Proposal for the Inclusion of Bortezomib, Lenalidomide and Thalidomide in the WHO Model List of Essential Medicines for the First-Line Treatment of Multiple Myeloma Report prepared by: Vanessa Piechotta, Marius Goldkuhle, Prof. Dr. med. Christof Scheid, PD Dr. med. Nicole Skoetz Involved actors: (1) Department I of Internal Medicine Director: Prof. Dr. med. Michael Hallek University Hospital of Cologne Kerpener Str. 62 50937 Cologne Germany (2) Cochrane Cancer CONTENT List of abbreviations ................................................................................................................................ 2 General Items .......................................................................................................................................... 5 1. Summary statement of the proposal for inclusion, change or deletion 5 2. Relevant WHO technical department and focal point 5 3. Name of organizations consulted and supporting the application 5 4. International Nonproprietary Name and Anatomical Therapeutic Chemical code of the medicine 5 5. Dose forms and strengths proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths 5 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class 10 Treatment details, public health relevance and evidence appraisal and synthesis .............................. 11 7. Treatment details (requirements for diagnosis, treatment and monitoring) 11 Diagnosis ................................................................................................................................... 11 First-line treatment with bortezomib ....................................................................................... 11 First-line treatment with lenalidomide .................................................................................... 12 First-line treatment with thalidomide ...................................................................................... 12 Monitoring ................................................................................................................................ 12 8. Information supporting the public health relevance 13 9. Review of benefits: summary of evidence of comparative effectiveness 15 Methodological approach ........................................................................................................ 15 Description of studies ............................................................................................................... 15 Risk of Bias ................................................................................................................................ 17 Efficacy of the interventions ..................................................................................................... 20 10. Review harms and toxicity: summary of evidence of safety 28 Safety of the interventions ....................................................................................................... 28 Summary of Findings (SoF) ....................................................................................................... 48 11. Summary of available data on comparative cost and cost-effectiveness of the medicine. 51 Regulatory information ......................................................................................................................... 56 12. Summary of regulatory status and market availability of the medicine 56 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopoeia) 58 References ............................................................................................................................................. 59 Appendix 1: Methodological approach ................................................................................................. 66 Appendix 2: Search strategies ............................................................................................................... 75 1 LIST OF ABBREVIATIONS AE Adverse events ASCT Autologous stem cell transplantation ATC Anatomical therapeutic chemical BNF British National Formulary CI Confidence interval CR Complete response CRAB Calcemia, renal, anemia, bone lesions CT Computed tomography CTD Cyclophosphamide thalidomide dexamethasone CTDa Cyclophosphamide thalidomide dexamethasone (attenuated) DALY Disability-adjusted life-years DDD Defined Daily Dose EMA European Medicines Agency EML Essential Medicines List ESMO - MCBS European Society for Medical Oncology Magnitude of Clinical Benefit Scale EU European Union FDA Food and Drug Administration FDF finished dosage form GBP Great British Pound GRADE Grading of Recommendations Assessment, Development and Evaluation HC Health Canada HIC High-income