Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study

Background : Improved therapeutic options are needed for patients with relapsed or relapsed andrefractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomibas it is associated with a more favourable toxicity profile. We investigated the activityand safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods : PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitalsand medical centres) across 21 countries. Patients aged 18 years or older with relapsedor relapsed and refractory multiple myeloma (as per International Myeloma WorkingGroup 2014 criteria), who had received one to four previous lines of therapy (includingan immunomodulatory agent), and had an Eastern Cooperative Oncology Group performancestatus of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneousbortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles.Randomisation was done by an interactive response technology provider, and stratifiedby number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patientsby intention to treat). Safety analyses included all patients who received at leastone dose of any study drug. No statistical comparisons between groups were planned.This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990. Findings : Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and83 to 10 mg panobinostat three times weekly). Median duration of follow-up acrossall treatment groups was 14·7 months (IQR 7·8–24·1). The overall response rate afterup to eight treatment cycles was 62·2% (95% CI 50·8–72·7; 51 of 82 patients) for the20 mg three times weekly group, 65·1% (53·8–75·2; 54 of 83 patients) for the 20 mgtwice weekly group, and 50·6% (39·4–61·8; 42 of 83 patients) for the 10 mg three timesweekly group. Grade 3–4 adverse events occurred in 71 (91%) of 78 patients in the20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weeklygroup, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the mostcommon (≥20% patients in any group) grade 3–4 adverse events were thrombocytopenia(33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18[23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weeklygroup; the most common serious adverse event (≥10% patients in any group) was pneumonia(nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14deaths during the study (five [6%] of 78 patients in the 20 mg three times weeklygroup, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation : The safety profile of panobinostat 20 mg three times weekly was more favourable thanin previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneousbortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasoneregimen. The overall response rate was highest in the 20 mg three times weekly and20 mg twice weekly groups, with 10 mg three times weekly best tolerated.

The Lancet Oncology 2020

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