versus 3.2% In the placebo group. The toxicity of panobinostat affects most vital functions, resulting in a risk of infections as well as haematological, gastrointestinal, cardiac, renal, hepatic and thyroid disorders. These adverse effects are often severe and sometimes fatal. Panobinostat is subject to pharmacokinetic interactions via cytochrome P450 enzymes and P-glycoproteln, and also to pharmacodynamic Interactions. Panobinostat was teratogenic in animal studies. In practice, even when several previous lines of treatment have failed, panobinostatis more toxic than useful In patients with myeloma. It should therefore not be used.

Topics: Antineoplastic Agents; Arrhythmias, Cardiac; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Diarrhea; Drug Interactions; Gastrointestinal Diseases; Hemorrhage; Humans; Hypothyroidism; Infections; Mortality; Multiple Myeloma; Myocardial Ischemia; Neutropenia; Panobinostat; Progression-Free Survival; Renal Insufficiency; Survival Rate; Thrombocytopenia

Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3-4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Prognosis

The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, interaction potential, adverse effects, and place in therapy of panobinostat are reviewed.. Panobinostat (Farydak, Novartis) is a novel pan-deacetylase inhibitor approved for use in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least two regimens containing an immunomodulatory drug and bortezomib. National Comprehensive Cancer Network (NCCN) guidelines recommend the use of panobinostat plus bortezomib and dexamethasone as a preferred regimen for previously treated multiple myeloma (MM). A Phase III trial comparing panobinostat or placebo use in combination with bortezomib and dexamethasone demonstrated improved median progression-free survival in the panobinostat group (11.99 months [95% CI, 10.33-12.94 months] versus 8.08 months [95% CI, 7.56-9.23 months]; hazard ratio, 0.63 [95% CI, 0.52-0.76]; p < 0.0001), as well as a significantly higher rate of complete or near complete response (27.6% [95% CI, 23.2-32.4%] versus 15.7% [95% CI, 12.2-19.8%]; p = 0.00006). Common grade 3 or 4 laboratory abnormalities and adverse events associated with panobinostat include thrombocytopenia, lymphopenia, diarrhea, asthenia, fatigue, and peripheral neuropathy.. Panobinostat is a promising alternative to well-studied, NCCN-recommended regimens for the treatment of RRMM. It has demonstrated efficacy when used in combination with bortezomib and dexamethasone for the treatment of patients with MM who have received at least two prior regimens including bortezomib and an immunomodulatory agent. Despite the observed benefits, concern regarding toxicity may limit panobinostat use in practice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence; Treatment Outcome

Despite advances in drug therapy of the orphan disease multiple myeloma, patients relapse or become refractory to first-line therapy, and the disease remains incurable. Therefore, histone deacetylase inhibitors have emerged as a new class of anti-myeloma drugs, with synergistic results on progression free survival when given in combination to current first-line therapy. Histone deacetylase inhibitors influence gene expression of target genes. Based on results of an extensive multicenter phase III trial, panobinostat was approved by the FDA in February 2015 as the first histone deacetylase inhibitor for the treatment of multiple myeloma. In Europe, panobinostat received marketing authorization by August 2015.

Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Rare Diseases

During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31-0.59, I(2) = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence; Treatment Outcome

The purpose of this study was to better understand the efficacy and safety of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma(R/RMM).. We retrieved and reviewed published reports including carfilzomib, panobinostat, and elotuzumab combination regimens for patients with R/RMM.. We identified 20 prospective studies that evaluated 2220 patients. Carfilzomib combination regimens produced an overall response rate (ORR ≥ PR) of 61 % in the 1211 relapsed/refractory patients. At least very good partial response (VGPR) was 29 % in patients with carfilzomib combinations. Finally, 49 % of the 597 patients achieved ORR in patients receiving panobinostat-containing combinations. At least VGPR was 16 % in patients with panobinostat combinations. Three hundred twenty-eight of these 449 patients (73 %) receiving elotuzumab-containing combinations achieved ORR. And at least VGPR was 37 %. And, the vital nonhematologic adverse events (AEs) were cardiac events and pneumonia.. Carfilzomib, panobinostat, and elotuzumab combination regimens produced clinical benefits in patients with R/RMM.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Heart Diseases; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Pneumonia; Prospective Studies; Salvage Therapy

Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe.. Editorial support, funded by Novartis Pharmaceuticals.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Europe; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Recurrence

Multiple myeloma is an incurable often devastating disease that is responsible for 1-2% of all cancers. Multiple myeloma is the second most common hematologic malignancy. Over the past two decades, advances in therapy have doubled life expectancy. Unfortunately, all patients ultimately relapse. Novel agents (immunomodulatory drugs and proteasome inhibitors) have changed the outlook for patients, but further breakthroughs are needed. Epigenetic treatments offer potential for advancing therapy by modifying oncogene responses. The acetylation status of various proteins can affect the availability of chromatin for transcription. This response may be modulated epigenetically to advantage using histone deacetylase inhibitors like panobinostat.

Topics: Antineoplastic Agents; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

Novartis has developed oral and intravenous formulations of panobinostat (Farydak(®)), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Approval; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Internationality; Molecular Structure; Multiple Myeloma; Panobinostat

Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Dexamethasone; Disease-Free Survival; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

Topics: Animals; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Randomized Controlled Trials as Topic

Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in combination with bortezomib and dexamethasone in patients with multiple myeloma who have received ≥2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression-free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome

Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and associated organ dysfunction and biomarkers. There have been multiple recent advances in the relapsed and refractory setting. Major steps forward include the introduction of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) in various combinations. These drugs have changed the management of multiple myeloma and have extended overall survival in the past decade. Established curative therapy is not yet available for patients diagnosed with multiple myeloma, supporting the development of new treatment targets. Histone deacetylase inhibitors have multiple proposed mechanisms of action in the treatment of multiple myeloma. Both vorinostat and panobinostat have demonstrated some activity against multiple myeloma, and due to the benefits reported with panobinostat, the U.S. Food and Drug Administration has recently approved the drug for the treatment of relapsed and refractory multiple myeloma. In this article, we describe the pharmacology, efficacy, and toxicity profile of vorinostat and panobinostat and their possible place in therapy.

Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Vorinostat

Topics: Activating Transcription Factor 3; Activating Transcription Factor 4; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclin-Dependent Kinase 5; Cytokines; Dexamethasone; DNA-Binding Proteins; Drug Discovery; Drug Resistance, Neoplasm; Humans; Hydroxamic Acids; Indoles; Kruppel-Like Transcription Factors; Molecular Targeted Therapy; Multiple Myeloma; Nicotinamide Phosphoribosyltransferase; Oligopeptides; Panobinostat; Phosphorylcholine; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Regulatory Factor X Transcription Factors; Toyocamycin; Transcription Factors

The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Phosphorylcholine; Piperidines; Proteasome Inhibitors; Pyridines; Remission Induction; Thalidomide; Thiazoles; Treatment Outcome; Vorinostat

Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM.

