Data sources

Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from 1999 to 2009 for English-language articles. Bibliographies of articles, grey literature sources and manufacturers' submissions (MSs) were also searched. Experts in the field were asked to identify additional published and unpublished references.

Study selection

Titles and, where available, abstracts were screened for eligibility by two reviewers independently. The inclusion criteria specified in the protocol were applied to the full text of retrieved papers by one reviewer and checked independently by a second reviewer. The inclusion criteria were as follows:

• Interventions Bortezomib in combination with an alkylating agent and a corticosteroid for first-line treatment of MM. Thalidomide in combination with an alkylating agent and a corticosteroid for first-line treatment of MM.
• Comparators (i) The interventions compared with each other or (ii) melphalan or cyclophosphamide in combination with prednisolone/prednisone or dexamethasone.
• Population People with previously untreated MM who are not candidates for high-dose chemotherapy with SCT.
• Outcomes Studies had to report one or more of the following outcomes – overall survival (OS); progression-free survival (PFS); time to progression (TTP); response rates; health-related quality of life (HRQoL); cost-effectiveness [such as incremental cost per quality-adjusted life-year (QALY) gained].

The study types that were eligible for inclusion in the systematic review of clinical effectiveness were:

• randomised controlled trials (RCTs); good-quality observational studies could be considered if the data from available RCTs were incomplete.

And for the systematic review of cost-effectiveness, eligible study types were:

• full cost-effectiveness analyses, cost–utility analyses and cost–benefit analyses.

Data extraction and quality assessment

Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage.

Data synthesis

Studies were synthesised through a narrative review with full tabulation of the results of all included studies.

Economic modelling

A cost–utility decision-analytic model was used to compare the cost-effectiveness estimates of bortezomib in combination with melphalan and prednisolone/prednisone (VMP), thalidomide in combination with cyclophosphamide and attenuated dexamethasone (CTDa), and thalidomide in combination with melphalan and prednisolone/prednisone (MPT) versus melphalan and prednisolone/prednisone (MP). The model used a survival analysis approach to estimate the OS and PFS for each of the interventions for a patient with newly diagnosed MM. The model consisted of cycles of 6 weeks in length, to be consistent with the cycle lengths used for chemotherapy treatment. The model survival curves were derived using trial data for the duration of trial follow-up and an exponential distribution was used to extrapolate beyond the length of the trial. Second-line treatment costs were included. The perspective of the analysis was that of the NHS and Personal Social Services (PSS). The model estimated the lifetime costs and benefits of treatment with discount rates of 3.5%. The intervention effect in terms of improvement in OS and PFS was derived from the systematic review of effectiveness. The outcome of the economic evaluation is reported as cost per QALY gained.

Number and quality of studies

A total of 1436 records were screened and 40 references were retrieved for consideration for the systematic review of clinical effectiveness. Five RCTs met the inclusion criteria for the clinical effectiveness systematic review. One RCT evaluated VMP, three evaluated MPT, and one evaluated CTDa. The comparator in all the included trials was MP. Study quality was uncertain for most RCTs because details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat (ITT) principles but none adequately reported the amount and pattern of data censoring. Two RCTs, one of the MPT versus MP trials and the CTDa versus MP trial, had a maintenance phase with thalidomide that did not meet the inclusion criteria. This meant that some results from these trials were not eligible for inclusion in the systematic review.

Summary of benefits and risks

The evidence from one RCT indicated that combination chemotherapy with VMP was more effective than MP in terms of the primary outcome TTP, and the secondary outcomes of OS and the proportion of participants achieving complete response (CR), or achieving a partial response (PR) or better (response outcomes, not ITT). Adverse events (AEs) occurred in both trial arms. The use of bortezomib was associated with a statistically significant increase in grade 3 AEs.

Evidence from two RCTs indicated that MPT was more effective than MP in terms of these trials' primary outcome of OS, and the secondary outcome of PFS. Three trials provided evidence indicating a statistically significant greater proportion of participants receiving MPT achieved CR. (AiC/CiC information has been removed.) AEs occurred in all MPT, CTDa and MP trial arms. The AEs associated with the use of thalidomide were difficult to summarise. The AE that was most consistently, and statistically significantly, associated with the use of thalidomide was peripheral neuropathy. AEs of thrombosis or embolism, somnolence, infections and constipation were reported as being statistically significantly increased in the thalidomide-containing arms of some trials but not others.

Limited evidence on HRQoL was provided by the single trial of VMP versus MP. This indicated that, after the onset of best response, participants treated with VMP had a higher sustained HRQoL improvement rate in 14 of the 15 European Organisation for Research and Treatment of Cancer QoL questionnaire C30 (EORTC QLQ-C30) scores than those participants receiving therapy with MP.

Summary of cost-effectiveness

The systematic review of published economic evaluations identified five abstracts that did not contain enough information for critical appraisal. The systematic review of quality-of-life (QoL) studies did not find any generic preference-based QoL studies that assessed QoL in the population of interest. However, two studies that used the EORTC QLQ-C30 questionnaire were identified and a mapping algorithm was available to map the EORTC QLQ-C30 to the European Quality of Life-5 Dimensions (EQ-5D).

Two manufacturers submitted evidence to be considered for this review:

• Janssen–Cilag, the manufacturer of bortezomib, constructed a survival model that estimated OS and PFS based on treatment effects from a mixed-treatment comparison (MTC) of the trials. They included second- and third-line treatment. The base-case results from the submission found all treatments to be cost-effective. The incremental cost-effectiveness ratio (ICER) for VMP versus MP is estimated to be £10,498. Furthermore, the ICERs of VMP versus MPT and VMP versus CTDa were estimated to be £11,907 and £10,411, respectively.
• Celgene, the manufacturer of thalidomide, constructed a Markov model with health states for preprogression (with or without AEs), post progression and death. They assumed that survival after disease progression was the same irrespective of first-line treatment. Treatment effects for disease progression were calculated using a random effects MTC. The base-case results from the submission estimated an ICER of £23,381 per QALY gained for MPT versus MP and £303,845 per QALY for VMP versus MPT.

The Southampton Health Technology Assessments Centre (SHTAC) developed an independent survival model. From this independent model, the incremental cost-effectiveness figures versus MP for MPT, VMP and CTDa were £9135, £29,820 and £33,031 per QALY gained, respectively. However, MPT dominated VMP as it was cheaper and more effective.

Sensitivity analyses

The effect of a range of parameter values in the economic model were evaluated in deterministic and probabilistic sensitivity analyses (PSAs). The model results were robust to changes in the parameter values tested. The model results were most sensitive to changes in the values of the hazard ratios for OS. The PSA estimated the probability of each of the treatments to be cost-effective at the £20,000 and £30,000 willingness-to-pay thresholds. MPT has the highest probability of being cost-effective, with probabilities of 0.95 at both the thresholds tested.