The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using bortezomib and thalidomide for the first-line treatment of multiple myeloma in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted 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 appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

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 gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on these technologies. 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 and thalidomide for the first-line treatment of multiple myeloma in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk)

The key dates for this appraisal are:

Closing date for comments: 23 June 2010

Second Appraisal Committee meeting: 8 July 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

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

1 Appraisal Committee’s preliminary recommendations

1.1  Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.

1.2  Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom:

• high-dose chemotherapy with stem cell transplantation is considered inappropriate and
• the person is unable to tolerate or has contraindications to thalidomide.

2  Clinical need and practice

2.1 Multiple myeloma is a cancer of a type of white blood cell (plasma cell) in the bone marrow. In people with multiple myeloma, a single plasma cell becomes cancerous to form a myeloma cell, which begins to multiply. These abnormal plasma cells, or myeloma cells, build up in the bone marrow, reducing the space available for making normal white cells, red cells and platelets. Normal blood cells are responsible for fighting infections, carrying oxygen around the body and blood clotting. Myeloma cells produce large amounts of one type of abnormal antibody, which does not work properly

2.2 Multiple myeloma is the second most common haematological cancer in the UK. In England and Wales there are approximately 3600 new diagnoses recorded annually. In 2007 most diagnoses were recorded in people aged 75–79 years. Multiple myeloma is about 1.5 times as common in men as in women, and twice as common in people of African or Caribbean descent. In the UK, the estimated lifetime risk of developing multiple myeloma is 1 in 148 for men and 1 in 186 for women. There are currently between 10,000 and 15,000 people living with multiple myeloma in the UK.

2.3  Multiple myeloma remains an incurable disease, with an average survival of 4–6 years, but it can be treated with a combination of supportive measures and chemotherapy. The aim of treatment is to extend the length and quality of life by alleviating symptoms, controlling disease and minimising adverse effects. Survival after diagnosis can vary from months to more than 10 years. Factors affecting survival and outcome include burden of disease, type of cytogenetic abnormality, age and performance status, and response to treatment.

2.4 First-line therapy is for treatment naïve patients. In England and Wales the choice of first-line treatment depends on a combination of factors. Most people with multiple myeloma are not able to withstand intensive treatment, such as high-dose chemotherapy with stem cell transplantation, because of their age, specific problems or poor performance status. These people are offered single-agent or combination chemotherapy, which is less intensive. Typically combination therapies include chemotherapy with an alkylating agent (such as melphalan or cyclophosphamide) and a corticosteroid (such as prednisolone or dexamethasone). More recent treatment options include drugs such as thalidomide and bortezomib. The main objective of first-line therapy is to achieve a period of stable disease (termed the plateau phase) for as long as possible, thereby prolonging survival and maximising quality of life. After initial treatment, most people usually experience a period of remission, but almost all relapse eventually, and some have disease that does not respond (is refractory) to treatment.

3 The technologies

Bortezomib

3.1  Bortezomib (Velcade, Janssen-Cilag) is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells.

3.2 Bortezomib in combination with melphalan and prednisone is licensed for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib is administered as an intravenous injection. The recommended starting dose of bortezomib is 1.3 mg/m² body surface area twice weekly for 2 weeks (days 1, 4, 8 and 11) followed by a 10-day rest period (days 12–21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses. It is recommended that patients with a confirmed complete response receive two additional cycles beyond a confirmation. The summary of product characteristics (SPC) also recommends that ‘responding patients who do not achieve a complete remission’ receive a total of eight cycles of bortezomib therapy.

3.3  Bortezomib treatment is associated with peripheral neuropathy, thrombocytopenia, gastrointestinal effects (diarrhoea, nausea, vomiting and constipation) and other side effects. For full details of side effects and contraindications, see the SPC.

3.4 The cost for a 3.5-mg vial of bortezomib is £762.38 (British national formulary [BNF] edition 59). Costs may vary in different settings because of negotiated procurement discounts.

Thalidomide

3.5 Thalidomide (Thalidomide Celgene, Celgene) is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action.

3.6 Thalidomide in combination with melphalan and prednisone is licensed ‘as first-line treatment of patients with untreated multiple myeloma, aged ≥ 65 years or ineligible for high dose chemotherapy’. The recommended dose is 200 mg daily, taken orally. A maximum number of 12 cycles of 6 weeks should be used. Thalidomide is prescribed and dispensed according to the Thalidomide Pharmion Pregnancy Prevention Programme.

3.7 Thalidomide treatment is associated with thromboembolic events, peripheral neuropathy, rash/skin reactions, bradycardia, syncope and somnolence. For full details of side effects and contraindications, see the SPC.

3.8 The cost for a 28-capsule pack of 50-mg thalidomide capsules is £298.48 (BNF edition 59). Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness

4.1.1 The remit of the scope allowed bortezomib and thalidomide to be appraised outside their respective marketing authorisations. For thalidomide this meant appraisal of evidence from the UK-wide, MRC-sponsored Multiple Myeloma IX (MMIX) trial. However for bortezomib there was no evidence base for its use outside its marketing authorisation. The following treatment strategies were investigated:

• thalidomide, melphalan and prednisolone/prednisone (MPT)
• thalidomide, cyclosphosphamide and attenuated dexamethasone (CTDa)
• bortezomib, melphalan and prednisolone/prednisone (VMP).

Each was compared with melphalan/cyclosphosphamide plus prednisolone/prednisone/dexamethasone.

The Assessment Group and manufacturers identified evidence on the clinical effectiveness of bortezomib and thalidomide against the relevant comparators within the licensed indications for each drug, and according to the appraisal scope.

Melphalan and prednisolone/prednisone plus thalidomide (MPT) versus melphalan plus prednisolone/prednisone (MP)

4.1.2 The Assessment Group identified three randomised controlled trial (RCTs) (Intergroupe Francophone du Myélome [IFM] 99/06, IFM 01/01 and GIMEMA) that compared MPT with MP. The numbers of participants recruited to the studies were 447, 232 and 331 respectively. The two IFM studies differed in the target age range of participants: IFM 01/01 included people aged at least 75 years, whereas IFM 99/06 mainly included people aged between 65 and 75 years, with younger people being eligible for inclusion providing they were not eligible for high-dose chemotherapy. The GIMEMA study included people older than 65 years without specifying any upper age limit, but also included participants younger than 65 years providing they were unable to undergo high-dose chemotherapy with stem cell transplantation. The quality of the RCTs was variable. The quality of some was difficult to determine because details needed for quality assessment were incompletely reported. The intention-to treat analyses and the methods used to account for missing data were in general poorly described. 

4.1.3 Overall survival was the primary outcome for IFM 99/06 and IFM 01/01. The secondary outcomes of these studies included response rates, progression-free survival and adverse events. The primary outcome measures for the GIMEMA study were response rates and progression-free survival. The secondary outcomes included overall survival and adverse events.