Topics: Antineoplastic Agents; Drug Synergism; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Molecular Targeted Therapy; Multiple Myeloma; Panobinostat; Tumor Microenvironment; Vorinostat

Multiple myeloma (MM) is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Although new therapeutic options have been introduced and response rates have improved in recent years, MM still remains incurable and new treatment options are urgently needed. The histone deacetylase inhibitors (HDACi) are a new class of anticancer agents in early clinical development in many malignancies including MM. HDACi target the enzyme histone deacetylase (HDAC) involved in the deacetylation of histone and non-histone cellular proteins that play important roles in epigenetic regulation of gene expression inducing death, apoptosis and cell cycle arrest in cancer cells. Panobinostat (LBH589) is a highly potent HDACi with demonstrated antitumor activities at low nanomolar concentration in several preclinical studies and its clinical efficacy is currently under investigation in several clinical trials.. In this review the authors discuss the role of HDACs in the regulation of gene expression and the biological mechanisms mediating the anticancer effects of HDACi with particular focus on the recent development of panobinostat as anti-MM agent in preclinical and clinical studies.. As a 'multi-target' drug, panobinostat appears attractive as potential anti-MM therapeutic for its ability to modulate a variety of biological pathways essential in MM biology. This 'multi-target' property of panobinostat may also be one its major shortcomings, and a better understanding of its mechanisms of action and targets will permit to identify the best combination therapies that will ultimately overcome and improve outcomes in MM patients.

Topics: Animals; Antineoplastic Agents; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

Panobinostat is a pan-deacetylase inhibitor that modulates the expression of oncogenic and immune-mediating genes involved in tumour cell growth and survival. We evaluated panobinostat-induced post-transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three-times weekly (TIW) on alternate weeks of 28-day cycles commencing 8-12 weeks post-transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9-9·7) months of panobinostat. In responders, T-lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non-responders. The reduction in the proportion of CD127

Topics: Adult; Aged; CD4 Antigens; CD8 Antigens; CD8-Positive T-Lymphocytes; Female; Follow-Up Studies; Histone Deacetylase Inhibitors; Histones; Humans; Interleukin-7 Receptor alpha Subunit; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Oncogenes; Panobinostat; Remission Induction; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Panobinostat, bortezomib, and dexamethasone combination therapy demonstrated progression-free survival (PFS) benefit over bortezomib and dexamethasone alone in the PANORAMA-1 study in relapsed/refractory multiple myeloma (MM). Here, we present data from a phase II study (NCT02290431) of this combination in Japanese patients with relapsed or relapsed-and-refractory MM.. Patients received 3-week cycles of 20-mg oral panobinostat (weeks 1 and 2), 1.3-mg/m2 subcutaneous bortezomib (days 1, 4, 8, and 11), and 20-mg oral dexamethasone (day of and the day following bortezomib administration) for a total of 8 cycles (24 weeks; treatment phase 1). Patients with treatment benefit had an option to enter the extension phase to receive 6-week (42-day) cycles of panobinostat (weeks 1, 2, 4, and 5) plus bortezomib (days 1, 8, 22, and 29) and dexamethasone (day of and the day following bortezomib treatment) for 24 weeks. The primary objective was complete response (CR) + near CR (nCR) rate after treatment phase 1 as per the modified European Society for Blood and Marrow Transplantation criteria.. Of the 31 patients, 4 (12.9%) completed the treatment and 27 (87.1%) discontinued; 17 (54.8%) entered the extension phase. In total, 24 patients (77.4%) entered the survival follow-up phase and followed until study closure when the last patient was treated for 1 year after treatment phase 1. The CR + nCR rate was 48.4% (90% CI: 33.6-63.2). The overall response rate (CR + nCR + partial response) was 80.6%. The median PFS, duration of response, time to response, and time to progression were 15.3, 22.7, 1.4, and 15.3 months, respectively. All patients experienced adverse events (AEs), with diarrhea (80.6%), decreased appetite (58.1%), and thrombocytopenia (54.8%) being the most frequent, regardless of relationship to the study treatment. Thrombocytopenia (48.4%), fatigue (25.8%), diarrhea (22.6%), neutrophil count decrease (22.6%), platelet count decrease (22.6%), and lymphocyte count decrease (22.6%) were the most frequent grade 3/4 AEs.. The study met the primary objective with 48.4% CR + nCR rate. The AEs associated with the combination treatment were safely managed using the existing AE management guidelines, including dose interruption/modification and/or supportive medical intervention. This treatment regimen is an effective option with a favorable benefit/risk profile for Japanese patients with relapsed/refractory MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Diarrhea; Drug Administration Schedule; Half-Life; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Panobinostat; Progression-Free Survival; Recurrence; Remission Induction; Thrombocytopenia

Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication.. PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990.. Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related.. The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated.. Novartis Pharmaceuticals and Secura Bio.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease Progression; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Multiple Myeloma; Panobinostat; Progression-Free Survival; Time Factors

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Follow-Up Studies; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Oligopeptides; Panobinostat

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease-Free Survival; Feasibility Studies; Follow-Up Studies; Multiple Myeloma; Panobinostat; Recurrence; Survival Rate; Thalidomide

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Odds Ratio; Oligopeptides; Panobinostat; Recurrence; Retreatment; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Prednisone; Prognosis; Survival Rate; Thalidomide

Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability.. In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m. Thirty-nine patients with a median number of previous treatments of 4 (range, 1-12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed.. Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dehydration; Dexamethasone; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Peripheral Nervous System Diseases; Thrombocytopenia; Treatment Outcome

The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ-Myeloma module (EORTC QLQ-MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients' QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Myeloma; Panobinostat; Quality of Life; Time Factors

Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma.. In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m. Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m. The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results.. Novartis and MD Anderson Cancer Center Support Grant.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Eligibility Determination; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Panobinostat; Transplantation, Autologous

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Dexamethasone; Disease Progression; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Transplantation, Autologous; Treatment Outcome

Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies.. Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies.. At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia.. Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Double-Blind Method; Drug Resistance, Neoplasm; Humans; Hydroxamic Acids; Indoles; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chemotherapy, Adjuvant; Dexamethasone; Female; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Panobinostat; Treatment Outcome

Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial.. PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m. Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50).. The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.. Novartis Pharmaceuticals.

