The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using bortezomib in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see section 10) and the public. This document should be read along with the evidence base (the evaluation report).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using bortezomib in the NHS in England and Wales.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 03 December 2013

Second Appraisal Committee meeting: 4 February 2014

Details of membership of the Appraisal Committee are given in section 9, and a list of the sources of evidence used in the preparation of this document is given in section 10.

 

1 Appraisal Committee’s preliminary recommendations

1.1  Bortezomib in combination with thalidomide and dexamethasone is not recommended within its marketing authorisation, that is, for the induction treatment of adults with previously untreated multiple myeloma for whom high‑dose chemotherapy with haematopoietic stem cell transplantation is suitable.

1.2  The Committee is minded not to recommend bortezomib in combination with dexamethasone within its marketing authorisation, that is, for the induction treatment of adults with previously untreated multiple myeloma for whom high‑dose chemotherapy with haematopoietic stem cell transplantation is suitable.

1.3  The Committee requests the following further information from the manufacturer:

• An indirect comparison between bortezomib in combination with dexamethasone, compared with cyclophosphamide in combination with thalidomide and dexamethasone; and compared with an alternative comparator in circumstances when cyclophosphamide in combination with thalidomide and dexamethasone is not suitable.
  
  In the absence of a network to facilitate a robust comparison, this should be a careful comparison using single arms from relevant clinical trials, taking into account differences in trial design and baseline characteristics. It should include sensitivity analyses using assumptions suggested by the Evidence Review Group:
  
  -    using data from wider sources than the MRC VII trial, including the Alvares and NMSG 5/94 studies, and extrapolation from the trials of bortezomib-containing regimens to inform overall survival in the economic model
  
  -    using post-stem cell transplant response rates from the IFM trial rather than post-induction response rates
  
  -    using transplant rates by response category rather than total stem cell transplant rates.
  
  -    updated costs to reflect the use of a subcutaneous formulation of bortezomib.
• Probabilistic incremental cost-effectiveness ratios for the revised comparisons.

1.4  People currently receiving bortezomib that is not recommended for them in NICE guidance should be able to continue treatment until they and their clinician consider it appropriate to stop.

2  The technology

2.1  Bortezomib (Velcade, Janssen-Cilag) is an anticancer drug that works by reversible proteasome inhibition. By inhibiting proteasomes (multi-enzyme complexes present in all cells), bortezomib interferes with the cell cycle leading to cell death. It is administered by intravenous infusion. Bortezomib has a UK marketing authorisation for use ‘in combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation’.

2.2  The summary of product characteristics lists the following as the most commonly reported adverse reactions for bortezomib: nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  The cost of bortezomib is £762 per 3.5-mg vial (excluding VAT; British National Formulary [BNF] online, May 2013). According to the marketing authorisation bortezomib should be given in combination with dexamethasone (4 cycles of 21 days each) or with dexamethasone and thalidomide (4 cycles of 28 days each; 2 additional cycles of 28 days each for patients with at least partial response after the fourth cycle). Four injections of bortezomib are administered per cycle, on days 1, 4, 8 and 11 of each cycle. The average cost of a course of treatment with bortezomib given with dexamethasone is estimated to be £12,261 and the average cost of a course of treatment with bortezomib given with dexamethasone and thalidomide is estimated to be £24,840. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturer’s submission

The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of bortezomib and a review of this submission by the Evidence Review Group (ERG; section 10).

Clinical effectiveness

3.1  The main clinical evidence submitted by the manufacturer for the bortezomib, thalidomide and dexamethasone regimen came from the PETHEMA trial in which in people with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation received up to 6 cycles of bortezomib, thalidomide and dexamethasone, or thalidomide and dexamethasone. The evidence for the bortezomib and dexamethasone regimen came from the IFM trial which compared 4 cycles of bortezomib and dexamethasone with 4 cycles of vincristine, adriamycin and dexamethasone. The manufacturer also submitted data from the GIMEMA trial which compared the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation followed by consolidation treatment with 2 cycles of either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone. However, the manufacturer highlighted that the PETHEMA trial study design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK and therefore was the focus of the manufacturer’s submission with regard to the bortezomib, thalidomide and dexamethasone regimen. Data from the HOVON trial were provided by the manufacturer, but the bortezomib-containing regimen included in this study, bortezomib, adriamycin and dexamethasone, was considered not approvable by the European Medicines Agency and is therefore not a licensed regimen.

3.2  The PETHEMA trial was a randomised, open-label phase III study that compared the efficacy and safety of bortezomib in combination with thalidomide and dexamethasone with thalidomide and dexamethasone in people with newly diagnosed symptomatic multiple myeloma and measurable disease (serum and/or urine M protein), who were eligible for autologous stem cell transplantation. Patients were randomised to either bortezomib, thalidomide and dexamethasone (n=130) or thalidomide and dexamethasone (n=127), both of which consisted of 6 cycles of 28 days, with each cycle including 4 injections of bortezomib, oral dexamethasone (40 mg on days 1–4 and 8–11 of each cycle) and oral thalidomide (50 mg daily). Post transplantation, patients who continued in the trial were re-randomised to receive 1 of 3 maintenance treatments (interferon alpha-2b, thalidomide, or bortezomib plus thalidomide). Maintenance therapy was continued for up to 3 years, or until disease progression. Although the PETHEMA trial did not incorporate the discontinuation rule as per the summary of product characteristics, because in the GIMEMA trial subjects received only 3 cycles, the manufacturer stated that the PETHEMA trial design better reflected how the bortezomib, thalidomide and dexamethasone regimen is expected to be used in the UK.

3.3  The GIMEMA trial was a randomised, open-label, phase III study in 480 patients in people with newly diagnosed, previously untreated symptomatic multiple myeloma with measurable disease. The study was designed to compare the efficacy and safety of 3 cycles of bortezomib, thalidomide and dexamethasone with 3 cycles of thalidomide and dexamethasone as induction treatment before autologous stem cell transplantation and to evaluate subsequent consolidation treatment consisting of 2 cycles of either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone. Maintenance treatment with dexamethasone was continued until disease progression or relapse. Each cycle of induction therapy consisted of 1.3 mg/m² of bortezomib on days 1, 4, 8 and 11, with 100 mg of thalidomide daily for the first 14 days and 200 mg thereafter. Dexamethasone 40 mg was administered on days 1, 2, 4, 5, 8, 9, 11 and 12. Instead of the dosage recommended in the summary of product characteristics, subjects randomised to the bortezomib, thalidomide and dexamethasone induction group received only 3 cycles of bortezomib-based treatment.

3.4  The IFM trial was a randomised, open-label study designed to compare the efficacy and safety of bortezomib plus dexamethasone (with or without consolidation treatment with dexamethasone, cyclophosphamide, etoposide and cis-platinum) with vincristine, adriamycin and dexamethasone (with or without intensification). Treatment with bortezomib and dexamethasone consisted of 4 21-day cycles of 1.3 mg/m² of bortezomib and 40 mg of dexamethasone. However, the manufacturer stated that only the results without the intensification step were relevant to the decision problem. Moreover, as discussed previously, the manufacturer stated that this comparison was not in line with the decision problem because the vincristine, adriamycin and dexamethasone regimen is not a thalidomide-containing regimen and therefore not an appropriate comparator. The manufacturer also stated that the vincristine, adriamycin and dexamethasone regimen is not routinely used in UK clinical practice and excluded this analysis from its base-case analysis.

