ArticlesPanobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial
Introduction
Proteasome inhibitors and immunomodulatory drugs have significantly improved outcomes in patients with multiple myeloma.1 Combinations of these drug types have led to responses in nearly all patients with newly diagnosed multiple myeloma.2, 3 Despite these advances, patients relapse or become refractory to first-line treatments, and the disease remains incurable. Thus, a need exists for drugs with novel mechanisms of action that enhance the activity of standard-of-care regimens.
Myeloma cells overproduce misfolded proteins and rely on proteasome and aggresome pathways for survival; therefore, dual-pathway inhibition represents a promising treatment approach.4 Pan-deacetylase inhibitors, which are epigenetic modulators that target class I and II histone deacetylase enzymes (including HDAC6, a key component of the aggresome pathway), have emerged as a novel class of anti-myeloma drugs.4 However, in a phase 3 trial,5 the addition of the pan-deacetylase inhibitor vorinostat to bortezomib did not lead to a clinically relevant increase in progression-free survival. Panobinostat is a pan-deacetylase inhibitor with more potent in-vitro inhibitory activity than vorinostat.6 Although deacetylase inhibitors, including panobinostat, have little to no activity as single agents in patients with multiple myeloma,7 results of preclinical studies have shown synergistic anti-myeloma activity of panobinostat with bortezomib and dexamethasone.8, 9 Results from phase 1 and 2 studies10, 11 have shown durable responses with this combination in patients with relapsed or refractory multiple myeloma, including bortezomib-refractory disease. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.
Section snippets
Study design and patients
PANORAMA1 (PANobinostat ORAl in multiple MyelomA 1) a multicentre, randomised, placebo-controlled, double-blind phase 3 trial done at 215 centres across 34 countries (appendix pp 3–8). Adult patients (aged 18 years and older) with measurable relapsed or relapsed and refractory multiple myeloma, 1–3 previous treatments, and an Eastern Cooperative Oncology Group performance status of 2 or lower were eligible for inclusion. Patients with primary refractory or bortezomib-refractory myeloma were not
Results
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 (figure 2). Baseline characteristics were well balanced between the treatment groups (table 1). Nearly half of the patients had received at least two previous treatment regimens; previous treatment regimens used included bortezomib, thalidomide, lenalidomide, and bortezomib-immunomodulatory drug combination
Discussion
In this phase 3 trial in patients with relapsed or relapsed and refractory multiple myeloma, panobinostat, bortezomib, and dexamethasone led to a clinically relevant and significant increase in progression-free survival compared with placebo, bortezomib, and dexamethasone. Efficacy in the placebo group was similar to that in historical controls.13, 17 The effect on progression-free survival was confirmed by sensitivity analyses and was consistent across all stratification factors and subgroups
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