4.1.4 IFM 99/06 and IFM 01/01 reported a statistically significant advantage in the MPT group in comparison with the MP group for progression-free survival (p=0.001). The IFM 99/06 study reported median progression-free survival of 27.5 months (SE 2.1) for MPT group compared with 17.8 months (SE 1.4) for the MP group at a median followup of 51.5 months. IFM 01/01 study reported median progression-free survival of 24.1 months (95% confidence intervals [CI] 19.4 to 29.0) for the MPT group compared with 18.5 months (95% CI 0.39 to 0.66) for the MP group after a median follow up of 47.5 months. Meta-analysis of the data on progression-free survival confirmed that MPT was superior to MP for this outcome. The hazard ratio for progression-free survival from the meta-analysis was 0.56 (95% CI 0.46 to 0.67) in favour of MPT. The meta-analysis suggested that there was little or no heterogeneity between the two trials for this outcome.

4.1.5 The GIMEMA study included maintenance therapy with thalidomide after first-line treatment and therefore overall survival, which was a secondary outcome in this study, was not eligible for inclusion in the Assessment Group’s systematic review. IFM 99/06 and IFM 01/01 reported a statistically significant difference in overall survival in favour of the group receiving MPT. IFM 99/06 study reported median survival of 51.6 (Inter-quartile range [IQR] 26.6 to not reached) months for the MPT group compared with 33.2 (IQR 13.8 to 54.8) months for the MP group after median follow up of 51.5 months. IFM 01/01 study found that the median survival of 44 months (95% CI 33.4 to 58.7) in the group receiving MPT compared with 29.1 months (95% CI 26.4 to 34.9) in the group receiving MP. The meta-analysis of the data on overall survival from the two studies confirmed the superiority of MPT over MP. The hazard ratio (HR) for overall survival from the meta-analysis was 0.62 (95% CI 0.50 to 0.77) and showed that there was little or no heterogeneity between the three trials for this outcome.

4.1.6 Response to treatment was a primary outcome of the GIMEMA study (at 6 months) and a secondary outcome in IFM 99/06 and IFM 01/01. At 6 months more participants in the MPT group had a complete response or a partial response or better (according to European Group for Blood and Marrow Transplantation [EBMT]). At 12 months, IFM 99/06 and IFM 01/01 reported that a statistically significantly greater proportion of participants had a complete response or at least a partial response. Complete response outcomes from the three studies were combined by meta-analysis, and this confirmed that MPT was superior to MP in terms of the proportion of patients achieving a complete response (relative risk [RR] 5.49, 95% CI 2.55 to 11.38).

4.1.7 Adverse events were difficult to summarise across the three studies because they were reported differently. Because the GIMEMA study included maintenance therapy with thalidomide, few data on adverse events from this study could be included in the Assessment Group’s systematic review. Adverse events that occurred statistically significantly more often in the MPT arms of IFM 99/06 and IFM 01/01 included neutropenia and peripheral neuropathy. The IFM 99/06 study found that non-haematological adverse events of grade 3 or more were statistically significantly more likely in the MPT group (p < 0.0001). For thrombosis or embolism, somnolence, constipation and infections, the results were inconsistent between IFM 99/06 and IFM 01/01, with no significant difference in incidence in the IFM 01/01 study and statistically significantly more of these events in the MPT group in the IFM 99/06 study. This inconsistency may be a result of the different methods of reporting adverse events.

4.1.8 The IFM 99/06 and IFM 01/01studies provided data on second-line treatment that could be included in the Assessment Group’s systematic review. In the IFM 99/06 study second-line treatment was administered to 65% of the MP group compared with 44% in the MPT group. The IFM 01/01study reported disease progression occurrence in 156 participants overall, with more participants with disease progression in the MP group than the MPT (72% versus 64%). Second-line treatment was administered to a similar proportion of participants with disease progression in each arm. In both RCTs thalidomide (alone or in combination) was the most commonly administered second-line treatment in the MP group, with about a fifth of participants in the MPT groups of these RCTs receiving thalidomide again as second-line therapy. The most commonly administered second-line treatment in the MPT group reported in the IFM 99/06 study was a combination of vincristine, doxorubicin, and dexamethasone (VAD). Only 13% of participants in the MPT group received bortezomib. In contrast, IFM 01/01 reported that 31% of participants in the MPT group received bortezomib as a second-line treatment. As the GIMEMA study included maintenance therapy with thalidomide after first-line treatment, data on second-line treatment was not eligible for inclusion in the Assessment Group’s systematic review.

Cyclophosphamide, thalidomide plus attenuated dexamethasone (CTDa) versus melphalan plus prednisolone/prednisone (MP)

4.1.9 The Assessment Group identified one ongoing RCT, the UK Multiple Myeloma IX (MMIX) trial, which compared CTDa with MP. People were eligible to participate if they had newly diagnosed symptomatic or non-secretory multiple myeloma and had not received previous treatment for myeloma (other than local radiotherapy). The non-intensive pathway of the MMIX study was designed for older (generally 70 years of age or older) or less fit participants (who could be younger than 70), but strict age restrictions were not in place. The primary outcomes were overall survival, progression-free survival and response. Secondary outcomes included quality of life and adverse events.

4.1.10 Data from the MMIX study on overall survival, progression-free survival, adverse events and health-related quality of life were not eligible for inclusion in the Assessment Group’s systematic review because participants were randomised to receive either maintenance therapy with thalidomide or no maintenance therapy after they had completed first-line treatment. Although the maintenance data was not included, the Committee considered very carefully data from the small number of patients who were randomised to receive no maintenance therapy. It considered that  the data was immature and for a small number of patients, so was not available to be included.

4.1.11 Data from the MMIX study on response were eligible for inclusion in the Assessment Group’s systematic review. Response was measured as complete, very good or partial. However, the principal investigators of the MMIX study identified data on response and adverse events as academic in confidence and therefore they cannot be reported in the appraisal consultation document.

Bortezomib plus melphalan and prednisolone/prednisone (VMP) versus melphalan plus prednisolone/prednisone (MP)

4.1.12 The Assessment Group identified one RCT (VISTA trial) comparing VMP with MP. People were eligible to participate if they had newly diagnosed, untreated, symptomatic, measurable myeloma and were not candidates for high-dose chemotherapy with stem cell transplantation because of their age (65 years or older) or coexisting conditions. The quality of the RCT was difficult to determine because details needed for quality assessment were incompletely reported. Risk of allocation bias and of unbalanced confounding factors could not be judged because details on these aspects were not reported. Most, but not all analyses had followed the intention-to-treat but the methods used to account for any missing data were not described.