3.5  The primary outcome measures in the PETHEMA, GIMEMA and IFM trials were response rates reported after induction and after transplant. The manufacturer’s submission reports ‘response’ in terms of:

• complete response
• near-complete response
• very good partial response (not used in the PETHEMA trial)
• partial response
• progressive disease
• overall response rate.

Overall response rate was calculated as the total proportion of patients who achieved partial response or better. All response rates were evaluated using the European Group of Blood and Bone Marrow Transplant (EBMT) criteria and the International Myeloma Working Group uniform criteria.

3.6  Patients who received bortezomib (bortezomib, thalidomide and dexamethasone) showed a statistically significant difference in overall response rate post induction compared with the thalidomide regimen (thalidomide and dexamethasone) in both the PETHEMA (84.6% compared with 61.4%, p<0.001) and GIMEMA (93.2% compared with 78.6%, p<0.0001) trials. This difference in treatment effect on overall response rate was maintained post transplant (77.7% compared with 56.7%, p<0.001 in the PETHEMA trial and 93.2% compared with 84.5%, p<0.0025 in the GIMEMA trial). Patients receiving bortezomib (bortezomib, thalidomide and dexamethasone) in PETHEMA and GIMEMA also showed statistically higher post-induction and post-transplant complete response rates than those on the thalidomide-containing regimen (thalidomide and dexamethasone). In the PETHEMA trial, 35.4% in the bortezomib, thalidomide and dexamethasone treatment group had a post-induction complete response compared with 13.4% in the thalidomide and dexamethasone group (p<0.001). In the GIMEMA trial 18.6% had a post-induction complete response in the bortezomib, thalidomide and dexamethasone treatment group compared with 4.6% in the thalidomide and dexamethasone group (p<0.0001). In the post-transplant period, statistically significant differences were maintained for the bortezomib, thalidomide and dexamethasone treatment groups in both the PETHEMA and GIMEMA trials (p<0.001 and p=0.0004 respectively). Both the PETHEMA and GIMEMA trials reported a statistically significant lower proportion of patients experiencing disease progression when treated with bortezomib, thalidomide and dexamethasone compared with patients treated with thalidomide and dexamethasone induction therapy in the post-induction period (6.2% and 23.6%, p=0.0004 in the PETHEMA trial; and 0% and 5.0%, p<0.0005 in the GIMEMA trial).

3.7  In the IFM trial, people who received bortezomib in combination with dexamethasone showed a statistically significant difference in overall response rate post induction compared with vincristine, adriamycin and dexamethasone (77.1% compared with 60.7%, p<0.001) but this difference was not maintained after stem cell transplantation (79.6% compared with 74.4%, p=0.179).

3.8  Secondary outcomes reported in the PETHEMA, GIMEMA, IFM and MRC Myeloma IX (described in section 3.10) trials included:

• progression-free survival,
• time to progression
• overall survival
• proportion of patients who underwent stem cell transplantation
• adverse events.

Progression-free survival was measured from the date of randomisation to the date of disease progression or death from any cause, whichever occurred first. Time to progression was calculated from the date of randomisation to the date of disease progression or death due to disease progression. Overall survival was calculated from the date of randomisation to the date of death from any cause for the intention-to-treat populations. The manufacturer reported the unadjusted hazard ratios for progression-free survival for the PETHEMA, GIMEMA and IFM trials. Median follow-up in the trials was 35.9 months (PETHEMA), 36 months (GIMEMA) and 33 months (IFM). Progression-free survival was longer in the bortezomib (bortezomib, thalidomide and dexamethasone) arm of both the PETHEMA and GIMEMA trials than the thalidomide and dexamethasone arm, and the difference was statistically significant (PETHEMA hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.45 to 0.92, p=0.015; GIMEMA HR 0.63, 95% CI 0.45 to 0.88, p=0.0061). Progression-free survival was longer in the bortezomib (bortezomib and dexamethasone) arm of the IFM trials compared with the vincristine, adriamycin and dexamethasone arm, but the difference was not statistically significant (IFM HR 0.88, 95% CI 0.70 to 1.11, p value not reported).

3.9  The manufacturer’s submission reported the median time to progression and time to progression hazard ratios from the PETHEMA and IFM trials. In the PETHEMA study there was a statistically significant lower hazard of progression in patients treated with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (HR 0.64, 95% CI 0.44 to 0.93, p=0.017). No statistically significant difference in median time to progression was reported. In the IFM study there was a numerically lower hazard of progression in patients treated with bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone but this was not statistically significant (HR 0.82, 95% CI 0.63 to 1.06, p value no reported).

3.10  The manufacturer’s submission reported unadjusted overall survival hazard ratios for the PETHEMA and IFM trials. Median overall survival was not reached in either the PETHEMA (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or IFM trials (bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19; p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The manufacturer’s submission highlighted clinical specialist opinion that the duration of the trials were too short to allow differences in overall survival and progression-free survival between treatment groups to be sufficiently captured, given the relatively long survival in this patient population following an autologous stem cell transplant.

3.11  In the absence of head-to-head trials comparing bortezomib-based regimens with cyclophosphamide in combination with thalidomide and dexamethasone, the manufacturer originally presented an indirect comparison based on the PETHEMA, GIMEMA, HOVON, IFM and MRC Myeloma IX randomised controlled trials. The MRC Myeloma IX trial is the only trial that has compared the efficacy of cyclophosphamide, vincristine, doxorubicin (adriamycin) and dexamethasone with cyclophosphamide, thalidomide and dexamethasone in 1111 patients with newly diagnosed symptomatic myeloma. In this trial, patients were randomised to receive induction chemotherapy following either an intensive or non-intensive (attenuated treatment) pathway. The manufacturer considered that the MRC Myeloma IX trial was the only potential evidence that allowed any form of comparison to be made between bortezomib-based regimens and cyclophosphamide, thalidomide and dexamethasone. The bortezomib in combination with adriamycin and dexamethasoneregimen (used in the HOVON trial) was included as part of the evidence submission but the manufacturer considered its inclusion in the indirect comparison to be inappropriate because this regimen was not included in the marketing authorisation. The manufacturer stated that a network could not be formed between the available trials, and an indirect comparison with cyclophosphamide, thalidomide and dexamethasone was not possible. In addition, bortezomib and dexamethasone could not be linked to a thalidomide-containing regimen. The manufacturer highlighted that assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. The manufacturer stated that an incremental analysis of the 2 licensed bortezomib regimens was therefore also not possible and stated that the base case should focus on the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone.

3.12  The manufacturer presented a summary of results for adverse events for the PETHEMA, GIMEMA, IFM and MRC Myeloma IX trials. Only adverse events for the post-induction phase were reported because the adverse events for the post-transplant phase were considered not to be relevant by the manufacturer. Across all trials a similar proportion of patients reported any adverse event, grade 3/4 adverse events, and serious adverse events in both the bortezomib and comparator treatment arms. However, in the PETHEMA trial a statistically significantly greater number of total treatment-related adverse events was reported during induction with bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone (relative risk [RR]=1.42; 95% CI 1.17 to 1.73). In the GIMEMA trial a statistically significantly greater proportion of patients receiving bortezomib, thalidomide and dexamethasone experienced any grade 3/4 adverse event than those receiving thalidomide and dexamethasone (RR=1.69; 95% CI 1.36 to 2.08). The 2 most common treatment-related adverse events in the PETHEMA trial (pneumonia and peripheral neuropathy) occurred more frequently in the bortezomib, thalidomide and dexamethasone arm than in the thalidomide and dexamethasone arm. The manufacturer’s submission highlights that in the 4 bortezomib-based studies, bortezomib was given intravenously. A subcutaneous formulation of bortezomib was recently approved, and the manufacturer claims that use of this is expected to decrease the incidence of peripheral neuropathy. In terms of tolerability, total withdrawals and withdrawals due to disease progression were statistically significantly less in the bortezomib, thalidomide and dexamethasone arm than the thalidomide and dexamethasone arm in the PETHEMA trial (HR 0.51 [95% CI 0.34 to 0.77] and HR 0.45 [95% CI 0.25 to 0.84] respectively).