Topics: Activities of Daily Living; Adult; Age Factors; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Asian People; Asthenia; Blood Cell Count; Bortezomib; Chromosome Aberrations; Creatinine; Dexamethasone; Diarrhea; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Resistance, Neoplasm; Fatigue; Female; Geography; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasm Staging; Panobinostat; Patient Dropouts; Peripheral Nervous System Diseases; Quality of Life; Renal Insufficiency; Sex Factors; Steroids; Survival Analysis; Thrombocytopenia; Time Factors; Treatment Outcome

Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen.. We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m. Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders.. Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma.. Novartis and Myeloma UK.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Constipation; Dexamethasone; Diarrhea; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Fatigue; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Hyponatremia; Hypophosphatemia; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Nausea; Pain; Panobinostat; Peripheral Nervous System Diseases; Thalidomide; Therapeutic Index, Drug; Treatment Outcome; United Kingdom

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Diarrhea; Humans; Hydroxamic Acids; Indoles; Induction Chemotherapy; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Preoperative Period; Stem Cell Transplantation; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome; Vomiting

The purpose of this study was to assess the safety and efficacy of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients with multiple myeloma who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation part of the study a standard 3+3 design was used to determine the maximum tolerated dose of four planned dose levels of the combination of carfilzomib and panobinostat. Panobinostat was administered on days 1, 3, 5, 15, 17, and 19. Carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Treatment was continued until progression or intolerable toxicity. Forty-four patients were accrued into the trial, 13 in the phase I part and 31 in the phase II part of the study. The median age of the patients was 66 years and the median number of prior therapies was five. The expansion dose was established as 30 mg panobinostat, 20/45 mg/m(2) carfilzomib. The overall response rate was 67% for all patients, 67% for patients refractory to prior proteasome inhibitor treatment and 75% for patients refractory to prior immune modulating drug treatment. At a median follow up of 17 months, median progression-free survival was 7.7 months, median time to progression was 7.7 months, and median overall survival had not been reached. The regimen was well tolerated, although there were several panobinostat dose reductions. In conclusion, the combination of panobinostat and carfilzomib is feasible and effective in patients with relapsed/refractory multiple myeloma. (Trial registered at ClinicalTrials.gov: NCT01496118).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Oligopeptides; Panobinostat; Retreatment; Treatment Outcome

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Indoles; Infections; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Salvage Therapy

Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.. PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308.. 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]).. Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival.. Novartis Pharmaceuticals.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hydroxamic Acids; Indoles; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Prognosis; Pyrazines; Remission Induction; Survival Analysis; Treatment Outcome

Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit both the aggresome and proteasome pathways in preclinical studies. PANORAMA 2 is a phase 2 trial of panobinostat in combination with bortezomib and dexamethasone to treat patients with relapsed and bortezomib-refractory multiple myeloma (with ≥2 prior lines of therapy, including an immunomodulatory drug, and patients who had progressed on or within 60 days of the last bortezomib-based therapy). Fifty-five heavily pretreated patients were enrolled (median, 4 prior regimens, including a median of 2 prior bortezomib-containing regimens). The overall response rate was 34.5% (1 near-complete response and 18 partial responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 52.7%. Median exposure and progression-free survival were 4.6 and 5.4 months, respectively. In patients who achieved a response, median time to response was 1.4 months, and median duration of response was 6.0 months. Common grade 3/4 adverse events, regardless of study drug relationship, included thrombocytopenia (63.6%), fatigue (20.0%), and diarrhea (20.0%). Only 1 patient had grade 3 peripheral neuropathy. Panobinostat, when combined with bortezomib and dexamethasone, can recapture responses in heavily pretreated, bortezomib-refractory multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01083602.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Hydroxamic Acids; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Pyrazines

Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM.. In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria.. The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response.. The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Humans; Hydroxamic Acids; Indoles; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Panobinostat; Pyrazines

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Boronic Acids; Bortezomib; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Male; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Panobinostat; Pyrazines; Recurrence; Remission Induction; Thalidomide; Thrombocytopenia; Treatment Outcome

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Hydroxamic Acids; Indoles; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Neutropenia; Panobinostat; Prednisone; Recurrence; Thalidomide; Thrombocytopenia; Time Factors; Treatment Outcome

The histone deacetylase inhibitor (HDACi), panobinostat (Pano), is approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of relapsed/refractory multiple myeloma (MM). Despite regulatory approvals, Pano is used on a limited basis in MM due largely to an unfavorable toxicity profile. The MM treatment landscape continues to evolve, and for Pano to maintain a place in that paradigm it will be necessary to identify treatment regimens that optimize its effectiveness, particularly those that permit dose reductions to eliminate unwanted toxicity. Here, we propose such a regimen by combining Pano with LTI6426, a first-in-class orally bioavailable protein disulfide isomerase (PDI) inhibitor. We show that LTI6426 dramatically enhances the anti-MM activity of Pano in vitro and in vivo using a proteasome inhibitor resistant mouse model of MM and a low dose of Pano that exhibited no signs of toxicity. We go on to characterize a transcriptional program that is induced by the LTI6426/Pano combination, demonstrating a convergence of the two drugs on endoplasmic reticulum (ER) stress pathway effectors ATF3 (Activating Transcription Factor 3), DDIT3/CHOP (DNA Damage Inducible Transcript 3, a.k.a. C/EBP Homologous Protein), and DNAJB1 (DnaJ homolog subfamily B member 1, a.k.a. HSP40). We conclude that LTI6426 may safely enhance low-dose Pano regimens and that ATF3, DDIT3/CHOP, and DNAJB1 are candidate pharmacodynamic biomarkers of response to this novel treatment regimen.

Topics: Animals; Histone Deacetylase Inhibitors; HSP40 Heat-Shock Proteins; Humans; Hydroxamic Acids; Mice; Molecular Targeted Therapy; Multiple Myeloma; Panobinostat; Protein Disulfide-Isomerases

The combination of panobinostat, bortezomib and dexamethasone (PanBorDex) is available as a treatment option for relapsed refractory multiple myeloma (RRMM) based on the PANORAMA-1 trial which investigated this triplet in early relapse. In routine clinical care, PanBorDex is used primarily in later relapses and is commonly administered in attenuated dosing schedules to mitigate the treatment-related toxicity. We set out to evaluate efficacy and safety outcomes with PanBorDex later in the disease course and evaluate the role of attenuated dosing schedules. This was a retrospective evaluation of patients treated in routine clinical practice between 2016-2019 across seven heamatology centres in the UK; patients who received at least one dose of PanBorDex were eligible for inclusion. The dosing schedule of panobinostat (10mg, 15mg or 20mg, twice or three times a week) and bortezomib (0.7mg/m2, 1mg/m2 or 1.3mg/m2 once or twice weekly) was as per treating physician choice. Patients received treatment until disease progression or unacceptable toxicity. The primary outcome is response rates according to IMWG criteria. Key secondary endpoints include progression-free survival (PFS) and overall survival (OS). Other secondary endpoints include rates of adverse events according to CTCAE criteria. In total, 61 patients were eligible for inclusion and received PanBorDex primarily as ≥5th line of treatment. One third of patients received PanBorDex at full dose, for the remaining two thirds, treatment was given in reduced dose intensities. The overall response rate was 44.2%, including 14.7% very good partial response (VGPR) rates; 68.8% of patients derived clinical benefit with stable disease or better. The median PFS was 3.4 months; non-refractory patients and those who achieved VGPR benefited from prolonged PFS of 11.4 months and 17.7 months, respectively. The median OS was 9.5 months. The triplet was associated with 45% and 18% incidence of grade 3-4 thrombocytopenia and diarrhea, respectively.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Multiple Myeloma; Panobinostat; Retrospective Studies; United Kingdom