4.1.13 The primary outcome was time to disease progression. Secondary outcomes included overall survival, progression-free survival, response, adverse events and health-related quality of life. Median time to subsequent myeloma therapy and treatment-free interval was reported as 20.8 months and 9.4 months respectively in the group receiving MP; these were not reached in the group receiving VMP. An advantage in terms of overall survival was reported for VMP compared with MP. A statistically significant survival benefit for VMP was reported after a median follow-up of 25.9 months (HR = 0.64, p = 0.0032). More recently reported 3-year survival rates after a median follow-up of 36.7 months are 68.5% versus 54% respectively. A median overall survival of 43.1 months for participants receiving MP; it was not possible to estimate overall survival in the group receiving VMP. Median progression-free survival was 21.7 months for the VMP group compared with 15.2 months for the group receiving MP (HR 0.56, p < 0.001). A number of response-to-treatment rates (including partial response and complete response) were reported as secondary outcomes. The time at which response was assessed was not reported. The proportion of participants with at least a partial response was 71% in the VMP group and 35% in the MP group (p < 0.001). The proportions with a complete response were 30% and 4% respectively (p < 0.001). The proportion with a partial response was 40% in the VMP group and 31% in the MP group, and the proportions with a minimal response were 9% and 22% respectively. The proportion with stable disease was 18% in the VMP group and 40% in the MP group and the progressive disease rates were 1% and 2% respectively.

4.1.14 Participants in both arms of the trial experienced adverse events. Although the occurrence of any adverse event and any grade 4 adverse event was similar in the two groups, there was a statistically significant increase in grade 3 adverse events in the group receiving VMP (53% versus 44%, p = 0.02). Haematological events were the most frequently reported and were similar in the two groups. Peripheral sensory neuropathy was reported more frequently in the group receiving VMP but at the time of the last analysis, 74% of peripheral neuropathy events had either resolved (56%) or decreased by at least one toxicity grade (18%) within a median of 2 months. All grade 3 and grade 4 gastrointestinal events were more frequent in the group receiving VMP (19% versus 5%, no p value given). The incidence of deep vein thrombosis was low and similar in the two groups.

4.1.15 Limited data on health-related quality of life were available. After best response, participants treated with VMP had a higher sustained improvement in 14 of the 15 EORTC QLQ-C30 scores (European Organisation for Research and Treatment of Cancer Quality of Life questionnaire C-30 scores) than participants treated with MP.

4.1.16 Data on second-line treatment was provided that could be included in the review. The study reported that 57% of participants started second-line treatment within two years in the MP group compared with 38% in VMP group. Over half of the participants in each group received either thalidomide or lenalidomide as a second-line therapy.

Summary of the clinical effectiveness

4.1.17 The Assessment Group concluded that the evidence from two studies (IFM 99/06 and IFM 01/01) indicated that MPT was more effective than MP in terms of increasing overall survival (HR O.62, 95% CI 0.50 to 0.77) and the secondary outcome of progression-free survival (HR 0.56, 95% CI 0.46 to 0.67). Three studies (IFM 99/06, IFM 01/01 and GIMEMA) provided evidence of a complete response in a statistically significantly greater proportion of participants receiving MPT (RR 5.49, 95% CI 2.155 to 11.38). Adverse events occurred in both trial arms, but peripheral neuropathy was most consistently, and statistically significantly, associated with the use of thalidomide.

4.1.18 Data from MMIX trial on overall survival and progression-free survival from the study comparing CTDa with MP were not eligible for inclusion in the systematic review undertaken by the Assessment Group because participants were randomised to maintenance therapy with thalidomide after first-line treatment.

4.1.19 The Assessment Group concluded that the evidence from one study (VISTA trial) indicated that combination chemotherapy with VMP was more effective than MP in terms of increasing overall survival and the proportion of participants achieving a complete response. Adverse events occurred in both trial arms. Bortezomib was associated with a statistically significant increase in grade 3 adverse events. 

4.2 Cost effectiveness

4.2.1 The two manufacturers submitted cost-effectiveness models. The Assessment Group developed its own economic model and critiqued the economic models submitted by the manufacturers.

The Celgene economic model

4.2.2 The manufacturer developed a Markov model to compare the costs and benefits of MPT with those of VMP and MP in people with multiple myeloma who are older than 65 years or are ‘ineligible for high-dose chemotherapy’. The model had four health states that were defined by the stage of disease progression or the occurrence of adverse events. The four health states were: pre-progression without adverse events, pre-progression with adverse events, post progression and death. The analysis was undertaken over a lifetime horizon (that is, 30 years). Treatment effects were calculated from a mixed-treatment comparison of data originating from three RCTs (VISTA, IFM 99/06, IFM 01/01). It used measures of survival time before and after progression as the primary outcomes. Resources and costs were obtained from several sources, including an unpublished survey of UK haematologists by the manufacturer of thalidomide, NHS reference costs, and BNF edition 57 with costs inflated to 2008 values.

4.2.3 The manufacturer’s model included the following assumptions:

• Post-progression survival was modelled to be the same across different treatment strategies, with the different arms assumed to receive the same alternative treatment after progression (that is, second- and third-line treatments).
• Patients were assumed to discontinue first-line treatment on disease progression.
• No costs for second- and third-line treatments were included.
• Deaths occurred at or after progression and were assumed to be because of disease-related deterioration.
• Adverse events included in the model incorporated a utility decrement at the time of the event and the additional cost of treating them. They were assumed not to affect the rate of disease progression or overall survival, or treatment duration, efficacy or dose.

4.2.4 Data on health-related quality of life were obtained from an RCT of intensive chemotherapy followed by myeloablative therapy with autologous stem cell rescue compared with intensive chemotherapy alone. The utility values used were 0.64 for people not responding to treatment and 0.81 for people who did respond (using the utility value for the general population of the same age). A utility value of 0.77 at 24 months was used for people who continue to respond to intensive chemotherapy and whose disease has not progressed.

4.2.5 The base-case cost-effectiveness results were as follows:

• MPT compared with MP was associated with an incremental cost-effectiveness ratio (ICER) of £23,381 per quality adjusted life year (QALY) gained based on an incremental effect of 0.85 QALYs and an incremental cost of £19,768.
• VMP compared with MPT was associated with an ICER of £303,845 per QALY gained based on an incremental effect of 0.07 QALYs and an incremental cost of £21,483.

4.2.6 One-way deterministic sensitivity analyses showed that the parameters with the greatest effect on the model results were changes in treatment efficacy, with a range of £16,586 to £33,275 per QALY gained for MPT versus MP and a range of £148,873 to £1,000,435 per QALY gained for VMP versus MPT. Probabilistic sensitivity analysis was not conducted because the manufacturer considered the efficacy of MPT and VMP to be essentially the same and therefore the cost differences would be the key driver for the model.