3.13  No health-related quality of life data were collected in the trials of bortezomib-containing regimens. To inform the cost-effectiveness evidence, the manufacturer conducted a systematic literature search to identify publications relevant to the decision problem in relation to health-related quality of life.

ERG comments

3.14  The ERG stated that the manufacturer’s search strategy was clear and comprehensive. The ERG noted that 5 trials were included in the manufacturer’s original submission, but highlighted that only 2 trials (PETHEMA and GIMEMA) met the NICE scope and focused its critique on these trials. This was in line with the manufacturer’s addendum. The ERG stated that both trials were unblinded and therefore at risk of detection bias. The ERG agreed with the manufacturer that the baseline characteristics were generally similar across the trials. The ERG’s clinical expert commented that the trials are fairly representative of patients in the UK, with the exception of International Staging System (ISS) stage. The proportion of patients with ISS stage III disease in both trials (16–25%) is lower than would be seen in clinical practice, in which around one third of patients have ISS stage III disease. The ERG also noted that patients in the thalidomide and dexamethasone arm of the PETHEMA trial had a slightly worse Eastern Co-operative Oncology Group (ECOG) performance status than patients in the bortezomib, thalidomide and dexamethasone arm. The thalidomide and dexamethasone arm had a higher proportion of patients with an ECOG performance status of 1 (55% thalidomide and dexamethasone vs 44% bortezomib, thalidomide and dexamethasone) and a lower proportion of patients with an ECOG performance status of 0 (32% thalidomide and dexamethasone vs 44% bortezomib, thalidomide and dexamethasone). The ERG also highlighted that the PETHEMA and GIMEMA trials excluded patients over 65 years which is not reflective of UK clinical practice.

3.15  The ERG commented that overall, the manufacturer’s approach to the trial statistics was appropriate and reasonably well reported. However, the ERG commented that long-term outcomes such as progression-free survival and overall survival may be confounded by post-induction consolidation and maintenance treatments that do not reflect current UK clinical practice. The ERG also noted that there is uncertainty in the robustness of the progression-free survival and overall survival results because of the high censoring of data in the bortezomib, thalidomide and dexamethasone and thalidomide and dexamethasone arms of the PETHEMA trial (57.7% and 44.9% respectively in the progression-free survival analysis, and 80.0% and 74.8% respectively in the overall survival analysis).

3.16  The ERG noted that the manufacturer had highlighted that the results from the indirect comparison were subject to substantial uncertainty and were therefore not included in the economic modelling. The ERG agreed with this approach.

Cost effectiveness

3.17  The manufacturer conducted a systematic search of the literature and identified 3 cost-effectiveness studies relevant to the decision problem. The manufacturer conducted a quality assessment of these studies but did not discuss them further in the submission.

3.18  The manufacturer developed an Excel-based economic model to assess the cost effectiveness of bortezomib-based induction regimens compared with thalidomide-based induction regimens. As discussed previously, the manufacturer’s base-case analysis focused on the cost-effectiveness analysis of bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The manufacturer presented cost-effectiveness analyses of bortezomib, thalidomide and dexamethasone (including the discontinuation rule stipulated in the marketing authorisation) compared with thalidomide and dexamethasone, and of bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone. The manufacturer acknowledged that the comparison with vincristine, adriamycin and dexamethasone did not reflect current best clinical practice in the UK. The manufacturer stated that no comparisons of the bortezomib and dexamethasone regimen with relevant thalidomide-containing regimens (such as cyclophosphamide, thalidomide and dexamethasone) were possible using indirect mixed treatment comparisons.

3.19  The manufacturer chose a state-transition Markov model, with a cycle length of 1 month, to reflect the length of a course of treatment with bortezomib, thalidomide and dexamethasone (28 days) and because clinical outcomes are reported in months. The model did not include a half-cycle correction because the cycle length was short relative to the time horizon used in the model. Costs and QALYs were discounted over a lifetime (30 years) time horizon at 3.5% per annum. The manufacturer stated that the model captured the 2 most important outcomes: post-induction response rate and overall survival. However, the manufacturer clarified that because the pivotal trials were not powered to detect a statistically significant difference in overall survival, the model was based on response rate, and the relationship between response rate and overall survival was quantified using long-term survival data from older trials in the same patient population. The model assumed that patients entered at the start of their induction therapy. After induction, patients in the model entered one of 3 health states: complete response, partial response, or non-responders (defined as minimal response, stable disease and progressive disease respectively). Depending on their post-induction response rate, patients subsequently proceeded to high-dose chemotherapy and stem cell transplantation or to the post-induction progression-free survival health state (non-stem cell transplant group). After induction, all patients were assumed to incur the same survival benefit, which is dependent only on their response rate following the induction phase and is independent of the actual induction regimen that they received. On disease progression, patients would then receive a second treatment, followed by third-line and subsequent lines of treatment following further progression.

3.20  Post-induction response rates were used as the main measure of efficacy in the model. Stem cell transplant rates for each response category in each treatment arm were used in the model evaluating bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The economic model for bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone used total stem cell transplant rates rather than transplant rates for each response category. The model also included mortality during the induction and transplant periods.

3.21  In order to model long-term survival based on the post-induction response rates, the manufacturer extracted overall survival data from the MRC VII trial because overall survival data from the PETHEMA trial was considered immature. The MRC VII trial randomised a total of 407 previously untreated multiple myeloma patients to conventional chemotherapy (n=200) or high-dose chemotherapy followed by autologous stem cell transplant (HDT-SCT) (n=201). The 5-year survival in the HDT‑SCT group was 88.6 months (95% CI: 61.4, upper CI not reported) for patients who had a complete response, 39.8 months (95% CI 33.8 to 61.4) for patients who had a partial response, and 25.6 months (95% CI 7.0 to 31.3) for patients who had no response. For a scenario analysis, the manufacturer also used long-term survival data from the IFM90 trial from 1996.

3.22  The manufacturer used post-transplant time to progression from the PETHEMA trial to determine the probabilities of transition from the post-transplant progression-free health state to the start of second-line therapies. The manufacturer assumed that time to progression is affected by the interventions because it is modelled using separate parametric curves by treatment and response category. In the base case, time-to-progression transition probabilities were derived from exponential curves fitted to the PETHEMA data. Constant transition probabilities were used for transition from the second-line to the third-line health state across the 2 interventions, the estimates for which were derived from the subgroups of patients who had 1 or 2 lines of treatment respectively in the APEX trial (which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma). Probabilities of transition from third to further lines of treatment were derived by applying an exponential distribution to the time-to-progression data from the APEX trial. The overall survival data from the MRC VII trial were used to determine the length of time that patients remain in the further lines of treatment health state before moving to the death state.

3.23  The manufacturer conducted a systematic search of the literature to identify publications that identified health-related quality of life data relevant to the decision problem. Five relevant studies were identified, of which 3 reflected the current UK patient population and clinical practice. The manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ-5D. The study by van Agthoven et al. compared chemotherapy (n=129) with intensive chemotherapy followed by myeloablative chemotherapy with stem cell transplantation (n=132) and total body irradiation treatment regimens in patients in the Netherlands and Belgium under the age of 65 years with newly diagnosed and untreated multiple myeloma. Patients received 3 or 4 cycles of VAD and 2 cycles of intermediate-dose melphalan, after which they were randomised to have either stem cell transplantation and interferon maintenance, or interferon maintenance only. With regard to adverse events the manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy.

