Bortezomib monotherapy, in its licensed indication, is not recommended for the treatment of patients with multiple myeloma except for use in well-designed clinical studies that focus on the establishment of the position of bortezomib in the pathway of care for people with multiple myeloma in comparison with other agents that are currently used in clinical practice in England and Wales.

Bortezomib (Janssen-Cilag Ltd) is an anticancer drug that belongs to a novel class of drugs known as proteasome inhibitors. Bortezomib has a UK marketing authorisation as monotherapy for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation. For further information about the drug, see the ‘Summary of product characteristics’ (SPC).

Bortezomib treatment is associated with peripheral neuropathy, myelosuppression and other side effects. For full details of side effects and contraindications, see the SPC.

The net price of bortezomib is £762.38 for a 3.5-mg vial (excluding VAT; ‘British national formulary’, 51st edition). The cost per patient for a course of six cycles of treatment would be approximately £18,000. Costs may vary in different settings because of negotiated procurement discounts.

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of bortezomib and a review of this submission by the evidence review group (ERG) (appendix B).

The manufacturer’s submission approached the decision problem by comparing the clinical effectiveness of bortezomib with that of high-dose dexamethasone (HDD) based on the results of the APEX (Assessment of Proteasome Inhibition for Extending Remissions) randomised controlled trial (RCT). The population under consideration in the decision problem consisted of people with multiple myeloma at first relapse or subsequent relapse; however, the manufacturer’s submission placed emphasis on patients at first relapse. The treatment protocol in the intervention arm of the APEX RCT was eight 3-week cycles of bortezomib followed by three 5‑week cycles of bortezomib, whereas the SPC recommends up to eight cycles of bortezomib. The manufacturer considered HDD to be the most appropriate comparator because it is an effective monotherapy agent for the treatment of multiple myeloma that is commonly used in clinical practice in the UK. In addition, HDD was the comparator agreed as the basis for regulatory approval of the APEX RCT. The primary outcome measure was time to disease progression. Secondary endpoints included overall survival, response rate, health-related quality of life (QoL) and adverse events.

Interim analyses of the APEX trial at a predetermined time interval (median follow-up of 8.3 months) found that people taking bortezomib had a significant prolongation of the median time to disease progression (6.2 vs. 3.5 months, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.44 to 0.69; p < 0.001), and a significantly improved overall survival (HR 0.57, 95% CI 0.40 to 0.81; p = 0.001) compared with people receiving HDD. Following the predetermined interim analysis, the independent data monitoring committee deemed it unethical to continue with the trial, and recommended that people in the HDD arm should be offered bortezomib. Updated analyses were performed at 15.8 months and 22 months of follow-up.

The manufacturer’s submission provided cost-effectiveness evidence using a state-transition-model described as ‘semi-Markov’ to compare bortezomib with HDD. The input data used to model disease progression and survival were based on an observational study (the Mayo Observational study) as well the APEX RCT results at interim analysis (median 8.3 months follow-up). The model had a 15-year time horizon with 3-month and 6-month cycles during the first 12 months, and 1-year cycles from 12 months onwards. The base-case included people at first relapse only, resulting in a point estimate of the incremental cost-effectiveness ratio (ICER) of £31,000 per life year gained (LYG). One-way sensitivity analysis resulted in a range of ICERs from £28,000 to £31,000 per LYG. Three scenario analyses were presented.

• When 40% of patients entered the model at first relapse and 60% at second or subsequent relapse, the ICER was £40,000 per LYG.
• When bortezomib treatment was stopped at three cycles for patients who had not responded, the ICER was £28,000 per LYG.
• When bortezomib was used in combination with HDD, the ICER was £28,000 per LYG.

In an additional analysis produced in response to questions raised in the evidence-review phase, the base-case cost per LYG of £31,000 was estimated to translate to £38,000 per quality-adjusted life year (QALY). However, the manufacturer requested that due consideration be given to the assertion that it is more appropriate to measure cost effectiveness in terms of cost per LYG in patients with multiple myeloma. The manufacturer argued that survival gain is the single most important outcome for people with relapsed multiple myeloma, that there is a lack of robust utility data to compute QALYs for people with relapsed multiple myeloma and that the EuroQoL-5D is not sensitive to some important facets of multiple myeloma.

The ERG raised a number of issues concerning the manufacturer’s submission.