The Janssen-Cilag economic model

4.2.7 The manufacturer developed a decision-analytic cost–utility model to compare the costs and benefits for VMP with those of MPT, CTDa and MP in people with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with stem cell transplantation. The model included four health states: before response to treatment; response to treatment without progression; post progression; and death. The time to response or death were estimated from life tables constructed directly from data from the VISTA trial. Progression-free survival at 6, 12, 18 and 24 months for MP was estimated from a meta-analysis of the MP arms of included RCTs. Progression-free survival was extrapolated beyond 24 months. Utility values for health-related quality of life were assigned to each of the states: 0.77 for before response to treatment; 0.81 for response to treatment without progression; and 0.64 for post progression. The model used a cohort of people newly diagnosed with multiple myeloma with MP as the baseline treatment. Treatment effects for VMP, MPT, and CTDa were then modelled over time by adjusting the baseline results via hazard ratios. Hazard ratios were estimated at 48 months for overall survival for each of the RCTs, except the VISTA trial which only had 36 month follow-up. For estimation of the overall survival for thalidomide, data from fives RCTs were used, which included RCTs that had included thalidomide maintenance.

4.2.8 The manufacturer’s model made the following assumptions:

• The resource use cost for the first-line management of multiple myeloma was the same for all regimens.
• Seven cycles of treatment with MP as in the VISTA trial.
• For bortezomib, 31.5 vials were used per patient (as in the VISTA trial).
• A dose of thalidomide of 150 mg/day for the MPT regimen and 167 mg/day for the CTDa regimen.
• Adverse events were included in the model as the cost of treating them; the incidence of adverse events does not influence the treatment duration, efficacy or patient utility.

4.2.9 Costs were included for second- and third-line treatments. On disease progression second-line treatment would consist of bortezomib plus high-dose dexamethasone, CTDa or high-dose dexamethasone. Most people received CTDa after first-line VMP. People on other first-line therapies usually received bortezomib and high-dose dexamethasone as second-line treatment. All patients received lenalidomide plus dexamethasone as third-line treatment. Most people receiving bortezomib as first-line treatment would not receive it as second-line treatment.

4.2.10 The manufacturer’s base-case cost-effectiveness results were as follows:

• MPT compared with MP was associated with an ICER of £8912 per QALY gained based on an incremental effect of 0.55 QALYs and an incremental cost of £4888.
• CTDa compared with MP was associated with an ICER of £10,905 per QALY gained based on an incremental effect of 0.21 QALYs and an incremental cost of £2234.
• VMP compared with MP was associated with an ICER of £10,498 per QALY gained based on an incremental effect of 1.17 QALYs and an incremental cost of £12,242.

4.2.11 One-way sensitivity analysis showed the model was most sensitive to the following parameters: underlying MP survival hazard, hazard ratios for overall survival, dose of thalidomide, and duration of treatment with thalidomide in the MPT arm. A probabilistic sensitivity analysis showed that at the £20,000 and £30,000 thresholds, VMP has the highest probability of being cost effective (64% and 75% respectively).

4.2.12 Two scenario analyses were conducted. The first excluded the costs of subsequent therapy after first-line treatment. In this scenario, the cost-effectiveness results were less favourable for each of the treatments and the ICERs increased to £48,437, £16,956 and £21,099 per QALY gained for CTDa, MPT, and VMP respectively, compared with MP. The second scenario assumed the same second-line treatments as for people treated with MP in the VISTA trial. For this scenario, the results were similar to the base-case analyses.

The Assessment Group model

4.2.13 The Assessment Group’s survival model was developed to estimate the costs, benefits and cost effectiveness of MPT, VMP and CTDa compared with MP, in people with newly diagnosed multiple myeloma who are ‘ineligible’ for high-dose chemotherapy with stem cell transplantation. The model consisted of cycles of six weeks in length to be consistent with the cycle lengths used for chemotherapy treatment. A lifetime horizon of 30 years was modelled. Survival was classified into three health states: treatment (defined as the time patients are treated with first-line therapy); post-treatment (defined as the mean time from end of first-line treatment therapy until disease progression) and post regression (defined as the mean time from disease progression until death).

4.2.14 The Assessment Group constructed two survival curves for overall survival and progression-free survival for each of the alternative treatments from the results of the RCTs included in the Assessment Group’s systematic review (see ACD sections 4.1.4, 4.1.5, 4.1.10 and 4.1.13). These survival durations were used to derive the time spent in the three health states. For each treatment option the relative risk of complete response compared with MP was derived from the complete response outcome data from the RCTs included in the Assessment Group’s systematic review (see ACD section 4.1.6, 4.1.11 and 4.1.13).

4.2.15 Health-related quality of life data were from a systematic review of studies of health-related quality of life. The Assessment Group did not identify any generic preference-based studies of people with untreated multiple myeloma who were not eligible for high-dose chemotherapy with stem cell transplantation, but did identify an additional study to those identified by the manufacturer that assessed health-related quality of life in this group using the EORTC QLQ C-30. The Assessment Group mapped the EORTC QLQ-C30 health related quality of life scores to the EQ-5D using a validated mapping algorithm by McKenzie and van der Pol. The utility estimates used were 0.58 for the treatment health state and 0.68 for post-treatment state.

4.2.16 Costs were derived from a number of sources including the BNF, RCTs included in the Assessment Group’s systematic review and clinical and expert clinical opinion. The Assessment Group’s model included the following assumptions:

• For bortezomib, each person receives one vial per administration.
• Following disease progression after first-line therapy patients receive second-line treatment. The model assumed that most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line treatment.
• Costs included for second-line treatment. Effect of second-line treatment on health outcomes not included in the model because treatment for second-line treatment varied between the RCTs included in the Assessment Group’s systematic review. (See ACD section 4.1.8 and 4.1.16).
• Cost and outcomes of third-line and subsequent treatments were assumed to be the same between arms.
• People discontinued first-line treatment on disease progression.
• Health-related quality of life was better for those with complete response than those with less than complete response and was assumed to improve when people stop treatment.
• Adverse events were not modelled explicitly in the model for overall survival and progression-free survival, but additional costs for treating the adverse events were included.

4.2.17 The base-case cost-effectiveness results were as follows:

• MPT compared with MP was associated with an ICER of £9174 per QALY gained based on an incremental effect of 1.22 QALYs and an incremental cost of £11,207.
• CTDa compared with MP was associated with an ICER of £33,216 per QALY gained based on an incremental effect of 0.26 QALYs and an incremental cost of £8592.
• VMP compared with MP was associated with an ICER of £29,837 per QALY gained based on an incremental effect of 1.20 QALYs and an incremental cost of £35,749.