3.24  The costs applied in the model were taken from the BNF 64 (2012) and the 2012–13 Chemotherapy Regimens List. Administration of chemotherapy drugs, outpatient visits and tests as part of disease and treatment monitoring and the costs relating to stem cell transplantation were taken from the 2011–12 National Schedule Reference costs. The costs associated with treating adverse events were based on inpatient, outpatient or day-case visit National Schedule Reference costs. The manufacturer presented unit costs associated with each of the first-line induction therapies as well as drugs for prophylaxis, administration and monitoring. The total cost, including prophylaxis, administration and monitoring, of the bortezomib, thalidomide and dexamethasone regimen was £28,034 which compared with a total cost of £8,865 for thalidomide and dexamethasone. The total cost of the bortezomib and dexamethasone regimen was £14,104 while the total cost of vincristine, adriamycin and dexamethasone was £2732. The total cost of a stem cell transplant was estimated to be £20,510.72, including mobilisation (£547.68), harvest (£823), ablation (£451.50), transplant (£17,813) and post-transplant (£875.56) costs. For second-line treatment, the weighted average treatment cost (based on 80% of patients receiving bortezomib plus high-dose dexamethasone, 15% receiving cyclophosphamide, thalidomide and dexamethasone and 5% receiving high-dose dexamethasone) was £24,440 for a mean duration of 9.8 months. For third-line treatment, the weighted average treatment cost (based on 75% of patients receiving lenalidomide plus dexamethasone, 20% receiving cyclophosphamide, thalidomide and dexamethasone and 5% receiving high-dose dexamethasone) was £34,271.

3.25  The manufacturer’s economic model estimated a difference in total costs between the bortezomib, thalidomide and dexamethasone and thalidomide and dexamethasone regimens of £20,682, while the bortezomib, thalidomide and dexamethasone regimen was associated with a 1.01 QALY gain compared with thalidomide and dexamethasone. The manufacturer’s estimated base-case incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone was £20,468 per QALY gained. The incremental cost difference between the bortezomib and dexamethasone and vincristine, adriamycin and dexamethasone regimens was £12,710, and bortezomib and dexamethasone was associated with a 0.88 QALY gain resulting in an estimated ICER of £14,446 per QALY gained for the bortezomib and dexamethasone regimen compared with vincristine, adriamycin and dexamethasone.

3.26  The manufacturer’s deterministic sensitivity analyses highlighted that the results are most sensitive to the mortality for patients with complete response after the induction therapy, and to bortezomib, thalidomide and dexamethasone drug costs. If the complete response mortality rate is varied within its 95% confidence interval, other things being equal, the ICER ranges from £17,018 to £28,867 per QALY gained. For the bortezomib, thalidomide and dexamethasone drug costs, sensitivity analyses were conducted using 4, 5 and 6 cycles of induction therapies. This was based on clinical opinion that the number of cycles will vary from one patient to another. The ICER range for the sensitivity analysis varying bortezomib, thalidomide and dexamethasone drug costs was £15,761 to £25,662 per QALY gained. For all other parameters varied in the sensitivity analyses, the ICER remained between £16,000 and £25,000 per QALY gained. Deterministic sensitivity analyses were also presented by the manufacturer for the comparison between the bortezomib and dexamethasone and vincristine, adriamycin and dexamethasone regimens. These sensitivity analyses demonstrated that the results are most sensitive to the mortality for patients with complete response after induction therapy, with ICERs ranging from £10,961 to £18,354 per QALY gained.

3.27  The results of the manufacturer’s probabilistic sensitivity analysis showed that, at ICER thresholds of £20,000 and £30,000 per QALY gained, there was a 35.4% and 71.3% probability, respectively, of the bortezomib, thalidomide and dexamethasone regimen being cost effective when compared with thalidomide and dexamethasone. With respect to the bortezomib and dexamethasone regimen, at the same thresholds, the manufacturer estimated that there was a 68.9% and 83.2% probability, respectively, of the bortezomib and dexamethasone regimen being cost effective compared with vincristine, adriamycin and dexamethasone.

3.28  The ERG stated that the structure of the model was consistent with the clinical pathway of care for multiple myeloma and was clearly presented. However, the ERG highlighted that the manufacturer’s analysis of bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone was outside the scope and also that, given that the comparator in routine use in UK clinical practice is the cyclophosphamide, thalidomide and dexamethasone regimen, the comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone was not entirely relevant to clinical practice.

3.29  The ERG also expressed some concerns that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC VII trial. The ERG cautioned that the MRC VII trial was old and its outcomes may not be reflective of the more advanced treatments available today. Moreover, the ERG stated that data from the MRC VII trial related to maximal response to treatment rather than post-induction response rate, and the resulting survival curves might be confounded to some extent with post-stem cell transplant response. The ERG clinical expert agreed that response rate at induction predicts progression-free survival and overall survival. However, the ERG stated that other surrogate outcomes, such as post-stem cell transplant response rate, may offer a better prediction of progression-free survival and overall survival. The ERG observed that although the model had separate states for those who receive a stem cell transplant and those who do not, the model attaches no explicit survival benefit to a stem cell transplant other than that achieved by delaying the transition to the post-induction/post-transplant progression-free survival state for the duration of the stem cell transplant period. The ERG clinical expert stated that stem cell transplantation offers a survival benefit of 12–18 months compared with no transplant, and the ERG stated that it would have been more transparent to distinguish the separate effects on survival of post-induction response and stem cell transplantation. Alternatively, post-stem cell transplant response rate could have been considered because it has been shown to be statistically significantly associated with improved overall survival. Overall, the ERG stated that external validity would have been strengthened if the model had been based on overall survival and time to progression Kaplan–Meier curves or post-stem cell transplant response, rather than post-induction response. The ERG was concerned that in the absence of this the results were systematically biased in favour of bortezomib, thalidomide and dexamethasone.

3.30  The ERG stated that, in contrast to the manufacturer’s description in the submission, the model implicitly assumed a continuing effect of induction treatment after induction is complete, because separate time to progression curves were used for each induction treatment arm and stem cell transplant mortality was also applied separately by treatment arm. The ERG also highlighted that, contrary to statements in the manufacturer’s submission, the probability of receiving a stem cell transplant is not dependent on post-induction response, but only on treatment received.

3.31  The ERG noted the manufacturer’s approach to calculating transition probabilities (section 3.21), and stated that the exponential distribution fitted to the PETHEMA complete response time to progression data for bortezomib, thalidomide and dexamethasone patients resulted in a shorter median survival time (approximately 61 months) than the exponential distribution fitted to complete response time to progression data for patients receiving thalidomide and dexamethasone (median survival approximately 98 months). The ERG stated that this contrasted with overall findings for progression-free survival in the trial publication in which median progression-free survival was significantly higher with bortezomib, thalidomide and dexamethasone than with thalidomide and dexamethasone. The ERG noted that the manufacturer derived transition probabilities for third and further treatment lines using data from the APEX trial, which compared bortezomib monotherapy with high-dose dexamethasone in patients with relapsed multiple myeloma. The ERG commented that because the APEX trial used bortezomib as a monotherapy treatment, it may have had different survival outcomes to those seen with bortezomib combination therapy.