• Lack of standardised treatment for relapsed and refractory multiple myeloma in clinical practice in the NHS means that there is no obvious comparator other than dexamethasone. There are various alternative treatment options including thalidomide, anti-cancer chemotherapy and repeat stem cell transplant.
• Lack of clarity and detail in reporting of the APEX RCT made the interpretation of clinical effectiveness results difficult.
• Measures of health-related QoL were not applied in the manufacturer’s economic model, in which cost effectiveness was expressed in terms of cost per LYG. An estimate of the base case cost per QALY gained was provided by the manufacturer at the request of the ERG.
• The overall structure of the model reflected treatment progression rather than the natural history of multiple myeloma and it may not adequately have captured important issues such as the impact of time to relapse on cost effectiveness.
• Adverse effects were not included in the economic model, either in terms of reduction in QoL or increased resource use.
• The model may have overestimated the effect of treatment on disease progression and survival compared with treatment effects demonstrated in the APEX RCT.
• Concerns were raised over the generalisability of the data used to inform inputs to the economic model to treatment practice in the NHS in England and Wales.
• The ERG’s review of sensitivity analyses indicated a greater variability in cost effectiveness estimates than was presented in the manufacturer’s submission. The ERG also presented a combination of the three scenarios described in the manufacturer’s submission resulting in a range of ICERs from £27,000 to £45,000 per LYG.

The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of bortezomib, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of bortezomib by people with multiple myeloma, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee considered current practice for the treatment of relapsed and refractory multiple myeloma in England and Wales. It noted that a variety of treatment options are currently used, and that the selection of treatment depends in particular on patient-specific factors such as duration of first remission, age and comorbidity. The Committee further noted that there is a lack of consensus on the pathway of care and timing of various treatments for people with multiple myeloma and for relapsed and refractory multiple myeloma in particular. It also noted the substantial amount of ongoing research in this area, including the use of novel therapies, established therapies, and combinations of therapies at various stages of disease. The Committee concluded that the position of bortezomib in the clinical pathway of care for people with multiple myeloma is uncertain at present and that it should be established more clearly by the results of ongoing research.

The Committee considered the framing of the decision problem in the manufacturer’s submission. The Committee discussed the explanation given in the manufacturer’s submission for the selection of HDD as the only relevant comparator. Although the Committee accepted that HDD is an appropriate comparator, it also noted that other agents including thalidomide are commonly used in current UK practice, particularly at first relapse. The Committee did not accept that these alternatives should be rejected as potential comparators on the grounds that some do not currently hold a UK marketing authorisation. Furthermore, the Committee was of the opinion that a lack of standardisation in the current management of multiple myeloma should not preclude efforts to establish the clinical and cost effectiveness of bortezomib within the spectrum of treatment options used in current practice in the NHS in England and Wales.

The Committee heard from clinical specialists that when bortezomib is used in the NHS in England and Wales it is usually given in combination with dexamethasone. Moreover, the manufacturer had presented evidence of the potential additional clinical and cost effectiveness of this combination over bortezomib monotherapy in comparison with HDD. The Committee was, however, mindful that the current UK marketing authorisation for bortezomib is for monotherapy only.

The Committee discussed the outcomes measured in the APEX RCT, of which time to disease progression was the primary endpoint, and overall survival, response rate, adverse events and health-related QoL were secondary endpoints. The Committee accepted that these endpoints were appropriate and relevant to this appraisal.

The Committee considered the evidence for the clinical effectiveness of bortezomib for the treatment of people with multiple myeloma who had received at least one prior therapy and had either undergone, or were considered unsuitable for, bone marrow transplantation. It accepted that the only RCT comparing bortezomib with other therapies that included patients with multiple myeloma at first relapse was the APEX study, which compared bortezomib with HDD. The Committee discussed the results of this study, noting the difficulties in interpreting the results because of the lack of clarity in reporting, the high degree of crossovers and the early termination of the trial. The Committee considered statements from patient experts and clinical specialists that bortezomib provides benefit when other treatment options have not done so or have ceased to do so. It noted that, for some patients, there are significant side effects associated with bortezomib treatment, notably peripheral neuropathy. The Committee concluded that bortezomib has shown clinical benefits compared with HDD, but that there remain uncertainties over its position in the clinical pathway of care for people with multiple myeloma, specifically when compared with alternative treatments currently in use in the NHS in England and Wales.

