Panobinostat in combination with bortezomib and dexamethasone in multiply relapsed and refractory myeloma; UK routine care cohort

Abstract

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.

Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics

“…3.1. PI3K Class IA Kinases Regulate a Signalling Node Involved in MM Drug Resistance to Dexamethasone Mediated by the BM Mesenchymal/Fibroblastic and OC Niches MM patients are commonly treated with dexamethasone alone or in combination with new therapeutic drugs at presentation, as well as during relapse [1,3,[23][24][25][26]. However, MM cells develop resistance to dexamethasone, and relapse is a widespread problem.…”

Multi-dimensional profiling of hepatoblastomas and patient-derived tumor organoids uncovers tumor subpopulations with divergent WNT activation profiles and identifies pan-hepatoblastoma drug sensitivities

“…In the same study by Pagella et al 38 , β-catenin was found to be dependent on HDAC for chromatin opening, and HDAC inhibition fully abolished its activity. In addition, many of these drugs identified in this study, including romidepsin and panobinostat, have been approved for clinical use [60][61][62][63] , presenting a great opportunity to assess their efficacy in pediatric liver cancer patients.…”