3.32  The ERG considered that the costs included in the model were reasonable. However, the ERG identified a number of changes to the updated economic model which were not documented in the manufacturer’s addendum. Although the manufacturer’s addendum refers to the original submission for discussion of resource identification, measurement and valuation, the ERG noted that many of the costs in the revised model were different from those in the original model. These include costs for drugs, induction, stem cell transplant, second-line treatment, third-line treatment; and some monitoring costs. The ERG noted that although these changes were generally minor, some were substantial. For example, the administration costs for high-dose dexamethasone increased from £168 to £1242 in second-line therapy, and from £168 to £1288 in third-line therapy. The ERG stated that when considering only model changes and assumptions that are documented in the manufacturer’s addendum, the ICER was £23,958 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, compared with the £20,468 per QALY gained reported in the manufacturer’s addendum.

3.33  The ERG conducted a series of additional exploratory analyses. It considered that the MRC VII trial was old and its outcomes may not be reflective of the more advanced treatments available today (see section 3.29) and noted that the manufacturer’s sensitivity analysis used an even older study (the IFM90). Therefore, the ERG obtained data from a study by Alvares and from the NMSG 5/94 study to conduct scenario analyses. The NMSG 5/94 study was a prospective study with 247 patients recruited between 1994 and 1997, while Alvares was a retrospective study with 383 patients in England diagnosed with multiple myeloma between 1985 and 2004. The ERG considered that the Alvares data provided the better fit to the PETHEMA overall survival data. The ERG commented that because median overall survival for partial and non-responders in the Alvares study was much better than in the MRC VII trial, this resulted in an increase in the base-case ICER from £20,468 per QALY gained to £30,368 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG also provided the ICER using the data from the NMSG 5/94 study, but this did not include the discontinuation rule for the bortezomib, thalidomide and dexamethasone regimen and is therefore not presented. However, it resulted in a higher ICER than using the Alvares study data. The ERG also highlighted that data from the MRC VII trial related to maximal response to treatment rather than post-induction response rate and that this was arguably more similar to post-stem cell transplant response. The ERG commented that post-stem cell transplant response rates provided a more consistent fit to the MRC VII data and would be more predictive of overall survival. Applying post-stem cell transplant response rates alone increased the manufacturer’s base-case ICER from £20,468 to £26,292 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The ERG combined its preferred scenario analyses, that is, using data from Alvares to inform long-term survival and using post-stem cell transplant response rates, and this resulted in an ICER of £38,985 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone.  

3.34  The ERG conducted further exploratory analyses using the relevant economic model outputs from the manufacturer’s base-case cost-effectiveness results to calculate ICERs for all treatments compared with thalidomide and dexamethasone and cyclophosphamide, thalidomide and dexamethasone, the latter of which is a more relevant comparator regimen in a UK population. The ERG commented that all results should be treated with extreme caution as they compare individual arms of separate trials, without adjusting for trial populations. Furthermore there are differences in the trial designs. For these reasons, the results should not be directly compared. Using the manufacturer’s base-case model to make a comparison between bortezomib, thalidomide and dexamethasone and cyclophosphamide, thalidomide and dexamethasone resulted in an exploratory ICER of £228,159 per QALY gained. The ERG then applied its preferred assumptions, that is using data from Alvares to inform long-term survival and using post-stem cell transplant response rates, which resulted in an exploratory ICER for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone of £81,983 per QALY gained. The ERG conducted the same exploratory analyses in order to calculate ICERs for the bortezomib and dexamethasone regimens compared with thalidomide and dexamethasone and with cyclophosphamide, thalidomide and dexamethasone. The ERG applied data from Alvares and used post-stem cell transplant response rates, and this resulted in an ICER of £26,701 per QALY gained for bortezomib and dexamethasone compared with thalidomide and dexamethasone. However, bortezomib and dexamethasone was dominated by (that is, was less effective and more expensive than) cyclophosphamide, thalidomide and dexamethasone.

3.35  Full details of all the evidence are in the manufacturer’s submission and the ERG report.

4  Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence on the nature of multiple myeloma and the value placed on the benefits of bortezomib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1  The Committee noted statements from the clinical specialists and patient experts that multiple myeloma is a complex and incurable disease associated with a range of co-morbidities and complications. It was aware that survival rates were historically poor until the introduction of drugs such as bortezomib, thalidomide and lenalidomide, which improved survival and quality of life. The patient experts highlighted the relapsing and remitting nature of multiple myeloma, emphasising the importance of the availability of a range of treatment options and the flexibility to choose the most appropriate treatment for individual patients because the best induction regimen is chosen based on both disease- and patient-related factors. The clinical specialists commented that, for example, in people with impaired renal function bortezomib might be a preferred option because of a more rapid response; however, thalidomide has the advantage of being administered orally. The clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma facing a high burden of disease, and when thalidomide is not a feasible treatment option because of contraindications. The Committee acknowledged the debilitating nature of the disease and the importance of having a range of treatment options available.

4.2  The Committee discussed the current management of multiple myeloma for people who are newly diagnosed and eligible for high-dose chemotherapy and stem cell transplantation. The Committee heard from clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. It heard from clinical specialists that inthe UK clinicians use biological age, fitness and co-morbidities rather than numerical age to decide eligibility for stem cell transplantation. The Committee noted that around 20–25% of all multiple myeloma patients would be fit enough for high-dose chemotherapy followed by a stem cell transplant. The clinical specialists stated that the aim of induction therapy was to enable more people to proceed to stem cell transplantation successfully. The clinical specialists stated that current standard induction therapy in the UK was the combination of cyclophosphamide, thalidomide and dexamethasone, and that although vincristine, adriamycin and dexamethasone had been used in the past, this regimen is no longer used and this was in line with the guideline from the British Committee for Standards in Haematology (Diagnosis and management of multiple myeloma). The Committee was aware that the manufacturer’s submission included a comparison of bortezomib in combination with dexamethasone (bortezomib and dexamethasone) with vincristine, adriamycin and dexamethasone, and noted that this was not a relevant comparison because it was outside the NICE scope of the appraisal, which specified thalidomide-containing regimens as comparators, and was not in line with UK clinical practice. The Committee was also aware that the manufacturer presented a comparison for bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone, rather than with cyclophosphamide, thalidomide and dexamethasone, assuming clinical equivalence between thalidomide and dexamethasone and cyclophosphamide, thalidomide and dexamethasone. The clinical specialists stated that thalidomide and dexamethasone may be a comparator and the 2 regimens could be considered broadly similar. However, they stated that the advantage of using a triple therapy such as cyclophosphamide, thalidomide and dexamethasone was that there was more flexibility to reduce doses in the case of toxicity. The Committee queried whether thalidomide and dexamethasone is used in UK clinical practice and heard that the cyclophosphamide, thalidomide and dexamethasone regimen is the standard induction treatment in the UK. The Committee concluded that the cyclophosphamide, thalidomide and dexamethasone regimen was the most appropriate comparator for its decision-making.

Clinical effectiveness

4.3  The Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib in combination with adriamycin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness considerations. It noted that the trials included different regimens of bortezomib and had different study designs. The Committee noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles of bortezomib, thalidomide and dexamethasone which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation (intensification therapy to sustain remission prior to lower dose maintenance therapy)  and maintenance treatments used following transplant, and that consolidation and maintenance treatment was not standard in UK clinical practice. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone.