4.2.18 The incremental analysis suggested extended dominance of MPT over CTDa, and that MPT dominates VMP because it is more effective and cheaper. The incremental baseline cost-effectiveness results were as follows: CTDa compared with MP was associated with an ICER of £33,216 per QALY gained; and VMP compared with MPT was associated with an ICER of £28,907 per QALY gained. The comparison of VMP versus MPT suggested that VMP and CTDa were unlikely to be cost-effective treatment options at the thresholds of £20,000 to £30,000 per QALY gained.

4.2.19 Sensitivity analyses showed the effects of a range of parameter values in the economic model. For each of the treatments the model results were most sensitive to the hazard ratios for overall survival, cost and dosage of the treatment and the overall baseline survival curve used for MP. The deterministic sensitivity results for MPT versus MP varied between £6470 and £22,855 per QALY gained. The deterministic sensitivity analysis for VMP versus MP gave ICERs between £20,451 and £87,716 per QALY gained. VMP was dominated by MPT in all analyses apart from that investigating sensitivity to changes in overall survival. The deterministic sensitivity results for CTDa versus MP gave ICERs between −£29,388 (dominant, that is CTDa is more effective and less costly than MP) and £16,989 per QALY gained.

4.2.20 In addition to the sensitivity analyses, four alternative scenarios were explored to investigate the uncertainty around structural assumptions. In scenario A (no subsequent therapies) the ICERs for MPT, CTDa and VMP versus MP increased from £9174, £29,837, £33,216 to £9738, £34,013 and £37,727 per QALY gained respectively.

4.2.21 Scenario B (vial sharing/fewer vials) investigated the cost effectiveness when patients share vials of bortezomib. With vial sharing and no wastage, the ICERs for MPT and CTDa versus MP increased from £9174 and £33,216 to £9,369 and £33,492 per QALY gained respectively. The ICER for VMP versus MP decreased from £29,837 to £22,549 per QALY gained. Following comments received from consultees on the draft assessment report, the Assessment Group undertook an additional scenario analysis in which it was assumed that four cycles or 31 vials of bortezomib was used, with no loss of efficacy. In this scenario, the ICER for VMP versus MP decreased from £23,947 to £18,996 per QALY gained. The ICER for VMP versus MPT decreased from ‑£1,000,000 (that is MPT dominates VMP) to £319,923 per QALY gained

4.2.22 Scenario C (inclusion of thalidomide maintenance trials) investigated the cost effectiveness using the estimate of efficacy for MPT from a meta-analysis that included trials with thalidomide maintenance. The manufacturer of thalidomide conducted a mixed-treatment comparison for MPT versus MP with trials that included thalidomide maintenance. Using the hazard ratio from this analysis the ICER for MPT versus MP increased from £9174 to £24,390 per QALY gained. The ICERs for CTDa and VMP remained the same as in the base case analysis (£33,492 and £22,549 per QALY gained respectively). In addition, MPT no longer dominated VMP, with an ICER of £32,739 for VMP versus MPT.

4.2.23 Scenario D (treatment effectiveness beyond the end of trial) investigated an alternative assumption whereby there is no treatment benefit for the three drug combinations over MP, that is, the event rates for these treatments are the same as for MP after the end of the trial. This assumption had a large effect on the model results and all treatments were less cost effective than MP. The ICERs for each of the treatment options more than doubled to £20,698 (MPT), £71,264 (VMP) and £80,840 (CTDa) per QALY gained versus MP.

4.2.24 The probabilistic sensitivity analysis estimated the probability of each of the treatments being cost effective at the £20,000 and £30,000 thresholds. MPT had the highest probability (0.95 at both thresholds) of being cost effective. The baseline probabilistic sensitivity analysis showed that MPT was cost effective compared with MP with an ICER of £9124. The comparisons of VMP versus MP and CTDa versus MP produced ICERs of £29,102 and £31,612 respectively.

Comparison of the manufacturer and Assessment Group models

4.2.25 The results for the manufacturers’ and Assessment Group’s economic analyses varied considerably. The costs varied substantially between the analyses; for example, the cost of MP varied between £1365 (manufacturer of thalidomide) to £54,434 (manufacturer of bortezomib). The costs from the manufacturer of thalidomide analysis were lower because they did not include any costs for subsequent treatment, whereas the Assessment Group’s analysis included costs for second-line treatment and the manufacturer of bortezomib analysis included costs for second- and third-line treatment.

4.2.26 The incremental costs for MPT versus MP varied between £4888 (the manufacturer of bortezomib) and £19,768 (manufacturer of thalidomide). The manufacturer of thalidomide model used higher dosages of thalidomide (238 mg/day) for longer periods (11 cycles) than the other two analyses. The incremental costs for VMP versus MP varied between £12,242 (manufacturer of bortezomib) and £41,251 (manufacturer of thalidomide). These differences were largely due to the assumptions around the number of vials of bortezomib used, with the manufacturer of bortezomib assuming a mean of 31.5 vials per person, and the Assessment Group and manufacturer of thalidomide assuming over 40 vials. The incremental costs for CTDa versus MP varied between £2234 (manufacturer of bortezomib) and £8592 (Assessment Group). These differences were due to an error in the cost calculation for third-line therapy for CTDa in the manufacturer of bortezomib analysis.

4.2.27 The total QALY estimates used by the manufacturers and the Assessment Group were similar, with estimates for all treatment arms varying between 2.42 and 4.03. The incremental QALY estimates for MPT versus MP varied from 0.55 (manufacturer of bortezomib) to 1.22 (Assessment Group). These differences were due to the estimates chosen for the hazard ratio for overall survival compared with MP.

4.2.28 There were differences in the way adverse events were modelled:

• The manufacturer of bortezomib included adverse events in the model as the cost of treating them; the incidence of adverse events did not influence the treatment duration, efficacy or patient utility.
• The manufacturer of thalidomide included adverse events in the model as a utility decrement at the time of the event and as the cost of treating them. They were assumed not to affect the rate of disease progression or overall survival, or treatment duration, efficacy or dose.
• The Assessment Group did not explicitly model adverse events for patient outcomes (that is, overall survival and progression-free survival), but included an additional cost for treating the adverse events in the model.

4.2.29 There were also differences in inclusion of costs after first-line treatment:

• The manufacturer of bortezomib included costs for second- and third-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive VMP as first-line treatment received it as second-line.
• The manufacturer of thalidomide assumed that patients discontinued first-line treatment on disease progression and did not include costs for second- and third-line treatments.
• The Assessment Group included costs for second-line treatments. Most people who received VMP as first-line treatment received CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment received it as second-line.