The zinc finger ubiquitin ligase RNF6 has been proposed as a potential therapeutic target in several cancers, but understanding its molecular mechanism of degradation has been elusive. In the present study, we find that RNF6 is degraded via auto-ubiquitination in a manner dependent on its Really Interesting New Gene (RING) domain. We determine that when the RING domain is deleted (ΔRING) or the core cysteine residues in the zinc finger are mutated (C632S/C635S), the WT protein, but not the ΔRING or mutant RNF6 protein, undergoes polyubiquitination. We also identify USP7 as a deubiquitinase of RNF6 by tandem mass spectrometry. We show that USP7 interacts with RNF6 and abolishes its K48-linked polyubiquitination, thereby preventing its degradation. In contrast, we found a USP7-specific inhibitor promotes RNF6 polyubiquitination, degradation, and cell death. Furthermore, we demonstrate the anti-leukemic drug Nilotinib and anti-myeloma drug Panobinostat (LBH589) induce RNF6 K48-linked polyubiquitination and degradation in both multiple myeloma (MM) and leukemia cells. In agreement with our hypothesis on the mode of RNF6 degradation, we show these drugs promote RNF6 auto-ubiquitination in an in vitro ubiquitination system without other E3 ligases. Consistently, reexpression of RNF6 ablates drug-induced MM and leukemia cell apoptosis. Therefore, our results reveal that RNF6 is a RING E3 ligase that undergoes auto-ubiquitination, which could be abolished by USP7 and induced by anti-cancer drugs. We propose that chemical induction of RNF6 auto-ubiquitination and degradation could be a novel strategy for the treatment of hematological malignancies including MM and leukemia.

Topics: Antineoplastic Agents; Cysteine; DNA-Binding Proteins; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Myeloma; Panobinostat; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitin-Specific Peptidase 7; Ubiquitination; Zinc Fingers

Topics: Clinical Trials, Phase II as Topic; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Panobinostat

Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.

Topics: DNA Repair; Humans; Leukocytes, Mononuclear; Melphalan; Multiple Myeloma; Panobinostat

The AAA-ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATPases Associated with Diverse Cellular Activities; Cell Cycle Proteins; Cell Proliferation; Crystallography, X-Ray; Disease Progression; Enzyme Inhibitors; Humans; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Panobinostat; Protein Conformation; Pyridines; Small Molecule Libraries; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Cell Line, Tumor; Cytotoxins; Deoxycytidine; DNA Fragmentation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gemcitabine; Humans; Melphalan; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signal Transduction; Sulfonamides

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Male; Middle Aged; Multiple Myeloma; Panobinostat; Retrospective Studies

Experimental data on resistance mechanisms of multiple myeloma (MM) to ixazomib (IXA), a second-generation proteasome inhibitor (PI), are currently lacking. We generated MM cell lines with a 10-fold higher resistance to IXA as their sensitive counterparts, and observed cross-resistance towards the PIs carfilzomib (CFZ) and bortezomib (BTZ). Analyses of the IXA-binding proteasome subunits PSMB5 and PSMB1 show increased PSMB5 expression and activity in all IXA-resistant MM cells, and upregulated PSMB1 expression in IXA-resistant AMO1 cells. In addition, sequence analysis of PSMB5 revealed a p.Thr21Ala mutation in IXA-resistant MM1.S cells, and a p.Ala50Val mutation in IXA-resistant L363 cells, whereas IXA-resistant AMO1 cells lack PSMB5 mutations. IXA-resistant cells retain their sensitivity to therapeutic agents that mediate cytotoxic effects via induction of proteotoxic stress. Induction of ER stress and apoptosis by the p97 inhibitor CB-5083 was strongly enhanced in combination with the PI3Kα inhibitor BYL-719 or the HDAC inhibitor panobinostat suggesting potential therapeutic strategies to circumvent IXA resistance in MM. Taken together, our newly established IXA-resistant cell lines provide first insights into resistance mechanisms and overcoming treatment strategies, and represent suitable models to further study IXA resistance in MM.

Topics: A549 Cells; Amino Acid Substitution; Antineoplastic Agents; Boron Compounds; Bortezomib; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression; Glycine; Histone Deacetylases; Humans; Indoles; Models, Biological; Multiple Myeloma; Mutation; Oligopeptides; Panobinostat; Phosphatidylinositol 3-Kinase; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrimidines; Thiazoles

Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.

Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Everolimus; Histone Deacetylase Inhibitors; Humans; Mice; Mitosis; Multiple Myeloma; Panobinostat; Receptors, CXCR4; rho GTP-Binding Proteins; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Prognosis; Retrospective Studies; Salvage Therapy

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Boron Compounds; Glycine; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Thalidomide

Topics: History, 21st Century; Humans; Multiple Myeloma; Panobinostat

To examine real-world treatment patterns in multiple myeloma (MM) patients treated with panobinostat.. Using a US claims database, MM patients treated with panobinostat during 02/01/2015-01/31/2017 were evaluated. Lines of therapy, combination regimens, dosing and duration were measured.. Ninety-five patients were included (mean age: 61.4 years). Patients were heavily pretreated, with 88.4% exposed to both a proteasome inhibitor and an immunomodulatory agent. A panobinostat containing regimen was started in the fourth or more (86%) lines of therapy within a median of 3.77 years from initial treatment. The most common treatment combination was bortezomib/dexamethasone/panobinostat (31.6%) with 69.5% receiving the recommended dose (20 mg). Mean duration was 98.8 days.. Patients received the recommended dose, most commonly with bortezomib and dexamethasone. Panobinostat was used in heavily pretreated patients within 4 years post-diagnosis, reflecting an advanced MM population.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Comorbidity; Female; Humans; Male; Medication Adherence; Middle Aged; Multiple Myeloma; Panobinostat; Treatment Outcome; Young Adult

Gene set enrichment (GSE) analyses play an important role in the interpretation of large-scale transcriptome datasets. Multiple GSE tools can be integrated into a single method as obtaining optimal results is challenging due to the plethora of GSE tools and their discrepant performances. Several existing ensemble methods lead to different scores in sorting pathways as integrated results; furthermore, it is difficult for users to choose a single ensemble score to obtain optimal final results. Here, we develop an ensemble method using a machine learning approach called Combined Gene set analysis incorporating Prioritization and Sensitivity (CGPS) that integrates the results provided by nine prominent GSE tools into a single ensemble score (R score) to sort pathways as integrated results. Moreover, to the best of our knowledge, CGPS is the first GSE ensemble method built based on a priori knowledge of pathways and phenotypes. Compared with 10 widely used individual methods and five types of ensemble scores from two ensemble methods, we demonstrate that sorting pathways based on the R score can better prioritize relevant pathways, as established by an evaluation of 120 simulated datasets and 45 real datasets. Additionally, CGPS is applied to expression data involving the drug panobinostat, which is an anticancer treatment against multiple myeloma. The results identify cell processes associated with cancer, such as the p53 signaling pathway (hsa04115); by contrast, according to two ensemble methods (EnrichmentBrowser and EGSEA), this pathway has a rank higher than 20, which may cause users to miss the pathway in their analyses. We show that this method, which is based on a priori knowledge, can capture valuable biological information from numerous types of gene set collections, such as KEGG pathways, GO terms, Reactome, and BioCarta. CGPS is publicly available as a standalone source code at ftp://ftp.cbi.pku.edu.cn/pub/CGPS_download/cgps-1.0.0.tar.gz.