4.4  The Committee discussed the results from the PETHEMA and IFM trials. It noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with a statistically significant gain in overall response rate after induction compared with thalidomide and dexamethasone (bortezomib, thalidomide and dexamethasone 84.6% compared with 61.4%, p<0.001) which was maintained after stem cell transplantation (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, adriamycin and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistically significant difference was not shown after stem cell transplantation (79.6% compared with 74.4%, p=0.179). It noted that progression-free survival was longer in the bortezomib, thalidomide and dexamethasone arm of the PETHEMA trial than in the thalidomide and dexamethasone arm, and that the difference was statistically significant (HR 0.65, 95% CI 0.45 to 0.92, p=0.015). It further noted that progression-free survival was longer in the bortezomib and dexamethasone arm of the IFM trial than in the vincristine, adriamycin and dexamethasone arm, but the difference was not statistically significant (HR 0.88, 95% CI 0.70 to 1.11, p value not reported). The Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, adriamycin and dexamethasone, whereas induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplant) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard of care in the UK and for the Committee’s decision-making.

4.5  The Committee considered the unadjusted overall survival reported in the manufacturer’s submission for the PETHEMA and IFM trials. It noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% CI 0.48 to 1.34, p=0.393) or the IFM trial (bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19; p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. The Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. The clinical specialists also stated that given the differences in trial design relating to the numbers of stem cell transplants and types of maintenance treatment received it was not possible to draw firm conclusions. The Committee concluded that there is uncertainty in the magnitude of overall survival associated with bortezomib.

4.6  The Committee considered the manufacturer’s indirect comparison. It acknowledged the manufacturer’s rationale that a network could not be formed to conduct an indirect comparison between the available trials and that assumptions to overcome the network limitations would generate considerable uncertainties and unreliable results. However, the Committee agreed that it might be possible to conduct further analysis comparing single arms of the available trials, adjusting for the differences between the trial designs and baseline characteristics of the patients included in each study. The Committee concluded that although there would be limitations to this approach, further analysis from the manufacturer would provide useful comparative data to draw conclusions on the relative effectiveness of bortezomib, thalidomide and dexamethasone and bortezomib and dexamethasone compared with the most relevant comparator cyclophosphamide, thalidomide and dexamethasone, or an alternative comparator in situations in which the cyclophosphamide, thalidomide and dexamethasone regimen is considered inappropriate.

4.7  The Committee considered the adverse events associated with using a bortezomib-containing regimen. It heard from clinical specialists that intravenously administered bortezomib had been associated with peripheral neuropathy, but that rapid dose reductions enabled clinicians to effectively manage it. In addition, clinicians highlighted that the introduction of a subcutaneous formulation of bortezomib has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics).

 Cost effectiveness

4.8  The Committee considered the structure, assumptions and results of the manufacturer’s economic model which was based on data from the PETHEMA and IFM trials for the bortezomib, thalidomide and dexamethasone and bortezomib and dexamethasone regimens respectively. The Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone and for bortezomib and dexamethasone with vincristine, adriamycin and dexamethasone, which is not in line with current clinical practice in the UK, and that the vincristine, adriamycin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone but it considered that it was possible to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials.

4.9  The Committee considered the manufacturer’s approach to using post-induction rates from the PETHEMA and IFM trials in the economic model for the bortezomib, thalidomide and dexamethasone and bortezomib and dexamethasone regimens respectively. It noted the ERG’s comments that data from the MRC VII trial used by the manufacturer to estimate long-term survival related to maximal response to treatment rather than post-induction response rate and therefore using post-stem cell transplant response rates from PETHEMA and IFM might offer a better prediction of progression-free survival and overall survival. The clinical specialists stated that post-stem cell transplant response rates would be more appropriate as long as they were based on an intention-to-treat analysis; however, if they were based only on patients who received a transplant, post-induction response rates would be more meaningful. The ERG confirmed that post-stem cell transplant rates in both the PETHEMA and GIMEMA trials were based on an intention-to-treat analysis. The Committee concluded that using post-stem cell transplant response rates rather than post-induction response rates was more appropriate.

4.10  The Committee considered the way in which long-term survival had been extrapolated in the manufacturer’s model. The Committee was aware that that the model extrapolated level of response after induction therapy to long-term survival and time to progression based on data from the MRC VII trial. It noted the ERG’s comments that the MRC VII trial was not very recent because it had recruited patients between 1993 and 2003, and that its rates for overall survival and progression-free survival were likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival endpoints had not been reached in the PETHEMA and IFM trials, the data available in these trials suggested that the manufacturer’s model, using data from MRC VIl, underestimated overall survival. It noted that other data were available (for example, from a study by Alvares and the NMSG 5/94 study) that could be a better fit with the data observed in the PETHEMA and IFM trials. The Committee concluded that the ERG’s exploratory analysis using the data from the study by Alvares was appropriate (see section 3.33) for estimating long-term survival.

4.11  The Committee considered the costs used in the manufacturer’s economic model. It was aware that the clinical trials were all conducted using intravenously administered bortezomib, and it heard from the manufacturer that this was also assumed in the economic model and was therefore associated with a day-patient cost. The Committee was however aware that bortezomib is available as a subcutaneous formulation which is widely used and would therefore only be associated with an outpatient cost. The Committee also noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy in patients and also reduce the need for thromboprophylaxis. The Committee concluded that these issues combined might reduce the total cost of bortezomib in the model. 

4.12  The Committee noted that the manufacturer’s comparison of bortezomib and dexamethasone with vincristine, adriamycin and dexamethasone was outside the NICE scope because the comparator does not contain thalidomide, and in addition, clinical specialists commented that the vincristine, adriamycin and dexamethasone regimen is no longer used as an induction therapy in multiple myeloma in the UK. The Committee considered therefore that it was not appropriate to consider the results from this comparison. However, the Committee also noted that the bortezomib and dexamethasone regimen was far cheaper than the bortezomib, thalidomide and dexamethasone regimen as it did not include thalidomide, and might provide a valuable treatment option, especially for patients who cannot tolerate thalidomide. The clinical specialists stated that the option to use a bortezomib-containing regimen in practice was important and there was no specific preference for bortezomib triple therapy also including thalidomide. The Committee was aware that the ERG’s exploratory analyses also included comparisons of bortezomib and dexamethasone with thalidomide and dexamethasone and bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone. Based on the analyses incorporating the Alvares survival data and post-stem cell transplant response rates that were preferred by the Committee for the bortezomib, thalidomide and dexamethasone analysis, the Committee noted that the ERG’s exploratory ICER for bortezomib and dexamethasone compared with thalidomide and dexamethasone was £26,700 per QALY gained and that in the comparison of bortezomib and dexamethasone with cyclophosphamide, thalidomide and the dexamethasone, bortezomib and dexamethasone regimen was dominated by (that is, it was more costly and less effective than) cyclophosphamide, thalidomide and dexamethasone. Based on the evidence available, the Committee was minded not to recommend bortezomib in combination with dexamethasone as a cost-effective use of NHS resources. However, acknowledging the lack of an appropriate comparison in the manufacturer’s submission and the caveats surrounding the ERG’s exploratory analysis, the Committee considered that it would be relevant to explore the cost effectiveness of the bortezomib and dexamethasone.

The Committee requested further analyses including: 

• An indirect comparison between bortezomib in combination with dexamethasone compared with cyclophosphamide in combination with thalidomide and dexamethasone, and compared with an alternative comparator in circumstances when cyclophosphamide in combination with thalidomide and dexamethasone is not suitable

In the absence of a network to facilitate a robust comparison, this should be a careful comparison using single arms from relevant clinical trials, taking into account differences in trial design and baseline characteristics. It should include sensitivity analyses using assumptions suggested by the ERG:
-     using data from wider sources than the MRC VII trial including the Alvares and NMSG 5/94 studies and extrapolation from the appraisal randomised controlled trials to inform overall survival in the economic model
-     using post-stem cell transplant response rates rather than post-induction response rates
-     using transplant rates by response category rather than total stem cell transplant rates
-     updated costs to reflect the use of a subcutaneous formulation of bortezomib.