Summary of the cost effectiveness

The different assumptions and methodology used (see sections 4.2.24 to 4.2.28) resulted in a range of ICERs for the options for first-line treatment of multiple myeloma in people for whom high dose chemotherapy with stem cell transplantation is considered inappropriate. The ICER for MPT versus MP varied between £9174 (Assessment Group) and £23,381 (manufacturer of thalidomide) per QALY gained. The ICER for VMP versus MP varied between £10,498 (manufacturer of bortezomib) and £44,838 (calculated by the Assessment Group to allow a comparison between the manufacturers’ and Assessment Group’s economic models) per QALY gained. The ICER for CTDa versus MP varied between £10,905 (manufacturer of bortezomib) and £33,216 (Assessment Group) per QALY gained.

4.3 Consideration of the evidence

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

4.3.2 The Committee discussed the pathway of care for people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee heard from the clinical specialist that in UK clinical practice before the advent of thalidomide and bortezomib, first-line treatment consisted of an alkylating agent (melphalan or cyclophosphamide) and a corticosteroid (attenuated dexamethasone or prednisolone). Since thalidomide and bortezomib had become available, one of these, according to patient preference, comorbidities and adverse events, was normally added to first-line treatment. The Committee heard from the clinical specialists and patient experts that although both the thalidomide and bortezomib regimens were well tolerated, administration of the bortezomib regimen took longer and was less convenient (because it involved intravenous infusion rather than oral administration). The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide, and attenuated dexamethasone (because of the mode of oral administration). They stated that they considered the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, to be equivalent in terms of safety and efficacy. Past studies of the two regimens before the addition of thalidomide had shown equivalent safety and efficacy and the clinical specialists did not consider that the addition of thalidomide would have a differential effect. The Committee heard that for those people who were intolerant of or had contraindications to thalidomide (such as those with clotting disorders or impaired renal function), bortezomib in combination with melphalan and prednisolone was considered the most appropriate treatment. Based on the testimonies of the clinical specialists, the Committee accepted that clinicians considered the three treatment regimens to be equivalent in terms of clinical efficacy but that the choice of treatment for an individual patient will depend on the comorbidities present and the different mechanisms of action and side effect profiles of the treatments.

Clinical effectiveness

4.3.3 The Committee then considered the evidence for the clinical effectiveness of thalidomide in combination with an alkylating agent (melphalan or cyclophosphamide) and a cortiscosteroid (attenuated dexamethasone or prednisolone/prednisone) as presented by the Assessment Group. It noted that thalidomide has been shown to improve overall survival and progression-free survival compared with melphalan in combination with prednisolone/prednisone. The Committee was aware that only the IFM99/06 and IFM 01/01 studies contributed data to the Assessments Group’s estimates of overall survival and progression-free survival and that data from the GIMEMA and ongoing MMIX studies had been excluded because participants in the studies had been randomised to receive maintenance with thalidomide or no therapy after they had completed first-line treatment. The Committee considered whether it was appropriate for the Assessment Group to have excluded studies in which participants received maintenance therapy with thalidomide.  The Committee heard from the clinical specialists that not all participants in the GIMEMA and MMIX studies that included maintenance treatment, benefited from maintenance treatment and that some people on thalidomide maintenance had a shorter overall survival, possibly because the prolonged thalidomide treatment induced disease resistance. The Committee was mindful that maintenance therapy data was not included in the Assessment Group’s systematic review but it considered very carefully data from the small number of patients who were randomised to receive no treatment therapy in the MMIX trial. It agreed that the data were very immature and from a small number of patients. In view of this and the fact that the two studies without maintenance treatment were the only complete studies matching the decision problem (which did not include maintenance), the Committee accepted that it was appropriate for the Assessment Group to exclude from its analysis survival data from studies which included participants who had received maintenance therapy. The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.

4.3.4 The Committee discussed the relative effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid as presented by the Assessment Group. It noted that bortezomib had been shown to be more effective than melphalan in combination with prednisolone in terms of overall survival and progression-free survival. It noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens had not been compared head to head because there were differences in participants’ characteristics, delivery of the comparator and length of follow-up. In addition, the evidence for the effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (the VISTA trial). The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.

Cost effectiveness

4.3.5 The Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group’s economic analyses. The Assessment Group calculated an ICER of £9170 per QALY gained for the MPT combination compared with MP and £33,200 per QALY gained for the CTDa combination compared with MP. The Committee accepted that if the safety and efficacy of the two thalidomide regimens were considered equivalent (see ACD section 4.3.2), the ICER of £9170 for MPT was likely to be the more robust estimate, because it was based on completed studies (without thalidomide maintenance treatment), therefore fitting the decision problem.

4.3.6 The Committee also noted the variation in the ICERs presented by the manufacturers for MPT compared with MP. The highest of these, £23,400, was from the manufacturer of thalidomide and assumed higher dosages of thalidomide and a greater number of cycles of treatment than the analyses from the manufacturer of bortezomib and the Assessment Group. The dosage of thalidomide used by the manufacturer of thalidomide was the maximum specified in the SPC but was higher than would be used in clinical practice (most patients are not able to tolerate such a high dose). The Committee considered that the ICER was likely to be lower than the manufacturer of thalidomide estimate and that the most plausible ICERs for the two thalidomide regimens would fall within the range considered a cost-effective use of NHS resources (£20,000 to £30,000). The Committee therefore concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate.

4.3.7 The Committee then considered the Assessment Group’s ICERs for VMP compared with MP and with the thalidomide regimens. The Committee accepted the concern raised by the manufacturer of bortezomib that the Assessment Group had assumed too many vials of bortezomib (over 40 as opposed to the 31.5 vials used in the VISTA trial). The Committee considered that the Assessment Group’s scenario that assumed four cycles (equivalent to 31 vials used) was likely to be more accurate. This gave an ICER of 22,500 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.

4.3.8 The Committee noted the differences in the ICERs presented by the Assessment Group and the manufacturer of bortezomib for VMP compared with MP. Apart from the fewer vials of bortezomib assumed by the manufacturer, which the Committee accepted, the manufacturer of bortezomib model also included costs for second-and third-line treatments. This included adding the cost of thalidomide to the bortezomib regimen, and of bortezomib to the thalidomide regimen, neutralising the approximately four-fold cost advantage of thalidomide, and greatly increasing the cost of MP. The Committee also noted that the manufacturer of bortezomib had used a hazard ratio for overall survival for thalidomide which was derived from a meta-analysis that included RCTs with thalidomide maintenance. For both these reasons the Committee did not accept the manufacturer of bortezomib’s assertion that the bortezomib regimen (VMP) was cost-effective compared with the thalidomide regimen (MPT).

4.3.9 However, the Committee did consider that bortezomib regimens could be cost effective for people who are unable to tolerate or have a contraindication for thalidomide. The Committee was aware of the testimonies from the clinical specialists that the only treatment available for people who are intolerant of or have contraindications for thalidomide is the bortezomib regimen (VMP). It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications for thalidomide.

