Panobinostat for treating multiple myeloma after at least 2 previous treatments

Clinical need and practice

4.1 The Committee considered the current pathway for people with multiple myeloma. It heard from the clinical experts that the pathway of treatment is heterogeneous and people could have either thalidomide or bortezomib, plus an alkylating agent (for example melphalan or chlorambucil) and a corticosteroid (for example dexamethasone), as first‑line treatment as recommended in NICE technology appraisal guidance on bortezomib and thalidomide for the first‑line treatment of multiple myeloma. This may be followed by bortezomib and then lenalidomide (see NICE technology appraisal guidance on bortezomib for relapsed multiple myeloma and lenalidomide as a subsequent treatment for people who have received at least 2 previous treatments). The Committee also heard from the clinical experts that almost all patients have bortezomib by subcutaneous rather than intravenous administration, even though recommendations in the current British Committee for Standards in Haematology guideline for the diagnosis and management of multiple myeloma (2014) suggest either can be used. The Committee considered that treatment with an immunomodulatory agent and bortezomib was established practice in the NHS and that bortezomib was most often administered to patients subcutaneously. The Committee also heard from the clinical experts that panobinostat plus bortezomib and dexamethasone would likely fit in the treatment pathway at the same point as lenalidomide plus dexamethasone (that is, after bortezomib and dexamethasone), and so the Committee considered that lenalidomide plus dexamethasone was the most appropriate comparator to panobinostat plus bortezomib and dexamethasone in this appraisal.

4.2 The Committee heard from patient experts about the nature of multiple myeloma and their experiences of treatment. It heard that multiple myeloma is a life‑long condition that has a serious effect on quality of life. It can develop at a young age, and affects all aspects of life including education, work, self‑care, and social and family life. The Committee heard from the patient experts that desired treatment outcomes are about both survival and quality of life. It also heard that people can be anxious about relapsing because few treatment options are available if they do, and that people consider a range of treatments to be important because they have different experiences with different treatments. The Committee heard from the clinical and patient experts that the multiple myeloma population is heterogeneous and has life‑long disease, so there may be a place in the treatment pathway for another therapy with a different mechanism of action. The Committee also heard from the clinical and patient experts that there is a clinical need for alternative treatments for multiple myeloma in people who have had at least 2 previous treatments including an immunomodulatory agent and bortezomib. The Committee recognised the importance of having effective and tolerable treatment options for people with multiple myeloma who have had at least 2 previous treatments.

Clinical effectiveness

4.3 The Committee considered the evidence presented by the company on the clinical effectiveness of panobinostat. It noted that the main source of evidence was the PANORAMA‑1 trial, which compared panobinostat plus bortezomib and dexamethasone with placebo plus bortezomib and dexamethasone in patients who had relapsed or relapsed and refractory multiple myeloma and had received 1–3 previous treatments (see sections 3.1 and 3.2). The Committee noted that the trial was well conducted and showed that progression‑free survival was statistically significantly greater for the panobinostat plus bortezomib and dexamethasone group than for the placebo plus bortezomib and dexamethasone group. The Committee considered the generalisability of the PANORAMA‑1 trial to UK clinical practice. It noted that, compared with clinical practice, the population in the trial was generally younger, a greater number of patients in the trial had a previous stem cell transplant, and bortezomib was prescribed for longer (up to 12 cycles in the trial rather than 8 used in established practice in the NHS). The Committee also noted that only a subset of the trial population matched the population for which panobinostat had received a marketing authorisation (that is, people with relapsed and refractory multiple myeloma who have had at least 2 treatments including an immunomodulatory treatment and bortezomib). It noted that this subgroup analysis was not pre‑specified in the trial. It further noted that the marketing authorisation for panobinostat was for the subgroup and not for the full population in the PANORAMA‑1 trial. Nevertheless, the Committee accepted that the results from the PANORAMA‑1 trial used in the post hoc subgroup analysis demonstrated that panobinostat plus bortezomib and dexamethasone was clinically more effective than bortezomib plus dexamethasone based on the PANORAMA‑1 trial interim and final overall survival data. The Committee concluded that the subgroup results were relevant and generalisable to patients who have had at least 2 previous treatments in established practice in the NHS and considered that panobinostat plus bortezomib and dexamethasone was clinically effective.

