TABLE I.
Primary and additional publications of identified randomized trials of bortezomib in multiple myeloma
| Study | Primarypublication and objective | Additional publications and objectives (when available) |
|---|---|---|
| Fully published trials | ||
| apex | Richardson et al., 200523 | |
| Efficacy: bortezomib compared with high-dose dexamethasone in relapsed disease | ||
| Richardson et al., 200732 | Update of apex results | |
| Richardson et al., 200733 | Extended follow-up | |
| San-Miguel et al., 200834 | Subgroup analysis of patients with renal impairment | |
| Chanan–Khan et al., 200835 | Herpes zoster events in bortezomib-treated patients | |
| Lee et al., 200836 | Health-related qol analysis | |
| Niesvizky et al., 200837 | Response and clinical benefit in bortezomib-treated patients | |
| Richardson et al., 200938 | Reversibility of peripheral neuropathy in bortezomib-treated patients | |
| Vogl et al., 200939 | Prior exposure to specific therapies | |
| San Miguel et al., 201140 (abs.) | Analysis of four phase iii studies: apex, mmy300, vista, and hovon65 to assess the risk of second primary malignancies after bortezomib treatment | |
| Kaura and Dranitsaris, 201278 (abs.) | Compare the number needed to treat as a measure of drug benefit from data in the apex study and a study of lenalidomide50 | |
| mmy-3001 | Orlowski et al., 200720 | |
| Efficacy and safety: pegylated liposomal doxorubicin plus bortezomib compared with bortezomib monotherapy in relapsed or refractory | ||
| disease | Sonneveld et al., 200841 | Subgroup analysis of patients who received prior thalidomide or lenalidomide |
| Shah et al., 200842 (abs.) | Subgroup analysis of patients with paraprotein heavy- and light-chain types | |
| Shah et al., 200843 (abs.) | Subgroup analysis of patients with bone marrow involvement | |
| Buda et al., 200944 (abs.) | Investigate association between gene polymorphisms and response | |
| vista | San Miguel et al., 200824 | |
| Efficacy: melphalan prednisone compared with melphalan prednisone bortezomib in previously untreated disease | ||
| San Miguel et al., 200845 (abs.) | Updated follow-up and results of subsequent therapy | |
| Harousseau et al., 200846 | Assess the prognostic impact of response on time-to-event parameters | |
| Dhawan et al., 200947 (abs.) | Health-related qol | |
| Dimopoulos et al., 200948 | Subgroup of patients with renal impairment | |
| Mateos et al., 201049 | Confirm os for melphalan–prednisone–bortezomib compared with melphalan–prednisone. Explore whether melphalan–prednisone–bortezomib induces relapses that are more resistant, and whether melphalan–prednisone–bortezomib used upfront was more effective than melphalan–prednisone | |
| Dimopoulos et al., 201150 | Frequency, characteristics, reversibility, and potential risk factors of peripheral neuropathy | |
| Favis et al., 201151 | Genetic variation associated with bortezomib-induced peripheral neuropathy | |
| Delforge et al., 201152 | Effects of bortezomib on bone events, remodelling, and healing | |
| San Miguel et al., 201153 (abs.) | 5-Year follow-up data | |
| Ludwig | Ludwig et al., 200918 (abs.) | |
| Efficacy and toxicity: bortezomib thalidomide dexamethasone compared with bortezomib thalidomide dexamethasone plus cyclophosphamide in previously untreated patients | ||
| gimema | Cavo et al., 201015 | |
| Effectiveness: bortezomib–thalidomide–dexamethasone compared with thalidomide–dexamethasone as front-line therapy | ||
| Cavo et al., 200958 (abs.) | Preliminary publication | |
| Brioli et al., 201159 (abs.) | Impact of novel agents on peripheral stem-cell collection | |
| Cavo et al., 201160 (abs.) | Per-protocol analysis of 321 patients who received the entire treatment program | |
| Cavo et al., 201261 | Efficacy and safety: bortezomib thalidomide dexamethasone compared with thalidomide dexamethasone as consolidation therapy after asct in newly diagnosed disease | |
| Tacchetti et al., 201162 (abs.) | Analysis of bortezomib- and thalidomide-induced peripheral neuropathy | |
| ifm2005/01 | Harousseau et al., 201016 | |
| Induction: bortezomib–dexamethasone compared with vincristine–doxorubicin–dexamethasone before asct | ||
