Abstract
Background: In the phase 3, randomized, international, double-blind PANORAMA 1 trial, panobinostat in combination with bortezomib and dexamethasone (PAN+BTZ+DEX, n=387) demonstrated superior progression-free survival (PFS, HR=0.63, 95% confidence interval [CI]: 0.52-0.76) over placebo+BTZ+DEX (n=381) in patients with relapsed or relapsed and refractory multiple myeloma (RR MM). PAN+BTZ+DEX produced a larger PFS benefit over BTZ+DEX in patients who had been previously treated with both an immunomodulatory drug (IMID) and a bortezomib-containing regimen and had at least 2 prior lines of treatments (prior IMID+BTZ+2LOT subgroup, PAN+BTZ+DEX: n=73, BTZ+DEX: n=74, HR=0.47, HR=0.47, 95% CI: 0.32-0.72). While the trial results support that PAN+BTZ+DEX is a valuable addition to the current treatment options for RR MM, toxicity of the triplet regimen of PAN+BTZ+DEX was of some concern. To assess the impact of PAN+BTZ+DEX versus BTZ+DEX on quality of life, the European Organization for Research and Treatment of Cancer's core questionnaire (EORTC QLQ-C30) were administered to non-progressing patients. However, the EORTC QLQ-C30 measure does not generate health state utility information which is key for health economic evaluations and reimbursement decision making. Therefore the aim of the present study was to derive PANORAMA-1 patient-level utilities using a published mapping algorithm between the EORTC and the EuroQol EQ-5D utility measure.
Methods: A targeted literature review was conducted in PubMed and in the University of Oxford Health Economics Research Centre (HERC) utility mapping database to identify an appropriate algorithm in rrMM that could be used to map the EORTC measure into EQ-5D utilities. The HERC mapping database lists published studies assessing mapping algorithms that estimate EQ-5D utilities from other quality of life measures and report the algorithm in sufficient detail. Using such mapping algorithm, each valid measurement of the EORTC measure for every PANORAMA-1 trial patient was converted into EQ-5D utility. The mean and median utility values were estimated for both treatment arms. Separate analyses were performed using the intent-to-treat (ITT) population and the prior IMID+BTZ+2LOT subpopulation.
Results: Four studies were identified that reported on mapping algorithms from EORTC QLQ-C30 to EQ-5D using multiple myeloma patient populations. Of these, one mapping algorithm was based on relapsed patients. The algorithm was derived using a multiple linear regression analysis (n=154, R2 =0.69).
At screening, the mean and median mapped utility estimates for the whole trial population (n=686) were 0.721 (standard deviation [sd]=0.201) and 0.768, respectively. Taking into account all measurements, the mean and median utility estimates were 0.702 (sd=0.190) and 0.724 for PAN+BTZ+DEX (n=1579), whereas the corresponding measures were 0.727 (sd=0.193) and 0.757 (n=1676), respectively, for BTZ+DEX. In the prior IMID+BTZ+2LOT subpopulation, at screening, the mean and median mapped utility estimates (n=124) were 0.709 (sd=0.201) and 0.752, respectively. Using all measurements, the mean and median utility estimates were 0.679 (sd=0.182) and 0.696 for PAN+BTZ+DEX (n=374), while 0.716 (sd=0.201) and 0.747 (n=357), respectively, for BTZ+DEX. The mean of the mapped utility values are plotted in Figure 1.
Discussion: The mean values were slightly lower for the triplet of PAN+BTZ+DEX than for the doublet of BTZ+DEX, but the difference was not considered to be clinically relevant. The difference in mean utility was -0.025 (ITT population) and -0.037 (prior IMID+BTZ+2LOT population), respectively. Higher health state utility is expected for the off-treatment period since patents off-treatment do not experience the adverse events associated with active treatment. This study provides health utility data in the absence of direct trial based preference information. The presented health utility data can be used as input parameters for economic evaluations that compare the treatment benefit of PAN+BTZ+DEX with BTZ+DEX in terms of quality-adjusted life expectancy. Future directions for the combination include strategies aimed at reducing toxicity and the development of other novel agent combinations with PAN to further improve patient outcome.
Results of the utility mapping (all measurements)
Majer:Novartis: Consultancy. Krishna:Novartis: Employment. van de Wetering:Novartis: Consultancy. San-Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.