Topics: Antineoplastic Agents; Base Sequence; Biosynthetic Pathways; Computational Biology; Databases, Genetic; Logistic Models; Machine Learning; Multiple Myeloma; Oligonucleotide Array Sequence Analysis; Panobinostat; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Software

Topics: Allografts; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bortezomib; Chromosome Aberrations; Dexamethasone; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Magnetic Resonance Imaging; Melphalan; Multiple Myeloma; Panobinostat; Prognosis; Protease Inhibitors; Risk; Risk Assessment; Salvage Therapy; Transplantation, Autologous

Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-κ. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-λ + BJP-λ. Amyloidosis was complicated. The first course of FVD was effective, but HD could not be discontinued. She developed G2 AEs, including nausea and fatigue. The cardiac amyloidosis worsened, and she died of heart and renal failure. Case 3: The patient was a 79-year-old male with BJP-κ. FVD was effective, and the HD could be discontinued on day 12 of treatment. No AEs were noted. However, he declined continuation of the FVD and died of MM relapse and renal failure. We analyzed the pharmacokinetics of panobinostat. There were no correlations between dose level and blood level of panobinostat or between blood level, efficacy, and incidence of AEs. We additionally measured the rate of elimination of the drug by HD.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Hydroxamic Acids; Indoles; Male; Multiple Myeloma; Panobinostat; Recurrence; Renal Dialysis; Renal Insufficiency

Topics: ADP-ribosyl Cyclase 1; Antibodies, Monoclonal; Antigens, Neoplasm; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Membrane Glycoproteins; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signaling Lymphocytic Activation Molecule Family; Tumor Cells, Cultured; Up-Regulation

Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes. The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways. DNA damage and S-phase arrest might be involved in Pter-related toxicity in H929R cells. Pter and the histone deacetylase inhibitors panobinostat or vorinostat inhibited proliferation of H929R cells in a synergistic manner. These data supported that Pter might be a promising natural compound for relapsed/refractory myeloma therapy, especially against myeloma resistant to bortezomib chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blueberry Plants; Bortezomib; Caspases; Cell Line, Tumor; Cell Proliferation; DNA Damage; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Recurrence, Local; p38 Mitogen-Activated Protein Kinases; Panobinostat; S Phase Cell Cycle Checkpoints; Stilbenes; Vorinostat

Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions.. The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population.. PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline.. PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Administration Schedule; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multicenter Studies as Topic; Multiple Myeloma; Neoplasm Staging; Panobinostat; Quality of Life; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome

BACKGROUND The aim of this study was to explore the impact of LBH589 alone or in combination with proteasome inhibitor bortezomib on multiple myeloma (MM) cell proliferation and its mechanism. MATERIAL AND METHODS MM cell line U266 and RRMM-BMMNC were treated with different concentrations of LBH589 alone or in combination with bortezomib. Cell proliferation was detected by MTT assay. Cell cycle and apoptosis was analyzed by flow cytometry. The protein and mRNA level of related genes was determined by Western blotting and qRT-PCR respectively. RESULTS U266 cell and RRMM-BMMNC proliferation were inhibited by different concentrations of LBH589 (0, 10, 20, and 50 nmol/L) alone or 50 nmol/L of LBH589 in combination with bortezomib (10 and 20 nmol/L) in a dose- and time-dependent manner. LBH589 significantly induced G0/G1phase arrest and apoptosis in RRMM-BMMNC in a dose-dependent manner. The effects were significantly higher in all combined groups than in single-agent groups (all P<0.05). The mRNA level of Caspase3 and APAF1 were up-regulated gradually, while TOSO gene expression in RRMM-BMMNC was down-regulated gradually in a dose- and time-dependent manner. Moreover, LBH589 significantly induced hyperacetylation of histone H4, the protein level of PARP notably increased, and the level of Bcl-X decreased. CONCLUSIONS LBH589 can inhibit MM cell growth, block the cell cycle, and induce cell apoptosis, which has an anti-resistant effect on multidrug-resistant cells. LBH589 in combination with bortezomib has a synergistic effect on myeloma cells; its mechanism and reversal of drug resistance mechanism is involved in multiple changes in gene expression.

Topics: Acetylation; Apoptosis; Apoptosis Regulatory Proteins; Apoptotic Protease-Activating Factor 1; bcl-X Protein; Bone Marrow Cells; Bortezomib; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Membrane Proteins; Multiple Myeloma; Panobinostat; Poly(ADP-ribose) Polymerases; Recurrence

In the UK, the standard of care for patients with multiple myeloma who received ≥2 prior treatments is lenalidomide plus dexamethasone (LEN + DEX) and pomalidomide plus DEX (POM + DEX) (in Wales only). Recently, panobinostat plus bortezomib and DEX (PAN + BTZ + DEX) was licensed in this setting. The current study assessed the progression-free survival (PFS) and overall survival (OS) outcomes with PAN + BTZ + DEX versus LEN + DEX (primary comparator) and POM + DEX (exploratory comparator).. Since an anchor-based indirect treatment comparison was not feasible, the matching-adjusted indirect treatment comparison approach was used. To compare the survival outcomes, patient-level data were generated for the comparators utilizing published Kaplan-Meier survival estimates. The use of approximated patient-level data and matched data for PAN + BTZ + DEX allowed the use of Cox proportional hazards models and the assessment of the proportional hazards assumption. In cases where there was evidence that the proportional hazards assumption was violated, time-dependent hazard ratios (HRs) were estimated. Median and mean values for PFS and OS were predicted.. For both PFS and OS, the proportional hazards assumption was not satisfied, therefore time-dependent HRs were estimated. Using time-dependent HRs, the mean PFS was estimated to be 11.83 months for PAN + BTZ + DEX and 10.96 months for LEN + DEX. The corresponding mean OS estimates were 30.73 and 27.76 months, respectively. Comparisons with POM + DEX were affected by large uncertainty and did not allow making robust inferences.. To our knowledge, this is the first study that combined matching-adjusted indirect treatment comparison with time-dependent HRs to address changing patterns in the HR. The results suggest that treatment with PAN + BTZ + DEX and LEN + DEX are associated with similar mean PFS and OS in the third-line treatment setting of multiple myeloma.

Topics: Antineoplastic Agents; Bortezomib; Drug Therapy, Combination; Female; Humans; Hydroxamic Acids; Indoles; Kaplan-Meier Estimate; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Panobinostat; Proportional Hazards Models; Recurrence; Survival Analysis; Thalidomide; Treatment Outcome

Cullin-RING ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates the cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Tyr-316 to recruit a small regulatory protein, DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3, in lenalidomide-treated multiple myeloma cells. Importantly, panobinostat, a recently approved anti-myeloma drug, and dexamethasone enhance lenalidomide-induced substrate degradation and cytotoxicity by activating c-Abl, therefore providing a mechanism underlying their combination with lenalidomide to treat multiple myeloma.