The Committee considered the evidence provided by the manufacturer on the cost effectiveness of bortezomib. The Committee was mindful that various treatment options are used in current practice, and that the model only provided an indication of cost effectiveness compared with HDD. The Committee considered the base-case and sensitivity analyses of the cost effectiveness of bortezomib compared with HDD. It discussed the issues raised by the ERG about the structure, methods and assumptions of the model as summarised in paragraph 3.5. The Committee concluded that the base-case cost per LYG had been underestimated and that there is greater variability in the cost effectiveness of treatment than presented in the manufacturer’s submission. The Committee therefore concluded that bortezomib had not been shown to be cost effective compared with current practice in the NHS in England and Wales.

The Committee con sidered the scenarios presented in the manufacturer’s submission and ERG report. It was persuaded that bortezomib becomes less cost effective compared with HDD when used at second or later relapse compared with its use at first relapse. The Committee heard from clinical specialists that, in their view, it would be inappropriate to restrict bortezomib to people who had experienced a specific number of relapses. The clinical specialists indicated that selection of treatment is patient and disease specific, and that it is currently unclear how a subgroup of patients who might gain more benefit from bortezomib than others might be defined. The Committee concluded that it could be inappropriate to make any recommendation for bortezomib for a subgroup of patients specified by the number of relapses they had experienced.

The Committee discussed the manufacturer’s assertion that it is more appropriate to consider cost per LYG rather than QALY gained as the measure of cost effectiveness in patients with multiple myeloma. The Committee did not accept the premises for this assertion, concluding that multiple myeloma and its treatments (including adverse effects of treatment) would have significant effects on health-related QoL, that such effects are important to patients, and that sources of information to allow estimation of QALYs gained are available. The Committee reviewed the additional analysis provided by the manufacturer at the request of the ERG, which estimated the impact of health-related QoL on the base-case ICER. The Committee was not persuaded that the utilities assumed for patients with relapsed multiple myeloma were an accurate reflection of the significant impairments in QoL that those in this clinical situation might experience. The Committee considered that the manufacturer’s base-case ICER of approximately £38,000 per QALY was therefore a substantial underestimate.

Summary of the considerations

The Committee was not persuaded that the economic model provided by the manufacturer had shown bortezomib to be cost effective compared with current practice in the NHS in England and Wales.

The Committee considered it important that the position of bortezomib in the clinical management of multiple myeloma should continue to be established by ongoing and planned clinical trials that compare bortezomib with other treatments that are used in the NHS in England and Wales. It also considered it important for data on health-related QoL and long-term effectiveness of bortezomib to be collected.

The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

Proposed recommendations for further research

The Committee noted that there are a number of ongoing studies of the treatment of multiple myeloma, some of which compare bortezomib in combination with other therapies with regimens that do not contain bortezomib.

The Committee considered that further research into the effectiveness of bortezomib for the treatment of multiple myeloma is required. Such studies should include:

• comparisons with other agents that are currently used in clinical practice in the NHS in England and Wales in order to establish the position of bortezomib in the pathway of care for people with multiple myeloma more clearly
• a robust design, adequate sample size and appropriate statistical analysis
• analysis of the effect of treatment on health-related QoL and adverse effects
• a consideration of subgroups of patients in whom the treatments may be particularly effective.

NICE has issued the following related technology appraisal.

• Erythropoietin for anaemia induced by cancer treatment (publication date to be confirmed).

The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.

Appendix A. Appraisal Committee members and NICE project team

A. Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

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 Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Mr Brian Buckley
Vice Chairman, InContact

Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine

Professor Mike Campbell
Statistician, University of Sheffield

Professor David Chadwick
Professor of Neurology, Walton Centre for Neurology and Neurosurgery

Dr Mark Chakravarty
Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals ( UK) Ltd

Dr Peter I Clark
Consultant Medical Oncologist, Clatterbridge Centre for Oncology NHS Trust, Merseyside

Dr Mike Davies
Consultant Physician, University Department of Medicine & Metabolism, Manchester Royal Infirmary

Mr Richard Devereaux-Phillips
Public Affairs Manager, Medtronic Ltd

Professor Jack Dowie
Health Economist, London School of Hygiene

Dr Fergus Gleeson
Consultant Radiologist, The Churchill Hospital, Oxford

Ms Sally Gooch
Former Director of Nursing & Workforce Development, Mid Essex Hospital Services NHS Trust

Mr Sanjay Gupta
Stroke Services Manager, Basildon and Thurrock University Hospitals NHS Trust

Professor Philip Home
Professor of Diabetes Medicine, University of Newcastle upon Tyne

