Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1195-1206
The Lancet Oncology

Articles
Panobinostat 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

https://doi.org/10.1016/S1470-2045(14)70440-1Get rights and content

Summary

Background

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.

Methods

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/m2 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.

Findings

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%]).

Interpretation

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.

Funding

Novartis Pharmaceuticals.

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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