• Probabilistic ICERs for the revised comparisons.

4.13  The Committee noted the manufacturer’s comparison of bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone which resulted in a deterministic incremental cost-effectiveness ratio (ICER) of £20,500 per QALY gained and that the manufacturer had not presented probabilistic ICERs. The Committee then discussed the results of the ERG’s exploratory analyses. The Committee noted that using post-stem cell transplant response rates instead of post-induction response rates (see section 4.9) resulted in an ICER of £26,300 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee also noted that using data from the Alvares study instead of the MRC VII study to model long-term survival resulted in an ICER of £30,400 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The clinical specialists raised concerns that the Alvares study was retrospective in design and also quite old and therefore a more recent study would be more appropriate. The ERG confirmed that it had also conducted an analysis based on data from the NMSG 5/94 study and this resulted in a higher ICER. The Committee noted that given the disparity between the overall survival results from the trials and those in the model, using an alternative data source such as Alvares, which was a better fit to the trial data, was appropriate. The Committee noted that incorporating both these changes together resulted in an ICER of £39,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone. The Committee concluded that the ERG’s exploratory analyses were appropriate and that £39,000 per QALY gained was an appropriate starting point for discussion on the most plausible ICER for bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone.

4.14  The Committee was aware that, in the absence of any results compared with cyclophosphamide, thalidomide and dexamethasone, the ERG conducted further exploratory analyses presenting results for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee understood that there were limitations with this approach because the data were drawn from a range of heterogeneous studies containing different comparators and different study designs and therefore could not be directly compared. Moreover, differences in trial design and baseline characteristics had not been taken into account. The Committee noted that this approach resulted in an ICER of £228,200 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone when using the manufacturer’s base-case assumptions. Applying post-stem cell transplant response rates and survival data from the Alvares study suggested an ICER of £82,000 per QALY gained for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone. The Committee agreed that although there was considerable uncertainty associated with such an approach, the most plausible ICER for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone was likely to be higher than the ICER of £39,000 per QALY gained compared with thalidomide and dexamethasone. The Committee concluded that bortezomib in combination with thalidomide and dexamethasone was not considered a cost-effective use of NHS resources.at the Committee meeting.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation		Section
Key conclusion
Bortezomib in combination with thalidomide and dexamethasone is not recommended within its marketing authorisation that is for the induction treatment of adults with previously untreated multiple myeloma for whom high‑dose chemotherapy with haematopoietic stem cell transplantation is suitable. The Committee is minded not to recommend bortezomib in combination with dexamethasone within its marketing authorisation that is for the induction treatment of adults with previously untreated multiple myeloma for whom high dose chemotherapy with haematopoietic stem cell transplantation is suitable. The Committee requests the following further information from the manufacturer: An indirect comparison between bortezomib in combination with dexamethasone, compared with cyclophosphamide in combination with thalidomide and dexamethasone; and compared with an alternative comparator in circumstances when cyclophosphamide in combination with thalidomide and dexamethasone is not suitable. In the absence of a network to facilitate a robust comparison, this should be a careful comparison using single arms from relevant clinical trials, taking into account differences in trial design and baseline characteristics. It should include sensitivity analyses using assumptions suggested by the Evidence Review Group (ERG): -  using data from wider sources than the MRCVII trial including the Alvares and NMSG 5/94 studies and extrapolation from the trials of bortezomib-containing regimens to inform overall survival in the economic model -  using post-stem cell transplant response rates from the IFM trial rather than post-induction response rates -  using transplant rates by response category rather than total stem cell transplant rates. -  Updated costs to reflect the use of a subcutaneous formulation of bortezomib. Probabilistic incremental cost-effectiveness ratios for the revised comparisons.			1.1, 1.2, 1.3
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from clinical specialists that stem cell transplantation is considered the gold standard treatment for multiple myeloma because it is associated with improved progression-free survival, greater depth of response and therefore improved survival. The clinical specialists stated that the aim of induction therapy was to enable more people to proceed to stem cell transplantation successfully.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee agreed that induction treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, adriamycin and dexamethasone, whereas induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplantation) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard of care in the UK and for the Committee’s decision-making.	4.4
What is the position of the treatment in the pathway of care for the condition?		The clinical specialists stated that induction treatment with bortezomib provides an important treatment option for patients with newly diagnosed multiple myeloma facing a high burden of disease, and when thalidomide is not a feasible treatment option because of contraindications.	4.1
Adverse reactions		Clinicians highlighted that the introduction of a subcutaneous formulation of bortezomib has substantially reduced the side effects related to peripheral neuropathy and also reduced the need for thromboprophylaxis. The Committee concluded that the adverse event profile of bortezomib was manageable (for full details of adverse reactions and contraindications, see the summary of product characteristics).	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted that the manufacturer presented evidence on the clinical effectiveness of bortezomib from the PETHEMA, GIMEMA, HOVON and IFM trials. The Committee was aware that the HOVON trial included the bortezomib in combination with adriamycin and dexamethasone regimen, which was not included in the bortezomib marketing authorisation. It therefore excluded it from its clinical and cost-effectiveness considerations. The Committee noted that the trials included different regimens of bortezomib and had different study designs. It noted that in the GIMEMA trial patients only received 3 cycles of bortezomib, thalidomide and dexamethasone whereas in the PETHEMA trial patients received 6 cycles of bortezomib, thalidomide and dexamethasone which was more in line with the marketing authorisation. Moreover, the Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants given and the type of consolidation and maintenance treatments used following transplant, and that consolidation and maintenance treatment was not standard in UK clinical practice. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone.	4.3
Relevance to general clinical practice in the NHS		The Committee noted that the PETHEMA and GIMEMA trials differed in the number of stem cell transplants and the type of consolidation and maintenance treatments used following transplant and that consolidation and maintenance treatment was not standard in UK clinical practice. The Committee was aware that none of the trials included a comparison with cyclophosphamide, thalidomide and dexamethasone. Moreover, the IFM trial included a comparison of bortezomib and dexamethasone with vincristine, adriamycin and dexamethasone, which is no longer used.	4.2, 4.3
Uncertainties generated by the evidence		The Committee concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen  considered to be current standard of care in the UK and for the Committee’s decision-making. The Committee heard from the manufacturer and from the clinical specialists that the duration of the trials was too short to allow differences in overall survival to be seen between treatment groups. It concluded that there was uncertainty in the magnitude of overall survival gain associated with bortezomib	4.4, 4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		None
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that in the PETHEMA trial, bortezomib, thalidomide and dexamethasone was associated with statistically significant gain in overall response rate post-induction compared with thalidomide and dexamethasone (bortezomib, thalidomide and dexamethasone 84.6% compared with 61.4%, p<0.001) which was maintained after stem cell transplant (77.7% compared with 56.7%, p<0.001). The Committee also noted that, in the IFM trial, bortezomib and dexamethasone was associated with a similar gain in overall response rate compared with vincristine, adriamycin, and dexamethasone (77.1% compared with 60.7%, p<0.001) but a statistical difference was not shown after stem cell transplant (79.6% compared with 74.4%, p=0.179). The Committee noted that median overall survival was not reached in either the PETHEMA trial (bortezomib, thalidomide and dexamethasone compared with thalidomide and dexamethasone, hazard ratio 0.80, 95% 0.48 to 1.34, p=0.393) or IFM trial (bortezomib and dexamethasone compared with vincristine, adriamycin and dexamethasone, HR 0.8, 95% CI 0.54 to 1.19; p value not reported) and there was no statistically significant difference in overall survival between the treatment arms in each study. It concluded that there was uncertainty in the magnitude of overall survival gain associated with bortezomib.	4.4, 4.5
For reviews (except rapid reviews): How has the new clinical evidence that has emerged since the original appraisal (TAXXX) influenced the current (preliminary) recommendations?		Not applicable
Evidence for cost effectiveness
Availability and nature of evidence		The Committee was aware that the model only provided comparisons for bortezomib, thalidomide and dexamethasone with thalidomide and dexamethasone and for bortezomib and dexamethasone with vincristine, adriamycin and dexamethasone, which is not in line with current clinical practice in the UK, and that the vincristine, adriamycin and dexamethasone regimen was outside of the scope of this appraisal. The Committee acknowledged that there was no direct evidence available to compare the bortezomib, thalidomide and dexamethasone and bortezomib and dexamethasone regimens with cyclophosphamide, thalidomide and dexamethasone but it considered that it was possible to further explore this by conducting a further indirect comparison using single arms from the relevant clinical trials.	4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that post-stem cell transplant response rates from PETHEMA and IFM may offer a better prediction of progression-free survival and overall survival. The Committee noted the ERG’s comments that the MRC VII trial was not very recent because it recruited patients between 1993 and 2003, and that patient survival rates for overall survival and progression-free survival are likely to be lower than would be seen in current clinical practice. The Committee was also aware that although long-term survival endpoints had not been reached in the PETHEMA and IFM trials, the data that was available in these trials suggested that the manufacturer’s model, using data from MRC VIl, underestimated overall survival.	4.9, 4.10
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The manufacturer selected the van Agthoven study as the base-case source of utility values because the utility values were obtained using EQ-5D. With regard to adverse events the manufacturer applied a disutility of 0.02 to each patient experiencing an adverse event associated with induction therapy. The Committee noted the comments from the clinical specialists that the subcutaneous formulation could reduce the risk of peripheral neuropathy in patients and also reduce the requirement for thromboprophylaxis. The Committee concluded that these issues combined might reduce the total cost of bortezomib in the model.	3.23 4.11
Are there specific groups of people for whom the technology is particularly cost effective?		No
What are the key drivers of cost effectiveness?		The manufacturer’s deterministic sensitivity analyses highlighted that the results are most sensitive to the mortality for patients with complete response after the induction therapy, and to bortezomib, thalidomide and dexamethasone drug costs.	3.26
Most likely cost-effectiveness estimate (given as an ICER)		The Committee agreed that although there was considerable uncertainty associated with the ERG’s approach, the most plausible incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone was likely to be substantially higher than the ICER of £39,000 per quality-adjusted life year (QALY) gained compared with thalidomide and dexamethasone. Based on the analyses incorporating the Alvares survival data and post-stem cell transplant response rates that were preferred by the Committee for the bortezomib, thalidomide and dexamethasone analysis, the Committee noted that the ERG’s exploratory ICER for bortezomib and dexamethasone compared with thalidomide and dexamethasone was £26,700 per QALY gained and that in the comparison of bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, bortezomib and dexamethasone was dominated by (that is, it was more costly and less effective than) cyclophosphamide, thalidomide and dexamethasone.	4.14 4.12
For reviews (except rapid reviews): How has the new cost-effectiveness evidence that has emerged since the original appraisal (TAXXX) influenced the current (preliminary) recommendations?		Not applicable
Additional factors taken into account
Patient access schemes (PPRS)		None submitted
End-of-life considerations		Not applicable
Equalities considerations and social value judgements		No equality issues relevant to the Committees preliminary recommendations were raised

