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Panobinostat, a potent oral pan-deacetylase inhibitor, is indicated for patients with relapsed multiple myeloma (MM) in combination with bortezomib and dexamethasone. This was based upon the sub-group analysis of the PANORAMA 1 phase 3 clinical trial, demonstrating an improvement in progression-free survival (PFS) of 12·5 vs. 4·5 months (Richardson et al, 2016). The Myeloma UK (MUK)-six (ISRCTN59395590, NCT02145715) was a multi-centre phase I/II clinical trial for patients with relapsed MM (1–4 prior lines), designed to improve the efficacy and tolerability by adding low dose thalidomide and incorporating low intensity subcutaneous bortezomib followed by panobinostat maintenance. The epigenetic mechanism of action, role in aggressome disruption and evidence of immunomodulation (Mitsiades et al, 2003; Hideshima et al, 2005; Govindaraj et al, 2014) provided a hypothesis that continuing panobinostat monotherapy may prolong response. We previously reported primary and secondary endpoints for the trial, interpreting that the regimen was efficacious and well tolerated (Popat et al, 2016). Here with extended follow-up, we report the updated secondary endpoint of PFS, overall survival (OS) and feasibility of panobinostat maintenance. Patients received bortezomib (V) 1·3 mg/m2 days 1, 8 with thalidomide (T) 100 mg/day (50 mg if peripheral neuropathy) dexamethasone (D) 20 mg days 1, 2, 8, 9 and panobinostat (P) days 1, 3, 5, 8, 10 and 12 of a 21-day cycle for 16 cycles (VTD-P) followed by 1 year of panobinostat maintenance (current dosing level or maximum tolerated dose [MTD]) for patients completing 16 cycles of therapy only. The primary objectives were to determine the MTD of panobinostat and the overall response rate at the recommended dose within 16 cycles. The trial was funded by Myeloma UK and Novartis, and approved by the UK National Ethics Committee and the Medicines and Healthcare Products Regulatory Agency (MHRA). Following a median follow-up of 28 months, 46 patients received at least one dose of the recommended 20-mg panobinostat dose and are reported for PFS overall; censoring patients coming off study for an autologous stem cell transplant (ASCT) at point of ASCT [see Popat et al (2016) for definitions, supplementary Figure S1 for CONSORT diagram]. The median overall PFS was 16·1 months [95% confidence interval (CI): 13·40, 21·55] and appeared similar for those with standard and adverse cytogenetic risk [standard (n = 23) 16·10 months (95% CI: 13·40, 24·80), adverse (n = 21) 17·90 months (95% CI: 9·40, Not calculable (>26·8)], with results not available for 2 patients; Fig 1). Twenty-four patients came off study to proceed to ASCT [median PFS 29·40 months (95% CI: 18·73, 37·65)] and 22 continued therapy [median PFS of 15·11 months (95% CI: 7·00, 20·47)]. The median OS was not reached, and the estimated 2-year OS was 71·4% (95% CI: 47·2%, 86·0%) for patients that did not come off therapy to proceed to ASCT (n = 22) (Fig 1). Fifteen of the 20 patients that completed 16 cycles of VTD-P went on to receive panobinostat maintenance (demographics in Table S1). Of the 5 that did not, 3 were eligible for ASCT and 2 had prior toxicity to panobinostat. Patients were predominantly at first relapse (11, 73·3%). Twelve (80·0%) patients started maintenance at panobinostat 20 mg and 3 at 15 mg due to dose reductions during initial therapy. Clinic visits were six-weekly for trial safety and response assessments (2 cycles of maintenance). Patients remained on maintenance for a median of 7·5 cycles (range 3–18): 5 completed the full 1 year, 9 stopped early due to disease progression and 1 withdrew consent for due to toxicity. Three patients maintained their response during maintenance, 2 had disease progression at the end of the 1-year maintenance and 9 had disease progression on therapy, with 1 patient beginning to lose their response (but not fulfilling criteria for disease progression) during maintenance before withdrawing after 4 cycles. No patients deepened their response on treatment (Fig 2). Median PFS for patients that received maintenance was 17·9 months (95% CI 13·4, 21·5). No serious adverse events were reported during maintenance. The commonest change in reported adverse events from initial therapy (all grades) were diarrhoea (grade 1: 3/15, 20%; grade 3: 2/15, 13·3%), anorexia (grade 1: 4/15, 26·7%) and infection (grade 1: 3/15, 20%; grade 2: 1/15, 6·7%). Overall, treatment compliance was maintained with a median overall dose taken of 20 mg (range 10–20 mg). Four patients (26·7%) required at least one dose reduction for toxicity during maintenance, all due to diarrhoea. Five patients (33·3%) required at least 1 dose omission of which 2 were due to nausea and diarrhoea. In comparison, the phase 3 PANORAMA 1 trial, which investigated VD-P (8 × 3 weekly cycles followed by 4 × 6 weekly cycles, with no maintenance) in patients with 1-3 prior lines of therapy (51% 1 prior line) reported a median PFS of 11·99 months (95% CI 10·33, 12·94, n = 387) and OS of 40·3 months (95% CI, 35·0–44·8 months)(San-Miguel et al, 2014, 2016). Here we report an overall median PFS of 16·1 months, and 15·11 months for those that did not proceed to ASCT in a smaller phase I/II study (1–4 prior lines, 80% 1 prior line). There is limited data to the efficacy of panobinostat monotherapy in MM. In a phase 2 trial of 38 patients, only 2 derived clinical benefit (1 partial response, 1 minimal response); however, both patients had long responses of 19 and 28 months (Wolf et al, 2012). A case report from a phase 1b trial of VD-P described 2 patients that gained long term benefit from ongoing panobinostat monotherapy (at least 65 months and 75 months) (Ocio et al, 2015). There are also ongoing trials investigating panobinostat post ASCT (Sengsayadeth et al, 2017). The MUK-six trial demonstrated that 1 year of panobinostat maintenance was feasible, with dose intensity maintained. The predominant adverse events were gastrointestinal, mainly grade 1-2. Some maintained their response during maintenance; however, 11 of the 15 patients developed disease progression on panobinostat. As a result, the clinical benefit of panobinostat monotherapy maintenance appeared minimal, although the conclusions are limited due to a small selected group without comparative data. This trial was developed through the Myeloma UK Early Phase Clinical Trials Network, and funded by Myeloma UK and Novartis. The authors acknowledge the patients who participated in this study, their families and carers as well as all staff, past and present, at the participating hospitals, Myeloma UK and the University of Leeds Clinical Trials Research Unit and the Independent Trial Steering Committee. This was a National Institute for Health Research (NIHR) portfolio adopted trial and carried out and supported by the NIHR UCLH Clinical Research Facility and the Cancer Research UK Experimental Cancer Medicine Centre (ECMC). RP and KY are supported by the NIHR UCLH Biomedical Research Centre. JC, SB, EL, WG, KY designed the research; RP, JC, BK, MS, KY, GC performed the research and collected data; SB, AH performed statistical analyses; JC, RP, SB, AH, LF reviewed the trial report and interpreted data; LF performed trial and data management; RP, AH, SB wrote the manuscript; All authors reviewed the manuscript. Table S1. Baseline demographics for patients receiving panobinostat maintenance Fig S1. Trial Consort Diagram Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.