Panobinostat in Combination with Bortezomib and Dexamethasone for Heavily Pre-Treated Myeloma: A UK Real-World Multi-Centre Cohort

Panobinostat (Pan), the first in-class histone deacetylase inhibitor is approved in combination with bortezomib (Bor) and dexamethasone (Dex) for relapsed/refractory multiple myeloma (RRMM) after ≥ 2 prior lines of therapy, including Bor and an IMiD, based on data from PANORAMA-1 trial. The trial excluded patients who are refractory to prior proteasome inhibitors (PIs). In clinical practice, PanBorDex is often introduced as 5^th or later line of therapy using a range of pre-planned attenuated dosing schedules to maintain therapy and improve tolerability. We conducted a UK multicentre retrospective study to evaluate efficacy and toxicity outcomes of PanBorDex in a heavily pre-treated, myeloma cohort treated in routine care.

Sixty two patients were eligible for inclusion, of whom 58.1% were male, 46% were ISS 3 staging and 32.3% had a high cytogenetic risk (HR), defined as one or more of the following: t(4;14), t(14;16) , del(17p), t(14;20), 1q gain. Median age was 72 years (IQR 62-76 years). Median time from diagnosis was 5.6 years.

Median number of prior therapies was 4 (range 1-7); 98.4% of patients were PI-exposed, all patients received a prior IMiD. 46.8% of patients were PI-refractory, 82.3% were IMiD-refractory, and 43.5% were double refractory.

Patients received a median of 4 cycles (IQR 2-8). Eighteen patients (29%) completed ≥8 cycles. Twenty patients (32.3%) initiated PanBorDex at full dosing, and the remainder at a reduced dose or frequency or both of Pan and/or Bor. The overall response rate in the total cohort was 45%; VGPR, PR and PD rates were 14.5%, 30.6%, and 30.6%, respectively.

At a median follow up of 35.9 months, median PFS for the total cohort was 5.1 months (95% CI 2.0-8.1months) (Figure A). Median OS was 9.5 months (95% CI 5.5-13.4months) (Figure B). Median PFS according to depth of response was 6.6 months and 17.7 months for PR and ≥VGPR, respectively (Figure C). PFS was significantly shorter in double refractory compared to non-PI and non-IMiD-refractory patients (2.1 vs 11.4 months, p=0.001) (Figure D). Patients who were either PI-refractory or IMiD- refractory only had a median PFS of 7.2 months. HR cytogenetics subgroup demonstrated a very short median PFS of 2.2 months (Figure E).

Most commonly observed grade 3/4 adverse events (AEs) were thrombocytopenia (45.1%) and diarrhoea (17.7%). Other any grade AEs included infections (32%), fatigue (21%) and peripheral neuropathy (21%). 25 patients had a baseline ECGs then repeat ECGs during therapy; 2 patients had QTcF prolongations (>60 msec) from baseline, and both had pre-existing heart failure.

AEs led to discontinuation of either Pan or Bor or both in 11.3%, 1.6% and 17.7% of patients respectively. Dose reductions (at least one) of Bor or Pan or both were introduced in 8%, 16.1% and 22.6% of patients respectively. The mean relative dose intensity for Bor and Pan were 67.5% and 64.2%, respectively.

Our cohort is characterised by more heavily pre-treated and refractory myeloma patients compared to participants of PANORAMA-1 trial. Median PFS is consistent with 5.4 months reported in PANORAMA-2 study investigating this combination is Bor-refractory patients. These results are consistent with outcomes observed with pomalidomide and dexamethasone, and with daratumumab monotherapy when used in similar heavily pre-treated cohort. Lower rates of grade 3/4 AEs in this cohort can be explained by dose attenuation compared to the trial cohort.