Panobinostat for the treatment of multiple myeloma: the evidence to date

Bailey, Hanna; Stenehjem, David D.; Sharma, Sunil

doi:10.2147/jbm.s69140

Cited by 24 publications

(10 citation statements)

References 36 publications

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“…Vorinostat and romidepsin are the most advanced HDAC inhibitors and are currently approved for treating cutaneous T-cell lymphomas 4–6. Belinostat is approved for the treatment of peripheral T-cell lymphoma, and panobinostat is approved for use in combination treatments for multiple myeloma 7,8. Several studies support the use of HDAC inhibitors in combination with EGFR-TKIs in NSCLC cells to restore EGFR-TKI sensitivity 9–14.…”

Section: Introductionmentioning

confidence: 99%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

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Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments.

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Section: Introductionmentioning

confidence: 99%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

OTT

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“…Currently there are a number of new drugs being studied for MM, such as oral deacetylase inhibitor and panobinostat (not included in our study) for which the safety with concurrent RT should be studied in the future before widespread concurrent utilization. 29 , 30 , 31 Maintenance systemic therapy and control is key to the management of MM, and we have shown that maintenance systemic therapy does not need to be stopped to treat MM.…”

Section: Discussionmentioning

confidence: 99%

The Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era

Salgado

Wang

Adler

et al. 2019

Advances in Radiation Oncology

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PurposeThe management of multiple myeloma has evolved in the modern era, partially owing to the increasing number of biologic therapeutics. Nonetheless, radiation remains an important treatment in the management of painful lytic lesions from multiple myeloma. The goal of this study is to evaluate the side effect profile of radiation therapy (RT) while patients are concurrently treated with biologic agents.Methods and MaterialsWe conducted a retrospective study based on data collected from patients receiving RT at our institute from 2007 to 2017. A total of 130 patients (279 treatment sites) were included in this study with a median follow-up time of 14 months. Patients were required to be receiving a biological agent at least within 1 month before starting and up to 1 month after RT. Generalized estimating equations with a log link function and binomial distribution were used to estimate the prevalence ratio (PR) and corresponding 95% confidence interval (CI) and compare the side effects between patients with RT alone and RT + biologic agent.ResultsThe median age of all patients in our cohort was 64 years, with 53 men (58.9%) and 37 women (41.1%). The mean Karnofsky performance status score of all cohorts was 80. No significant difference in incidence of acute (PR: 1.33; 95% CI, 0.80-2.22; P = .2660) or subacute (PR: 0.90; 95% CI, 0.49-1.67; P = .7464) toxicities was found between patients with or without biologic agents who were treated concurrently with RT. No significant difference was found in reduction in laboratory values between patients with or without biologic agents treated concurrently with RT for white blood cells (P = .6916), platelets (P = .7779), or hematocrit (P = .0858).ConclusionsOur study did not detect any significant toxicity rates from palliative radiation while patients were concurrently treated with biologic agents.

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“…Panobinostat as well as lenalidomide are known substrates for P-glycoprotein 20,21 and we therefore evaluated the possibility of a PK drug interaction in this combination study. The plasma PK data obtained from this study showed lenalidomide parameter estimates were similar to the values reported previously in lenalidomide single-agent studies, 22,23 and therefore the surprisingly low ORR observed in this trial cannot be explained by altered lenalidomide plasma PKs.…”

Section: Discussionmentioning

confidence: 99%

A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma

Maly

Christian

Zhu

et al. 2017

Clinical Lymphoma Myeloma and Leukemia

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On the basis of previous studies showing single-agent efficacy with lenalidomide and panobinostat in patients with relapsed or refractory Hodgkin lymphoma (HL), we conducted a phase I/II study to evaluate the safety and efficacy of the combination in this patient population. The recommended phase II dose was 25 mg lenalidomide on days 1 to 21 with 15 mg panobinostat 3 times per week, and an overall response rate of 16.7% in patients was observed, with a durable response in 1 patient with lymphocyte-predominant HL. Background Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. Patients and Methods In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). Results Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg pan-obinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), throm-bocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. Conclusion Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.

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Panobinostat for the treatment of multiple myeloma: the evidence to date

Cited by 24 publications

References 36 publications

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

The Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era

A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma

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