Topics: Angiogenesis Inhibitors; Cell Line, Tumor; Cell Survival; Dexamethasone; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Multiple Myeloma; Panobinostat; Protein Binding; Proteolysis; Proto-Oncogene Proteins c-abl; Thalidomide; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination

Topics: Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Panobinostat; Vorinostat

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Panobinostat; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Panobinostat; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Retreatment; Risk Assessment; Survival Analysis; Treatment Outcome; United Kingdom

Multiple myeloma is an incurable B-cell malignancy with a natural history that involves alternating periods of remission and subsequent relapse. For relapsed and/or refractory multiple myeloma (RRMM), the typical patient currently receives more lines of therapy than has been feasible in the past, translating into longer progression-free survival (PFS). Consequently, cost issues have become more prominent because patients may be offered newer and more expensive therapies during a more prolonged overall treatment course.. To estimate the economic impact of adding panobinostat to a U.S. health plan formulary as a treatment option with bortezomib and dexamethasone for patients with RRMM previously treated with a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), using a budget impact and cost-benefit model.. Total costs of commonly used salvage therapy regimens were combined with market share data and population prevalence estimates of RRMM to yield the total cost of treatment, from the perspective of a U.S. third-party payer (commercial or Medicare) with a time horizon of 1 year. Comparator treatment regimens included bortezomib-dexamethasone, lenalidomide-dexamethasone, lenalidomide-bortezomib-dexamethasone, carfilzomib monotherapy, carfilzomib-lenalidomide-dexamethasone, and pomalidomide-dexamethasone. Costs (2015 U.S. dollars) included drug costs for oral oncology agents, medical and administration costs for injectable oncology agents, costs of adverse event (AE) prophylaxis and monitoring, and costs of grade 3/4 AEs.. In a hypothetical health plan with 1 million members, the annual number of RRMM patients with previous PI and IMiD treatments was estimated at 16 and 118 for a commercial and Medicare plan, respectively. Introduction of panobinostat as part of the panobinostat-bortezomib-dexamethasone regimen was not expected to result in a substantial budget impact to either commercial or Medicare plans, with an incremental cost < $0.01 per member per month. Panobinostat-bortezomib-dexamethasone had a low cost per treated patient per month without progression, owing to the minimal increase in expenditure over existing bortezomib-based regimens and long median PFS, compared with median duration of treatment.. Adding panobinostat to a plan formulary as a treatment option is expected to be cost neutral (and potentially cost saving in the context of new and more expensive treatment regimens). With a low cost per month without progression, panobinostat-bortezomib-dexamethasone represents good value for the money.. Funding for this study was sponsored by Novartis, East Hanover, New Jersey. Bloudek and Kish are employees of Xcenda, a consulting company contracted by Novartis to conduct this analysis. Roy, Globe, and Kuriakose are employees of Novartis. Siegel is on the advisory boards and speaker's bureau of Celgene, Onyx/Amgen, Millennium/Takeda, and Novartis and is on the advisory boards of Merck. Jagannath is a consultant to Sanofi, Bristol-Meyers Squibb, and Celgene. Orloski is a contractor to Xcenda and provided medical writing support, which was funded by Novartis. Study design and concept were contributed by Bloudek, Roy, and Kish, assisted by Globe. Bloukek took the lead in data collection, along with Kish, and data interpretation was performed by Siegal, Jagannath, Globe, and Kuriakose. The manuscript was written primarily by Orloski, along with Roy and Kish, and revised by Roy, along with Siegal, Jagannath, Globe, Orloski, and Kuriakose.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Humans; Hydroxamic Acids; Indoles; Insurance, Health; Medicare; Models, Economic; Multiple Myeloma; Panobinostat; Pharmacopoeias as Topic; Salvage Therapy; United States

Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of

Topics: Animals; Calcineurin; Cell Line, Tumor; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Panobinostat; Tacrolimus; Xenograft Model Antitumor Assays

Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.

Topics: Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Proteasome Inhibitors; Sp1 Transcription Factor; Up-Regulation

Topics: Bortezomib; Dexamethasone; Humans; Hydroxamic Acids; Multiple Myeloma; Panobinostat

Topics: Bortezomib; Dexamethasone; Humans; Hydroxamic Acids; Multiple Myeloma; Panobinostat; Thalidomide

Topics: Antineoplastic Agents; Bortezomib; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence

Topics: Antineoplastic Agents; Drug Approval; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; United States; United States Food and Drug Administration

Topics: Drug Approval; Epigenomics; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

Relapse of disease and subsequent resistance to established therapies remain as major challenges in the treatment of multiple myeloma (MM). New therapeutic options are needed for these extensively pretreated patients. To explore an optimized combinational therapy, interactions between the irreversible proteasome inhibitor carfilzomib exhibiting a well-tolerated side-effect profile and histone deacetylase inhibitor (HDACi) panobinostat (LBH589) were examined in MM cells. Coadministration of carfilzomib and LBH589 led to a synergistic inhibition of proliferation in MM cells. Further studies showed that the combined treatment synergistically increased mitochondrial injury, caspase activation, and apoptosis in MM cells. Lethality of the carfilzomib/LBH589 combination was associated with the reactive oxygen species (ROS) generation and ERK1/2 inactivation. In addition, the free radical scavenger N-acetylcysteine (NAC) could block carfilzomib and LBH589-induced oxidative stress and the subsequent apoptosis. Together, these findings argue that the strategy of combining carfilzomib and LBH589 warrants attention in MM.

Topics: Apoptosis; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Drug Synergism; Enzyme Activation; Humans; Hydroxamic Acids; Indoles; MAP Kinase Signaling System; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Multiple Myeloma; Oligopeptides; Panobinostat; Reactive Oxygen Species

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Drug Approval; Drug Resistance, Neoplasm; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Pyrazines; Treatment Outcome; United States; United States Food and Drug Administration

Histone deacetylase inhibitors (HDACis) have emerged as novel therapeutic agents for cancer. Currently, four HDACis are approved by the Food and Drug Administration (FDA) to treat various hematologic malignancies. Panobinostat (LBH-589, trade name Farydak®, developed and marketed by Novartis) is a potent pan-HDACi with demonstrated anticancer activities against multiple myeloma, a B-cell malignancy, at a low nanomolar range in preclinical settings, and in 2015 was granted FDA approval for the treatment of relapsed and refractory multiple myeloma. Here, we review the development of HDACis, the unique features of panobinostat, and the rationale for developing panobinostat in a combination setting for the treatment of multiple myeloma. We also review the completed and ongoing clinical trials testing the efficacy of panobinostat in combination therapies and highlight future therapeutically relevant strategies.