country HR Hazard ratio HTA Health Technology Assessment ICER Incremental cost-effectiveness ratio IFNγ Interferon gamma IL Interleukin INN International Nonproprietary Name i.v. Intravenous LIC Low-income country 2 LMIC Low- and middle-income country MA Meta-analysis MD Mean Differences MDCT Multi-detector computed tomography MIC Middle-income country MM Multiple myeloma MP Melphalan, prednisone MPc Melphalan, prednisone continuous MPT Melphalan, prednisone, thalidomide MPR-R Melphalan, prednisone, lenalidomide (revlimid), followed by lenalidomide (revlimid) maintenance MR Minimal response MRI Magnetic resonance imaging NHS National Health Service NICE National Institute for Health and Care Excellence NK Natural killer NMA Network meta-analysis OS Overall survival PET Positron emission tomography PFS Progression-free survival PMDA (Japanese) Pharmaceuticals and Medical Devices Agency PR Partial response QALY Quality-adjusted life-years RCD Lenalidomide (revlimid), cyclophosphamide, dexamethasone RCPc Lenalidomide (revlimid), cyclophosphamide, prednisone continuous RCT Randomised controlled trial RD Lenalidomide (revlimid), dexamethasone RDc Lenalidomide (revlimid), dexamethasone continuous RMP Lenalidomide (revlimid), melphalan, prednisone RMPc Lenalidomide (revlimid), melphalan, prednisone continuous RR Risk ratio SAE Serious adverse events 3 s.c. Subcutaneous SLiM Sixty, light, magnetic SD Standard deviation SoF Summary of Findings SR Systematic review TCD Thalidomide, cyclophosphamide, dexamethasone TDc Thalidomide, dexamethasone continuous TGA Therapeutic Goods Administration TMP Thalidomide, melphalan, prednisone TMPc Thalidomide, melphalan, prednisone continuous TNF- α Tumor necrosis factor-α UI Uncertainty interval UK United Kingdom USA United States of America VMP Bortezomib (velcade), melphalan, prednisone VMPc Bortezomib (velcade), melphalan, prednisone continuous VRD Bortezomib (velcade), lenalidomide (revlimid), dexamethasone VRDc Bortezomib (velcade), lenalidomide (revlimid), dexamethasone continuous VTDc Bortezomib (velcade), thalidomide, dexamethasone continuous VTMP Bortezomib (velcade), thalidomide, melphalan, prednisone VTPc Bortezomib (velcade), thalidomide, prednisone continuous WHO World Health Organization 4 GENERAL ITEMS 1. Summary statement of the proposal for inclusion, change or deletion This application advocates the inclusion of bortezomib, lenalidomide and thalidomide in the core list of essential medicines for the treatment of newly diagnosed multiple myeloma patients in non-transplant settings. Studies of combination regimens of the indicated medicines showed significant, clinically meaningful prolongation of overall and progression free survival, yet an increased number of adverse events. Multiple myeloma (MM) is the second most common haematological malignancy with a global incidence of 138,509 (95% uncertainty interval [UI]: 121,000 to 155,480) and an age-standardized incidence rate of 2.1 per 100,000 population (95% UI: 1.8 to 2.3) in 2016. Since 1990, the incidence rate increased by 126% worldwide (1). 2. Relevant WHO technical department and focal point Lorenzo Moja, Technical Officer, EML Secretariat 3. Name of organizations consulted and supporting the application Department I of Internal Medicine, University Hospital of Cologne Cochrane Cancer 4. International Nonproprietary Name and Anatomical Therapeutic Chemical code of the medicine International Nonproprietary Name (INN) Bortezomib Lenalidomide Thalidomide Anatomical Therapeutic Chemical (ATC) In the ATC classification system, bortezomib, lenalidomide and thalidomide are classified as “antineoplastic and immunomodulating agents”. Furthermore bortezomib is classified as “other neoplastic agents” and can be identified by the ATC code: L01XX32 (2). Lenalidomide and thalidomide are further classified as “other immunosuppressant” and can be identified by the ATC codes: L04AX04 and L04AX02, respectively (3). 5. Dose forms and strengths proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths Internationally / On the global market, bortezomib is currently available in different vial sizes (ranging from 1 mg to 3.5 mg) (cf. table 1). Before intravenous (i.v.) or subcutaneous (s.c.) injection, the lyophilized drug needs to be reconstituted. For reconstitution, 1 ml of sterile 9 mg/ml (0.9%) sodium chloride solution per 1 mg of the drug needs to be added to the bortezomib containing vial (4). Lenalidomide and thalidomide are both internationally available in different capsule sizes (ranging from 5 mg to 25 mg, or 50 mg to 200 mg, respectively) (cf. tables 2 and 3). The capsules are to be taken orally (5). 5 Tables 1, 2, and