The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective

Abstract

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. Funding: Editorial support, funded by Novartis Pharmaceuticals.

LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR‐193a/MCL1 pathway

“…Despite advances in supportive and systemic therapies, it remains an essentially incurable disease with a high rate of relapse, rapid acquisition of drug resistance, and a median survival of approximately 4 years . Dexamethasone (DEX) is a key front‐line chemotherapeutic for B‐cell malignant MM, however, MM cells often become DEX resistant . Therefore, further investigation of the molecular mechanisms involved in carcinogenesis and progression of MM is essential for developing new effective therapeutic targets of MM.…”

Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Therapies

“…Panobinostat is a potent oral pan-deacetylase inhibitor. It affects growth and survival of MM cells through alteration of (1) gene expression through epigenetic modification and (2) protein metabolism by inhibiting protein degradation [168][169][170][171]. The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168][169][170][171].…”

“…It affects growth and survival of MM cells through alteration of (1) gene expression through epigenetic modification and (2) protein metabolism by inhibiting protein degradation [168][169][170][171]. The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168][169][170][171]. Panobinostat, in combination with bortezomib and dexamethasone, was recently approved in the USA, Europe and Japan for the treatment of patients with MM who had failed at least two prior regimens including bortezomib and an immunomodulatory agent [168][169][170][171].…”

“…The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168][169][170][171]. Panobinostat, in combination with bortezomib and dexamethasone, was recently approved in the USA, Europe and Japan for the treatment of patients with MM who had failed at least two prior regimens including bortezomib and an immunomodulatory agent [168][169][170][171]. A meta-analysis that included 11 clinical trials and 700 patients with R/R-MM treated with panobinostat demonstrated not only efficacy but also safety of panobinostat in combination with other agents [172].…”

“…The main toxic effects of panobinostat are thrombocytopenia and diarrhea. However, several studies showed other adverse effects including lymphopenia, neutropenia and anemia, nausea, vomiting, constipation and abdominal pain, asthenia, fatigue, peripheral edema and peripheral neuropathy [167][168][169][170][171][172]. Ongoing clinical trials are evaluating the role of panobinostat in combination with drugs other than bortezomib in R/R-MM, in combination with various drugs in newly diagnosed disease and in maintenance therapy of myeloma [169].…”