Topics: Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat

To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.. HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.. Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.. The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow Cells; Boronic Acids; Bortezomib; Drug Resistance, Neoplasm; Endothelial Cells; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Hydroxamic Acids; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Kaplan-Meier Estimate; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Panobinostat; Proteome; Pyrazines; Reactive Oxygen Species; Thalidomide; Transcription, Genetic

We examined the pre-clinical activity of pan-histone deacetylase inhibitor LBH589 in combination with mTORC1 inhibitor RAD001 and observed that the drug combination strongly synergized in inducing cytotoxicity in multiple myeloma (MM) cells. LBH589 caused an increase in acetylated histones and RAD001 inhibited mTORC1 activity. RAD001 caused potent G0/G1 arrest while LBH589 induced pronounced apoptosis, both of which were enhanced when the drugs were used in combination. LBH589/RAD001 combination led to down regulation of pStat3, cyclins, CDKs and XIAP and up regulation of pro-apoptotic Bcl-2 family proteins. A clinical trial is underway using LBH589/RAD001 combination in relapsed MM patients.

Topics: Apoptosis; Cell Line, Tumor; Drug Synergism; Everolimus; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Sirolimus; Tumor Microenvironment

Topics: Acetylation; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Depsipeptides; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Protein Processing, Post-Translational; Pyrimidines; Tubulin; Tumor Cells, Cultured

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azacitidine; Biphenyl Compounds; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Myeloma; Nitrophenols; Panobinostat; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Receptors, Death Domain; Recombinant Proteins; Sulfonamides; TNF-Related Apoptosis-Inducing Ligand

Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism.

Topics: Animals; Antineoplastic Agents; Apoptosis; Diphosphonates; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Humans; Hydroxamic Acids; Imidazoles; Indoles; Male; Mevalonic Acid; Mice; Mice, Nude; Models, Biological; Multiple Myeloma; p38 Mitogen-Activated Protein Kinases; Panobinostat; Prostatic Neoplasms; Reactive Oxygen Species; Signal Transduction; Xenograft Model Antitumor Assays; Zoledronic Acid

Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Survival; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hydroxamic Acids; Indoles; Kruppel-Like Transcription Factors; Multiple Myeloma; Oligonucleotide Array Sequence Analysis; Panobinostat; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transcription Factors

Topics: Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Multiple Myeloma; Panobinostat

We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.. The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.. In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G(2)-M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.. The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589.

Topics: Animals; Apoptosis; Caspase 8; Cell Adhesion; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Gene Expression Profiling; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Mice; Mice, Inbred C57BL; Multiple Myeloma; Panobinostat; Podophyllotoxin; Receptor, IGF Type 1; Transcriptome; Tumor Cells, Cultured

This study was purposed to explore the effect of a new generation of histone deacetylase inhibitor LBH589 alone or combined with bortezomib (Bor) on multiple myeloma cells (MM1R) in vitro. The effect of LBH589 (10, 20, 50 nmol/L) alone or combined with Bor (10, 20 nmol/L) on MM1R proliferation was detected by MTT method; the effect of LBH589 on cell cycle and apoptosis of MM1R cells were determined by flow cytometry; the histone H4 acetylation level of MM1R cells treated with LBH589 (10, 20, 50 nmol/L) for 24 h was analyzed by Western blot. The results showed that the LBH589 alone or combined with Bor all could inhibit the proliferation of MM1R cells in a concentration- and time-dependent manner. After MM1R cells were treated with drugs for 48 h, the cells in G(0)/G(1) phase increased, the cells in G(2)/M and S phase decreased, suggesting the arrest of cells in G(0)/G(1) phase, at the same time, the apoptosis rate of MM1R cells treated with drugs increased in a concentration-dependent manner, while the effect of LBH589 combined with Bor was more obvious than that of LBH589 alone (P < 0.001). Western blot analysis showed that the histone H4 acetylation level was enhanced in concentration-dependent manner after MM1R cells were treated with different concentrations of LBH589 for 24 h. It is concluded that the LBH589 can inhibit the proliferation of MM1R cells, block the cell cycle, induce cell apoptosis, moreover LBH589 combined with Bor has synergistic effect on MM1R cells.

Topics: Acetylation; Apoptosis; Boronic Acids; Bortezomib; Cell Cycle; Cell Line, Tumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Pyrazines

To explore the impact of a new generation of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on multiple myeloma (MM) cells proliferation and its mechanism.. MM cell line U266 and dexamethasone resistant cell line MM1R cells were treated with different concentrations of LBH589 alone or in combination with bortezomib, the inhibition of cells proliferation was detected by MTT, the cell cycle and apoptosis by flow cytometry. The expression level of histone H4 acetylation and PARP, Bcl-X protein was analyzed by western blot, expression level of caspase-3, APAF-1 and TOSO gene by real-time fluorescence quantitative PCR.. U266 and MM1R cell proliferation were inhibited by different concentrations of LBH589 (0, 10, 20, 50 nmol/L) alone or 50 nmol/L of LBH589 in combination with bortezomib (10, 20 nmol/L) in a dose- and time-dependent manner. Inhibition effect was significantly higher in all combinative groups than in single agent groups (all P < 0.05). The percentage of G(0)/G(1) phase in MM1R cells were 36.60%, 46.50%, 51.40%, 57.10%, 75.48%, 79.73%, respectively, and the apoptosis rate were 5.27%, 31.41%, 39.78%, 44.07%, 73.60%, 83.27%, respectively. The effects appeared to occur in a dose-dependent manner, and being significantly higher in all combinative groups than in single agent groups (all P < 0.05). The expression of the caspase-3 and APAF-1 gene up-regulated gradually, while TOSO gene expression in MM1R cells down-regulated gradually in a dose- and time-dependent manner (all P < 0.05).. LBH589 can inhibit the growth of MM cells, block the cell cycle and induce cell apoptosis, which has anti-resistant effect on multidrug resistant cell. At the same time LBH589 in combination with bortezomib on myeloma cell has a synergistic effect, its mechanism and reversal of drug resistance mechanism involves in multiple changes in gene expression.

Topics: Acetylation; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Pyrazines

Panobinostat (LBH589) is a potent histone deacetylase inhibitor (HDACi) that has shown anti-tumor activity in preclinical studies in both solid and hematological malignancies. We evaluated the anti-multiple myeloma (MM) effects of LBH589 alone and with melphalan or doxorubicin using MM cell lines and our human MM xenograft model LAGλ-1. LBH589 treatment resulted in increased acetylation of histones, induction of caspase cleavage, inhibition of cell proliferation and synergistic anti-MM effects with melphalan or doxorubicin in vitro. LBH589 with melphalan or doxorubicin also showed significantly enhanced anti-myeloma activity in vivo. These findings provide the basis for clinical development of these combination therapies.