4.3.10 In summary the Committee considered that the combination of thalidomide plus an alkylating agent and steroid was both clinically effective and cost-effective for these patients. Bortezomib plus an alkylating agent and steroid was not cost-effective when compared with the thalidomide combination, and was cost-effective where thalidomide was not appropriate, that is in people who are intolerant to or are contraindicated to thalidomide.

Summary of Appraisal Committee’s key conclusions

TAXXX (MTA)	Appraisal Title: Bortezomib and thalidomide for the first-line treatment of multiple myeloma	ACD section
Key conclusion
Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high dose chemotherapy with stem cell transplantation is considered inappropriate. Bortezomib in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom: high-dose chemotherapy with stem cell transplantation is considered inappropriate and the person is unable to tolerate or has contraindications to thalidomide. The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid. The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid is a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. The Committee did not accept the manufacturer of bortezomib’s assertion that the bortezomib regimen (VMP) was cost-effective compared with the thalidomide regimen (MPT). The Committee considered that bortezomib plus an alkylating agent and steroid was not cost-effective when compared with the thalidomide combination, and was cost-effective where thalidomide was not appropriate, that is in people who are intolerant to or are contraindicated to thalidomide.		1.1 1.2 4.3.3 4.3.4 4.3.6 4.3.8, 4.3.10
Current practice
Clinical need, including the availability of alternative treatments	Multiple myeloma remains an incurable disease, with an average survival of 4–6 years, but it can be treated with a combination of supportive measures and chemotherapy. Most people with multiple myeloma are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation. These people are offered single-agent or combination chemotherapy, which is less intensive. Typically combination therapies include chemotherapy with an alkylating agent (such as melphalan or cyclophosphamide) and a corticosteroid (such as prednisolone or dexamethasone). More recent treatment options include drugs such as thalidomide and bortezomib. The main objective of first-line therapy is to achieve a period of stable disease (termed the plateau phase) for as long as possible, thereby prolonging survival and maximising quality of life.	2.3 2.4
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	Thalidomide is an immunomodulatory agent. Its precise mechanism of action is under investigation and is currently unknown, but it is thought to have multiple actions, including anti-inflammatory activity and the ability to inhibit the growth and survival of myeloma cells and the growth of new blood vessels. It is also a non-barbiturate hypnotic sedative with central action. Bortezomib is an anticancer drug that works by reversible proteasome inhibition. This inhibition leads to arrest of the cell cycle and apoptosis (cell death), which reduces tumour growth. Myeloma cells are more sensitive to the action of bortezomib than normal cells	3.5 3.1
What is the position of the treatment in the pathway of care for the condition	Thalidomide (in combination with melphalan and prednisone) is licensed for the first-line treatment of patients with untreated multiple myeloma aged ≥ 65 years or ineligible for high dose chemotherapy’. Bortezomib (in combination with melphalan and prednisone) is licensed for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant.	3.6 3.2
Adverse effects	Thalidomide treatment is associated with thromboembolic events, peripheral neuropathy, rash/skin reactions, bradycardia, syncope and somnolence. Bortezomib treatment is associated with peripheral neuropathy, thrombocytopenia, gastrointestinal effects and other side effects. Adverse events were not a key driver in the economic evaluation; however, see section 4.2 for details of how adverse events were modelled in the submissions.	3.7 3.3 4.2.3, 4.2.8, 4.2.16
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The following treatment strategies were investigated (using data from five clinical studies): thalidomide, melphalan and prednisolone/prednisone (MPT) thalidomide, cyclosphosphamide and attenuated dexamethasone (CTDa) bortezomib, melphalan and prednisolone/prednisone (VMP). Each was compared with melphalan/cyclosphosphamide plus prednisolone/prednisone/dexamethasone. Three RCTs (Intergroupe Francophone du Myélome [IFM] 99/06, IFM 01/01 and GIMEMA) compared MPT with MP. The GIMEMA study included maintenance therapy with thalidomide after first-line treatment and therefore data on overall survival were not eligible for inclusion. One ongoing RCT (the Multiple Myeloma IX [MMIX} trial) compared CTDa with MP. Data from the MMIX study on overall survival, progression-free survival, adverse events and health related quality of life were not eligible for inclusion because participants were randomised receive either maintenance therapy with thalidomide or no maintenance therapy after they had completed first-line treatment to. One RCT (VISTA trial) compared VMP with MP.	4.1.1 4.1.2, 4.1.5 4.1.9 4.1.13
Relevance to general  clinical practice in the NHS	Both thalidomide containing regimens and the bortezomib containing regimen are used in clinical practice for first-line treatment of multiple myeloma. The clinical specialists stated that a thalidomide regimen would be considered more appropriate for 70–75% of patients and that their preferred choice of regimen was thalidomide in combination with cyclophosphamide, and attenuated dexamethasone (because of the mode of administration). They stated that they considered the two thalidomide regimens (CTDa and MPT) to be equivalent in terms of safety and efficacy. The Committee heard that for those people who were intolerant to or had contraindications for thalidomide, the bortezomib containing regimen was considered the most appropriate treatment.	4.3.2
Uncertainties generated by the evidence	The Committee was persuaded by advice from the clinical specialists that the two thalidomide regimens (CTDa and MPT), which both included an alkylating agent and a steroid, to be equivalent in terms of safety and efficacy. The evidence for the clinical effectiveness of bortezomib in combination with an alkylating agent and a corticosteroid was derived from a single study (VISTA). The Committee noted survival rates with bortezomib were similar to those for thalidomide. However the two regimens were not compared head to head. The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid.	4.3.2 – 4.3.4
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness	The Committee was aware of the testimonies from the clinical specialists that the only treatment available for people who are intolerant of or have contraindications for thalidomide is the bortezomib regimen (VMP). It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications for thalidomide.	4.3.9
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded that thalidomide in combination with an alkylating agent and a corticosteroid improved outcomes when compared with an alkylating agent and a corticosteroid in people with multiple myeloma for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. It noted that survival rates with bortezomib were similar to those for thalidomide but that the two regimens had not been compared head to head The Committee concluded that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide regimens when compared with an alkylating agent and corticosteroid alone.	4.3.3 4.3.4
Evidence for cost effectiveness
Availability and nature of evidence	The two manufacturers submitted cost-effectiveness models. The Assessment Group developed their own economic model and critiqued the economic models submitted by the manufacturers.	4.2.1
Uncertainties around and plausibility of assumptions and inputs in the economic model	The results for the manufacturers’ and Assessment Group’s economic analyses varied considerably. Within the submissions there were differences in the dosage and number of cycles of thalidomide, number of vials of bortezomib used, the estimates for the hazard ratio of overall survival for melphalan and MPT compared with MP, subsequent treatment costs and how adverse events were modelled. These were explored in sensitivity analyses and alternative scenarios. The Committee also noted the variation in the ICERs presented by the manufacturers for MPT compared with MP. The highest of these, £23,400, was from the manufacturer of thalidomide and assumed higher dosages of thalidomide and a greater number of cycles of treatment than the analyses from the manufacturer of bortezomib and the Assessment Group. The Committee considered that the ICER was likely to be lower than the manufacturer of thalidomide estimate and that the most plausible ICERs for the two thalidomide regimens would fall within the range considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The Committee then considered the Assessment Group’s ICERs for VMP compared with MP and with the thalidomide regimens. The Committee accepted the manufacturer of bortezomib’s point that the Assessment Group had assumed too many vials of bortezomib (over 40 as opposed to the 31.5 vials used in the VISTA trial). The Committee considered that the Assessment Group’s scenario that assumed four cycles (equivalent to 31 vials used) was likely to be more accurate.	4.2.24 4.2.25-4.2.29 4.3.6 4.3.7
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?	No health-related benefits were identified that were not included in the economic models
Are there specific groups of people for whom the technology is particularly cost-effective?	The Committee was aware of the testimonies from the clinical specialists that the only treatment available for people who are intolerant of or have contraindications for thalidomide is the bortezomib regimen (VMP). It therefore concluded that bortezomib in combination with an alkylating agent and a corticosteroid is likely to be a cost-effective option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate and who are intolerant of or have contraindications for thalidomide	4.3.9
What are the key drivers of cost effectiveness?	The Committee concluded that it was likely that bortezomib in combination with an alkylating agent and corticosteroid improved outcomes to a similar degree to thalidomide in combination with an alkylating agent and corticosteroid. The Committee considered that the combination of thalidomide plus an alkylating agent and steroid was cost-effective for these patients. Bortezomib plus an alkylating agent and steroid was not cost-effective when compared with the thalidomide combination, and was cost-effective where thalidomide was not appropriate, that is in people who are intolerant to or are contraindicated to thalidomide.	4.3.4 4.3.10
Most likely cost-effectiveness estimate (given as an ICER)	The Committee considered the base-case ICERs for thalidomide in combination with an alkylating agent and a corticosteroid from the Assessment Group’s economic analyses: £9170 per QALY gained for melphalan and prednisolone/prednisone plus thalidomide (MPT) compared with melphalan plus prednisolone/prednisone (MP) and £33,200 per QALY gained for cyclophosphamide, thalidomide plus attenuated dexamethasone (CTDa) compared with melphalan plus prednisolone/prednisone (MP). The Committee accepted that, as the two thalidomide regimens are considered equivalent, the ICER for melphalan and prednisolone/prednisone plus thalidomide (MPT) was the more robust estimate because it was based on completed studies (without thalidomide maintenance) fitting the decision problem. The Committee considered that the Assessment Group’s scenario that assumed four cycles (equivalent to 31 vials used) was likely to be more accurate. This gave an ICER of 22,500 per QALY gained for VMP compared with MP and £320,000 per QALY gained for VMP compared with MPT.	4.3.5 4.3.7
Additional factors taken into account
Patient access schemes (PPRS)	Not applicable.
End of life considerations	Not applicable.
Equalities considerations	Not applicable.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the 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 Related NICE guidance