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Professor Peter Jones
Professor of Statistics & Dean Faculty of Natural Sciences, Keele University

Dr Mike Laker
Medical Director, Newcastle Hospitals NHS Trust

Dr George Levvy
Lay representative

Ms Rachel Lewis
Nurse Advisor to the Department of Health

Mr Terence Lewis
Mental Health Consultant, National Institute for Mental Health in England

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Ruairidh Milne
Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology

Dr Neil Milner
General Medical Practitioner, Sheffield

Dr Rubin Minhas
General Practitioner, CHD Clinical Lead, Medway PCT

Mr Miles Scott
Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, Adur, Arun and Worthing PCT

Dr Ken Stein
Senior Lecturer in Public Health, Peninsula Medical School, University of Exeter

Professor Andrew Stevens
Professor of Public Health, University of Birmingham

B. 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 advisor and a project manager.

Helen Chung and Ebenezer Tetteh
Technical Leads

Elisabeth George
Technical Advisor

Emily Marschke
Project Manager

Appendix B. Sources of evidence considered by the Committee

The following manufacturer/sponsor provided a submission for this appraisal:

• Janssen-Cilag Ltd

The evidence review group report for this appraisal was prepared by Southampton Health Technology Assessment Centre (SHTAC):

C Green, J Bryant, A Takeda, K Cooper, A Clegg, A Smith, and M Stephens, ‘Bortezomib for the treatment of multiple myeloma patients’ , April 2006.

The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on bortezomib by providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).

• Professor Gareth Morgan, Professor of Haematology & Head of Clinical Unit, The Institute of Cancer Research – clinical specialist
• Dr Graham Jackson, Consultant Haematologist, British Committee for Standards in Haematology – clinical specialist
• Dr Stephen A Schey, Chair, UK Myeloma Forum – clinical specialist (present at the Appraisal Committee meeting on behalf of Dr Graham Jackson who was unable to attend)
• Mr Brian Jago, nominated by the International Myeloma Foundation – patient expert
• Mr Eric Low, Chief Executive, International Myeloma Foundation (UK) – patient expert

Appendix C. List of organisations involved in this appraisal

The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the Appraisal Consultation Document (ACD) and supporting evidence. Consultee organisations have the opportunity to appeal against the Final Appraisal Determination.

Professional/specialist and patient/carer groups:

• Cancer BACUP International Myeloma Foundation ( UK )
• Leukaemia Care Society
• Long Term Medical Conditions Alliance
• Macmillan Cancer Relief
• Marie Curie Cancer Care
• National Cancer Alliance
• National Council for Palliative Care
• Tenovus Cancer Information Centre
• Association of Cancer Physicians
• Association of Surgeons of Great Britain and Ireland
• British Association of Surgical Oncology
• British Oncological Association
• British Oncology Pharmacy Association (BOPA)
• British Psychosocial Oncology Society
• British Society for Haematology
• Cancer Research UK
• Community Practitioners' & Health Visitors Association
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians of Edinburgh
• Royal College of Physicians' Medical Oncology Joint Special Committee
• Royal College of Radiologists
• Royal College of Surgeons
• Royal Pharmaceutical Society
• UK Myeloma Forum
• Department of Health
• Sedgefield PCT
• Southend PCT
• Welsh Assembly Government

Commentator organisations (without the right of appeal):

• Board of Community Health Councils in Wales
• British National Formulary
• Medicines and Healthcare products Regulatory Agency (MHRA)
• National Public Health Service for Wales
• National Coordinating Centre for Health Technology Assessment (NCCHTA)
• NHS Confederation
• NHS Purchasing and Supplies Agency
• NHS Quality
• Baxter Healthcare Ltd (cyclophosphamide)
• Bristol-Myers Squibb Pharmaceuticals Ltd (carmustine)
• Clonmel Healthcare Ltd (vincristine)
• GlaxoSmithKline (melphalan)
• Mayne Pharma plc (doxorubicin, vincristine)
• Medac (UK) (doxorubicin)
• Pfizer Ltd (cyclophosphamide, doxorubicin)
• Pharmion Ltd (thalidomide)
• Schering-Plough Ltd (interferon alfa-2b)
• Teva Pharmaceuticals Ltd (doxorubicin
• National Collaborating Centre for Cancer
• Institute of Cancer Research
• King's College Hospital's haemato-oncology department
• Leukaemia Research Fund
• MRC Clinical Trials Unit
• National Cancer Research Institute
• Scottish Medicine Consortium