 

5  Implementation

5.1  NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6  Proposed recommendations for further research

6.1  Not applicable. 

7  Related NICE guidance

Details are correct at the time of consultation. Further information is available on the NICE website.

• Bortezomib and thalidomide for the first-line treatment of multiple myeloma. NICE technology appraisal guidance 228 (2011).

8  Proposed date for review of guidance

8.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in November 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
November 2013

9  Appraisal Committee members, guideline representatives and NICE project team

9.1  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Professor Eugene Milne
Vice Chair of Appraisal Committee C, Deputy Regional Director of Public Health, North East Strategic Health Authority, Newcastle upon Tyne

Dr David Black
Medical Director, NHS South Yorkshire and Bassetlaw

Dr Andrew Burnett
Formerly - Director for Health Improvement and Medical Director, NHS Barnet, London

Gail Coster
Advanced Practice Sonographer, Mid Yorkshire Hospitals NHS Trust

Professor Peter Crome
Honorary Professor, Dept of Primary Care and Population Health, University College London

Dr Maria Dyban
General Practitioner, Kings Road Surgery, Cardiff

Dr Greg Fell
Consultant in Public Health, Bradford Metropolitan Borough Council

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Dr Janice Kohler
Senior Lecturer and Consultant in Paediatric Oncology, Southampton University Hospital Trust

Emily Lam
Lay Member

Dr Allyson Lipp
Principal Lecturer, University of South Wales

Dr Grant Maclaine
Formerly - Director, Health Economics & Outcomes Research, BD, Oxford

Dr Andrea Manca
Health Economist and Senior Research Fellow, University of York 

Henry Marsh
Consultant Neurosurgeon, St George's Hospital, London

Dr Paul Miller
Director, Payer Evidence, Astrazeneca UK Ltd

Professor Stephen O’Brien
Professor of Haematology, Newcastle University

Dr Anna O’Neill
Deputy Head of Nursing & Healthcare School/Senior Clinical University Teacher, University of Glasgow

Professor Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Professor Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Dr Tim Stokes
Senior Clinical Lecturer, University of Birmingham

Dr Paul Tappenden
Reader in Health Economic Modelling, School of Health and Related Research, University of Sheffield

Dr Judith Wardle
Lay Member

9.2  NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Christian Griffiths
Technical Lead

Raisa Sidhu
Technical Adviser

Lori Farrar
Project Manager

10  Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Technology Assessment Centre:

• Cooper K, Hartwell D, Copley V et al. Bortezomib for induction therapy in multiple myeloma before high dose chemotherapy and autologous stem cell transplantation: A Single Technology Appraisal. SHTAC. May 2013

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I. Manufacturer/sponsor:

• Janssen

II. Professional/specialist and patient/carer groups:

• Myeloma UK
• South Asian Health Foundation
• British Society of Haematology
• Cancer Research UK
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• UK Myeloma Forum

III. Other consultees:

• Department of Health
• Welsh Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Medicines and Healthcare products Regulatory Agency
• Celgene
• Pfizer
• National Cancer Research Institute
• Southampton Health Technology Assessment Centre (SHTAC)
• National Institute for Health Research Health Technology Assessment Programme
• National Collaborating Centre for Cancer

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on Bortezomib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Jenny Bird, Consultant Haematologist, nominated by Royal College of Pathologists and British Society of Haematology – clinical specialist
• Professor Kwee Yong, Consultant Haematologist, nominated by UK Myeloma Forum, Royal College of Pathologists and British Society of Haematology – clinical specialist
• Eric Low, Chief Executive, nominated by UK Myeloma Forum – patient expert
• Stuart Fullerton, nominated by UK Myeloma Forum – patient expert

D. Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Janssen