Published

• Bortezomib monotherapy for relapsed multiple myeloma. NICE technology appraisal guidance 129 (2007). Available from www.nice.org.uk/guidance/TA129
• Lenalidomide for the treatment of multiple myeloma in people who have received at least one prior therapy. NICE technology appraisal guidance 171 (2009). Available from www.nice.org.uk/guidance/TA171

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Denosumab for the treatment of bone metastases from solid tumours and multiple myeloma. NICE technology appraisal guidance (expected date of issue January 2012).

 

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in August 2013. 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 C
May 2010

 

Appendix A: Appraisal Committee members and NICE project team

A 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 four 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.

Dr David Black

Director of Public Health, Derbyshire County Primary Care Trust

Dr Daniele Bryden

Consultant in Intensive Care Medicine and Anaesthesia, Sheffield Teaching Hospitals NHS Trust

Mr David Chandler

Lay member

Dr Mary Cooke

Lecturer, School of Nursing, Midwifery and Social Work, University of Manchester

Dr Chris Cooper

General Practitioner, St John’s Way Medical Centre, London

Professor Peter Crome

Consultant Physician,Bucknall Hospital, Staffordshire

Dr Christine Davey

Senior Researcher, North Yorkshire Alliance R&D Unit

Mr Richard Devereaux-Phillips 

Public Affairs and Reimbursement Manager UK and Ireland, Medtronic Limited, Hertfordshire

Dr Wasim Hanif

Consultant Physician and Honorary Senior Lecturer, University Hospital Birmingham

Dr Peter Jackson

Clinical Pharmacologist, University of Sheffield

Henry Marsh

Consultant Neurosurgeon, St George's Hospital

Professor Gary McVeigh

Professor of Cardiovascular Medicine, Queen’s University Belfast and Consultant Physician, Belfast City Hospital

Dr Eugene Milne

Deputy Medical Director, North East Strategic Health Authority

Dr Katherine Payne

Health Economics Research Fellow, University of Manchester

Dr Danielle Preedy

Lay member

Miles Scott

Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

Dr Peter Selby

Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Dr Surinder Sethi

Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens

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

Dr Matt Stevenson

Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle

Lay member

Dr Alan Haycox

Reader in Health Economics, University of Liverpool Management School

C NICE project team

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

Carina Righetti

Technical Lead

Nicola Hay

Technical Adviser

Lori Farrar

Project Manager

Appendix B: Sources of evidence considered by the Committee

A          The assessment report for this appraisal was prepared by Southampton Health Technology Assessments Centre:

• Picot J, Cooper K, Bryant J, et al. The clinical and cost-effectiveness of bortezomib and thalidomide for the first-line treatment of multiple myeloma. February 2010.

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, assessment report and the appraisal consultation document (ACD). Organisations listed in I and II were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I            Manufacturers/sponsors

• Celgene
• Janssen-Cilag

II           Professional/specialist, patient/carer and other groups:

• Myeloma UK
• Leukaemia CARE
• Macmillan Cancer Support
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Myeloma Forum

The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on bortezomib and thalidomide by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Gordon Cook, Director of Blood and Marrow Transplantation, Leeds; Consultant Haematologist & Honorary Senior Lecturer, University of Leeds, nominated by UK Myeloma Forum – clinical specialist
• Dr Steven Schey, Consultant Haematologist, nominated by Royal College of Physicians – clinical specialist
• Dr Kwee Yong, Reader & Honorary Consultant, nominated by the Royal College of Pathologists – clinical specialist
• Mr Eric Low, Chief Executive (Myeloma UK), nominated by Myeloma UK­ – patient expert
• Mr Michael Brown, nominated by Myeloma UK­–patient expert