Topics: Acetylation; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Synergism; Flow Cytometry; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunoglobulin G; In Vitro Techniques; Indoles; Melphalan; Mice; Mice, SCID; Multiple Myeloma; Panobinostat

Topics: Animals; Doxorubicin; Drug Synergism; Drug Therapy, Combination; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Melphalan; Mice; Multiple Myeloma; Panobinostat

Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.. The activity of these combinations was explored in vitro in cell lines by using MTT and annex-in V, ex vivo by flow cytometry, and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profiling and immunohistochemical studies were performed.. The addition of panobinostat (LBH589) to dexamethasone and either bortezomib or lenalidomide resulted in clear potentiation in multiple myeloma cell lines, freshly isolated plasma cells, and murine models of multiple myeloma. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indices for all of them. This effect derived from the deregulation of a cluster of genes that was completely different from the sum of genes affected by the single agents (895 and 1323 genes exclusively deregulated by panobinostat and dexamethasone plus bortezomib or lenalidomide, respectively). Functional experiments, such as annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease.. The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cell Line, Tumor; Cells, Cultured; Dexamethasone; Disease Models, Animal; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Mice; Mice, SCID; Multiple Myeloma; Panobinostat; Pyrazines; Random Allocation; Thalidomide; Xenograft Model Antitumor Assays

Insulin-like growth factor-1 (IGF-1) is an important growth and survival factor in multiple myeloma (MM). Here, we demonstrate that IGF-1 induces significant down-regulation of the proapoptotic BH3-only protein Bim in MM cells. Reduced Bim levels by RNA interference (RNAi) protected cells from drug-induced cell death. The IGF-1-mediated down-regulation of Bim was the result of (1) reduced transcription by activation of the Akt pathway and inactivation of the transcription factor FoxO3a, (2) increased proteasome-mediated degradation of the Bim extra-long protein by activation of the mitogen-activated protein kinase pathway, and (3) epigenetic regulation of both the Bim and the FoxO3a promoter. Treatment of cells with the histone deacetylase inhibitor LBH589 resulted in a clear up-regulation in the expression of Bim. Furthermore, the methylation inhibitor 5-aza-2'deoxycytidine (decitabine) significantly increased the effects of LBH589. On IGF-1 treatment, the Bim promoter region was found to be unmethylated, whereas chromatin immunoprecipitation analysis of the IGF-1-treated cells showed both a reduced histone H3 tail Lys9 (H3K9) acetylation and an increased H3K9 dimethylation, which contributed actively to its silencing. These data identify a new mechanism in the IGF-1-dependent survival of MM cells and emphasize the need for IGF-1-targeted drug therapy.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Cell Line, Tumor; Cell Survival; Down-Regulation; Epigenesis, Genetic; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Histones; Humans; Hydroxamic Acids; Immunoglobulin G; Indoles; Insulin-Like Growth Factor I; Kidney; Melphalan; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Multiple Myeloma; Panobinostat; Phosphatidylinositol 3-Kinases; Protein Processing, Post-Translational; Proto-Oncogene Proteins

Multiple myeloma as the second most common hematological malignancy is characterized by proliferation of monoclonal plasma cells. This entity still remains a non-curable disorder leading, amongst others, to complications as myeloma bone disease, bleeding events, kidney failure and neurological impairment. LBH589 is a histone deacetylase inhibitor with an epigenetic mechanism of action and the potential for treatment in myeloma.. We report here about the successful treatment of a 44-year-old woman suffering from progressive myeloma with LBH589 after five different chemotherapies. During the 9 years after first diagnosis of myeloma in April 2000, our patient twice underwent an autologous stem cell transplantation and was also treated with the new substances bortezomib, thalidomide and lenalidomide.. A rapid decline of myeloma activity parameters could be reached, with an approximately exponential decrease of kappa light chains in the 24-h urine. As a consequence, a near-complete remission was determined after about 6 months of LBH589 treatment. Additionally, the adverse event profile was acceptable, and the patient's quality of life showed a considerable advancement of well-being.. LBH589 may be very effective in multiple myeloma after a multitude of preceding treatments that could not induce a long-term anti-myeloma effect. Future trials with LBH589 should search for the specific characteristics of responding patients.

Topics: Adult; Antineoplastic Agents; Boronic Acids; Bortezomib; Feasibility Studies; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Lenalidomide; Multiple Myeloma; Panobinostat; Pyrazines; Thalidomide; Treatment Failure; Treatment Outcome

Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

Topics: Adenosine; Adenosylhomocysteinase; Animals; Apoptosis; Blotting, Western; Cadherins; Cell Line, Tumor; Cells, Cultured; Chemokine CXCL12; Chromatin Immunoprecipitation; Computational Biology; DNA Methylation; GATA2 Transcription Factor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Interferon Regulatory Factors; Kaplan-Meier Estimate; Mice; Multiple Myeloma; Panobinostat; Polycomb-Group Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction

Preclinical evidence supports the investigation of histone deacetylase inhibitors for the treatment of myeloma. Results from early studies demonstrate clinical activity and further studies investigating combination strategies should be explored.

Topics: Antineoplastic Agents; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Treatment Outcome

The purpose of this study was to investigate expression and epigenetic regulation of CD9 in multiple myeloma (MM) cells during disease progression.. CD9 expression was retrospectively analyzed on bone marrow myeloma samples from 81 patients by immunophenotyping. CD9 expression by murine 5TMM cells was detected by flow cytometric staining and quantitative PCR. The methylation status of the CD9 promoter was determined by bisulfite PCR sequencing.. Primary plasma cells in the majority of MM patients with nonactive disease (n = 28) showed CD9 expression, whereas most cases with active disease (n = 53) were CD9 negative. CD9 expression in diagnostic bone marrow samples (n = 74) correlated with survival. Moreover, CD9 expression on murine 5T33 and 5T2MM cells was significantly down-regulated during disease development. Treatment of CD9-nonexpressing 5T33MMvt cells with the clinically relevant histone deacetylase inhibitor LBH589 resulted in a significant increase in CD9 expression. In contrast, cells treated with the demethylation agent 5-aza-2'deoxycytidine barely showed any increase. A combination study with both compounds resulted in a strong synergistic reactivation of CD9. CD9-expressing 5T33MMvv cells and 5T33MMvt cells stably transduced with a mCD9 lentiviral transferplasmid were shown to be more susceptible to natural killer cell-mediated cytolysis than CD9-negative 5T33MMvt cells.. CD9 expression correlates with disease status and survival of MM patients. In the murine 5T33MM model, we show that histone modifications, and to a lesser extent CpG methylation, are key epigenetic events in CD9 down-regulation. Furthermore, as CD9 expression becomes down-regulated, 5T33MM cells become less susceptible to natural killer cell-mediated cytolysis.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antigens, CD; Cytotoxicity, Immunologic; Disease Progression; DNA Methylation; Enzyme Inhibitors; Epigenesis, Genetic; Female; Flow Cytometry; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Immunophenotyping; Indoles; Kaplan-Meier Estimate; Killer Cells, Natural; Male; Membrane Glycoproteins; Mice; Middle Aged; Multiple Myeloma; Panobinostat; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Tetraspanin 29

Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells. LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional therapies via caspase activation and poly-(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of bortezomib in combination with LBH589.

Topics: Boronic Acids; Bortezomib; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydrolases; Hydroxamic Acids; Indoles; Multiple Myeloma; Panobinostat; Poly(ADP-ribose) Polymerase Inhibitors; Protease Inhibitors; Pyrazines; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid-derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC(50) < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients.

Topics: Acetylation; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Boronic Acids; Bortezomib; Cell Cycle; Cell Line, Tumor; Dexamethasone; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Melphalan; Multiple Myeloma; Panobinostat; Pyrazines