4.4 The Committee noted that there were no direct head‑to‑head trials comparing panobinostat plus bortezomib and dexamethasone with lenalidomide plus dexamethasone and therefore an indirect comparison would be needed. The Committee considered the comparators in the indirect comparison and the indirect methods used by the company. The Committee heard from the clinical experts that comparing the lenalidomide trials MM‑009 and MM‑010 with the PANORAMA‑1 trial was difficult because the baseline characteristics of the patients were very different. The clinical experts commented that MM‑009 and MM‑010 took place when fewer and less effective treatment options were available, making a comparison based on previous lines of treatment unreliable. The Committee considered the company's matching adjusted indirect comparison of panobinostat plus bortezomib and dexamethasone with lenalidomide plus dexamethasone, one of the comparators in the NICE scope and included in the company's submission (see section 3.6). It heard from the ERG that the methods used to identify both published and unpublished studies for the network meta‑analysis were appropriate, and the studies were mostly well reported. The Committee understood that the company had incorporated a population into the comparison who had received 2 or 3 previous treatments but not necessarily bortezomib and an immunomodulatory drug. It heard from the company that the matched patients taken from the PANORAMA‑1 trial and the MM‑009 and MM‑010 trials were based on baseline prognostic factors which predict survival. The company explained that it considered time since diagnosis, number of previous treatments, beta‑2‑microgobulin levels and International Staging System (ISS) stage to be significant predictors of survival. The company also explained that ISS data were not reported in the 2 to 3 previous treatment subgroup analysis of the MM‑009 and MM‑010 trials. The Committee heard from the company that adjusting for a limited number of patient characteristics avoids smaller sample sizes, which would reduce the statistical power of the analyses. The Committee was aware that there were other baseline characteristics in both the PANORAMA‑1 and MM‑009 and MM‑010 trials that could have been adjusted for, and that further adjustments to these baseline characteristics might have increased the robustness of the analysis. The Committee was also aware that the matching adjusted indirect comparison was done in a population who had received 2 to 3 previous treatments but not necessarily bortezomib and an immunomodulatory agent, so was not consistent with the population in the marketing authorisation for panobinostat plus bortezomib and dexamethasone. The Committee noted the limitations of the company's comparison but accepted that the hazard ratio results suggested that panobinostat plus bortezomib and dexamethasone had a similar level of clinical effectiveness to lenalidomide plus dexamethasone.

4.5 The Committee considered the adverse event profile associated with panobinostat in the PANORAMA‑1 trial. It noted that diarrhoea was the most common adverse event in the trial, and was more frequent in the panobinostat plus bortezomib and dexamethasone group than in the bortezomib and dexamethasone group in treatment phases 1 and 2. It also noted that frequently observed adverse events with panobinostat included thrombocytopenia, anaemia, fatigue and nausea. The Committee noted consultee statements from a patient and carer group which highlighted patients' concerns that some of the adverse events may lead to increased hospitalisation, but it was also aware that clinical experts considered it possible to adequately manage the adverse events. The Committee was also aware that the rates of discontinuation because of adverse events and on‑treatment deaths with panobinostat plus bortezomib and dexamethasone were within the ranges reported for lenalidomide plus bortezomib, but were higher than in the bortezomib plus dexamethasone group in the trial (36% compared with 20%). The Committee concluded that although there were some adverse events associated with panobinostat plus bortezomib and dexamethasone treatment, they were manageable in clinical practice.

Cost effectiveness

4.6 The Committee considered the company's new models and cost‑effective analyses which were submitted as a response to the appraisal consultation document (see sections 3.24 to 3.27) and the ERG's critique (see sections 3.28 to 3.33). These concerned the main comparison of panobinostat plus bortezomib and dexamethasone compared with lenalidomide plus dexamethasone, and the additional comparison of panobinostat plus bortezomib and dexamethasone compared with bortezomib plus dexamethasone.

4.7 The Committee considered the comparison with bortezomib plus dexamethasone. It recalled that the PANORAMA‑1 trial provided trial data for this comparison in the population included in the marketing authorisation for panobinostat. However, the Committee considered that this analysis was not needed for its decision‑making because the company had provided a new indirect comparison (see section 4.8) with the relevant comparator (lenalidomide plus dexamethasone). The Committee therefore considered that bortezomib plus dexamethasone was not the appropriate comparator and agreed not to consider this comparison further. The Committee agreed that the new cost‑effectiveness analyses provided by the company for the comparison of panobinostat plus bortezomib and dexamethasone with lenalidomide plus dexamethasone were relevant to its decision‑making.

4.8 The Committee considered how the company applied time‑dependent hazard ratios for progression‑free survival and overall survival from the matching adjusted indirect treatment comparison in the new evidence for the comparison of panobinostat plus bortezomib and dexamethasone with lenalidomide. The Committee noted that the company had fitted curves to the data but based only on the prognostic factors that predict survival (see section 4.4). The Committee considered that this was preferable to using a single model with the caveat that the company had used a Weibull distribution for extrapolating the progression‑free survival data without also exploring exponential distribution. Nevertheless, the Committee concluded that the use of time‑dependent hazard ratios based on the matching adjusted indirect comparison was acceptable in its decision‑making.

