title: The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation.
abstract: BACKGROUND
  Multiple myeloma (MM) is the second most common haematological cancer in the UK. MM is not curable but can be treated with a combination of supportive measures and chemotherapy that aim to extend the duration and quality of survival. The majority of patients are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation (SCT), and so they are offered single-agent or combination chemotherapy. Combination therapies typically include chemotherapy with an alkylating agent and a corticosteroid. More recently, combination therapies have incorporated drugs such as thalidomide (Thalidomide Celgene®, Celgene) and bortezomib (Velcade®, Janssen-Cilag).
  
  
  OBJECTIVE
  To assess the clinical effectiveness and cost-effectiveness of bortezomib or thalidomide in combination chemotherapy regimens with an alkylating agent and a corticosteroid for the first-line treatment of MM.
  
  
  METHODS
  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 were also searched. Experts in the field were asked to identify additional published and unpublished references.
  
  
  METHODS
  Titles and 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. 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. 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).
  
  
  RESULTS
  A total of 1436 records were screened and 40 references were retrieved for the systematic review of clinical effectiveness. Five randomised controlled trials (RCTs) met the inclusion criteria for the review: one RCT evaluated VMP, three evaluated MPT and one evaluated CTDa. The comparator in all of the included trials was MP. The review found that VMP and MPT can both be considered more clinically effective than MP for the first-line treatment of MM in people for whom high-dose therapy and SCT would not be appropriate. CTDa was more effective than MP in terms of complete response but data on survival outcomes did not meet the inclusion criteria. Cost-effectiveness analysis indicated that MPT has a greater probability of being cost-effective than either VMP or CTDa.
  
  
  CONCLUSIONS
  For most RCTs, details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat principles but none adequately reported data censoring. Only one RCT contributed data on VMP and the published peer-reviewed follow-up data were immature. For MPT, overall survival data from two trials were eligible for inclusion but the doses of thalidomide differed between the trials and the treatment period was not reflective of current UK practice so the generalisability of the findings was uncertain. Two RCTs had a maintenance phase with thalidomide that did not meet the inclusion criteria so some of these results were not eligible for the review. Limited evidence on health-related quality of life (HRQoL) was provided by the single trial of VMP versus MP.
  
  
  CONCLUSIONS
  Service provision is unlikely to change greatly. As uncertainties remain, further research is needed regarding the use of bortezomib- and thalidomide-containing combination regimens. Head-to-head trials of bortezomib- and thalidomide-containing combination regimes are required, including assessments of patient HRQoL in response to treatment.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Southampton Health Technology Assessments Centre, Southampton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Picot
authors.forename: K
authors.initials: K
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Bryant
authors.forename: A J
authors.initials: AJ
authors.lastname: Clegg
mesh_terms: D000305:Adrenal Cortex Hormones / Q000191:economics / Q000627:therapeutic use; D000477:Alkylating Agents / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000191:economics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000191:economics / Q000627:therapeutic use; D000069286:Bortezomib; D003362:Cost-Benefit Analysis; D003520:Cyclophosphamide / Q000191:economics / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D008558:Melphalan / Q000191:economics / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000191:economics / Q000627:therapeutic use; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013792:Thalidomide / Q000191:economics / Q000627:therapeutic use
chemical_list: D000305:Adrenal Cortex Hormones; D000477:Alkylating Agents; D001897:Boronic Acids; D007166:Immunosuppressive Agents; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003520:Cyclophosphamide; D008558:Melphalan