4.9 The Committee discussed how health‑related quality of life was incorporated into the economic model, noting that the company had measured health‑related quality of life in the PANORAMA‑1 trial using the EORTC QLQ‑C30 questionnaire, MM‑specific module and EORTC‑MY20 and mapped it onto the EQ‑5D to provide utility values for the pre‑progression with panobinostat treatment health state. The Committee noted that EQ‑5D data were not available for lenalidomide plus dexamethasone and that the company used 2 scenarios for the utility value for pre‑progression patients having lenalidomide (see section 3.16), but that both of these estimates were conservative and favoured lenalidomide. The Committee noted that the utility value for pre‑progression no treatment was taken from Acaster et al. and was higher than pre‑progression with treatment, but considered this to be an acceptable assumption because patients in this health state would not experience adverse events (because they are assumed to have no treatment). The Committee also noted that disutilities had not been incorporated in the model. However, because health‑related quality of life data were collected in the PANORAMA‑1 trial, these values would have included chronic adverse events. The Committee concluded that the utility values used by the company were appropriate.

4.10 The Committee discussed the costs included in the model, particularly the administration costs of bortezomib. The Committee heard from the clinical experts that almost all patients have bortezomib by subcutaneous administration (see section 4.1) and so it concluded this to be the most appropriate bortezomib cost to be included in the model.

4.11 The Committee questioned the face validity of both the calculated quality‑adjusted life year (QALY) gains and the calculated cost differences. It noted that the QALY advantage for panobinostat occurred after treatment discontinuation. It heard from the company that people in the panobinostat group of the PANORAMA‑1 trial remained progression‑free without treatment for a longer period than in the bortezomib comparator group. The Committee also noted that the costs in the post‑progression health state were lower for panobinostat plus bortezomib and dexamethasone than for lenalidomide plus dexamethasone, even though panobinostat was an additional component to the comparator regimen. The company explained that the post‑progression state analyses took into account the different percentage of people who had subsequent treatment in the PANORAMA‑1 trial. The company further explained that the subsequent treatments provided in the trial were not all standard treatments in clinical practice in the UK and therefore it adjusted the treatments to reflect clinical practice in the UK. The company highlighted that because subsequent treatment data had not been published for lenalidomide plus dexamethasone, it assumed that patients in this comparator group received the subsequent treatments in similar proportions to those reported for panobinostat plus bortezomib and dexamethasone. The Committee was aware that in its new analyses, the company had removed the costs of subsequent treatment but did not adjust the clinical effectiveness, causing a mismatch between the total costs and efficacy of panobinostat. However, the Committee heard from the company that it considered the analysis to be a conservative estimate for panobinostat because the previous treatment received in the lenalidomide trials would have been different. The Committee noted that the company's view was consistent with the clinical experts (see section 4.4). The Committee concluded that it wasn't clear which subsequent treatments and costs had been included by the company and that there was potential bias in assuming the costs of UK‑specific treatments but using the efficacy of the subsequent treatments in the PANORAMA‑1 trial.

4.12 The Committee considered the company's new cost‑effectiveness analyses for panobinostat plus bortezomib and dexamethasone compared with lenalidomide plus dexamethasone. Considering all of the new evidence available for this comparison, which included the updated patient access scheme (see section 3.24),the Committee agreed that the ICER was likely to be no higher than £25,000 per QALY gained and therefore within the range that would normally be considered a cost‑effective use of NHS resources (£20,000 to £30,000 per QALY gained). The Committee concluded that it could, therefore, recommend panobinostat plus bortezomib and dexamethasone as a treatment option for adult patients with relapsed and/or refractory multiple myeloma who have received at least 2 prior treatment regimens including bortezomib and an immunomodulatory agent.

4.13 The Committee discussed whether panobinostat could be considered innovative. It heard from the clinical and patient experts that panobinostat may provide an additional treatment option for patients because of its different mode of action to existing treatments. However, given its previous conclusion on clinical efficacy (see section 4.3 and 4.4), the Committee considered that panobinostat was not a step‑change in treatment. The Committee concluded that there were no additional gains in health‑related quality of life over those already included in the QALY calculations, and that there was no need to change its conclusions on that basis.

4.14 The Committee considered whether it should take into account the consequences of the 2014 Pharmaceutical Price Regulation Scheme (PPRS), and in particular the PPRS Payment Mechanism, when appraising panobinostat. The Committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS Payment Mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there was any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of panobinostat. It therefore concluded that the PPRS Payment Mechanism was not applicable for the consideration of the cost effectiveness of panobinostat plus bortezomib and dexamethasone.

Summary of Appraisal Committee's key conclusions