| Avet–l’Oiseau et al., 201055 | Effectiveness in overcoming the poor prognosis linked to translocation t(4;14)(p16;q32) in elderly patients | |
| Moreau et al., 201056 | Evaluate stem-cell collection in the dexamethasone arm | |
| Moreau et al., 201157 | Achievement of very good partial response at induction as a prognostic factor for longer pfs | |
| Lonial | Lonial et al., 201017 | |
| Evaluate the safety and efficacy of combining bortezomib with high dose melphalan and the conditioning for high-dose therapy and asct | ||
| Mateos, Spanish Myeloma Group, gem2005mas65 | Mateos et al., 201019 | |
| Compare bortezomib–melphalan–prednisone plus maintenance with bortezomib–thalidomide–prednisone plus maintenance to investigate a bortezomib-based regimen that is less intensive than the regimen used in vista to maintain efficacy and to reduce toxic effects | ||
| Mateos et al., 201164 (abs.) | Phase ii of the 2010 study; all arms were randomly assigned to maintenance with bortezomib–prednisone or bortezomib–thalidomide | |
| Palumbo | Palumbo et al., 201021 | |
| Compare bortezomib–melphalan–prednisone–thalidomide plus maintenance with bortezomib–thalidomide with bortezomib–melphalan–prednisone and no maintenance in newly diagnosed patients | ||
| Bringhen et al., 201054 | Assess the impact of schedule change on clinical outcomes and safety | |
| ifm-2007–02 | Moreau et al., 201128 | |
| Bortezomib–dexamethasone compared with reduced-dose bortezomib–thalidomide–dexamethasone before asct in newly diagnosed disease | ||
| Moreau et al., 201069 (abs.) | Prior abstract publication of main study | |
| Moreau, mmy-3021 | Moreau et al., 201129 | |
| E efficacy and safety: subcutaneous compared with intravenous administration of bortezomib | ||
| Moreau et al., 201168 (abs.) | Pharmacokinetics and pharmacodynamics of subcutaneous compared with intravenous administration of bortezomib | |
| Reece | Reece et al., 201122 | |
| Pharmacokinetics and pharmacodynamics of bortezomib | ||
| mmvar/ifm 2005–04 | Garderet et al., 201230 | |
| Efficacy and safety: triple combination (bortezomib thalidomide dexamethasone) compared with dual combination (thalidomide dexamethasone) in disease progressing or relapsing after asct | ||
| Hjorth | Hjorth et al., 201225 | |
| Low-dose thalidomide–dexamethasone compared with bortezomib–dexamethasone in melphalan-refractory disease | ||
| evolution | Kumar et al., 201226 | |
| Evaluate safety and efficacy of bortezomib dexamethasone lenalidomide, dexamethasone–cyclophosphamide–lenalidomide in newly diagnosed patients | ||
| Kumar et al., 200965 | Abstract report of main study | |
| Kumar et al., 201166 | Abstract report of main study | |
| Kumar et al., 201167 | Minimal residual disease assessment with multiparameter flow cytometry | |
| Sharma | Sharma et al., 201227 | |
| Determine the efficacy and safety of adding bortezomib to a preparative regimen of arsenic trioxide, ascorbic acid, and melphalan in newly diagnosed patients | ||
| Sharma et al., 200963 (abs.) | Previous publication | |
| hovon-65/gmmg-hd4 | Sonneveld et al., 201231 | |
| Induction: vincristine–doxorubicin–dexamethasone compared with bortezomib–doxorubicin–dexamethasone plus high dose melphalan and asct; maintenance: thalidomide compared with bortezomib in newly diagnosed disease | ||
| Sonneveld et al., 200870 (abs.) | Abstract of interim analysis | |
| Neben et al., 201271 | Prognostic value of 12 chromosomal abnormalities | |
| Abstracts of interim analyses | ||
| Mellqvist | Mellqvist et al., 200979 (abs.) | |
| Explore the effect of a 21-week consolidation period of single-agent bortezomib given during months 3–8 after asct | ||
| Mellqvist et al., 201172 (abs.) | Updated results | |
| Vantage088 | Dimopoulos et al., 201180 (abs.). | |
| Efficacy and safety: bortezomib plus vorinostat compared with bortezomib plus placebo in relapsed or refractory disease | ||
| Dimopoulos | Dimopoulos et al., 201181 (abs.) | |
| Efficacy: bortezomib dexamethasone compared with bortezomib dexamethasone cyclophosphamide as second-line treatment | ||
| upfront | Niesvizky et al., 201182 (abs.) | |
| Safety and efficacy: bortezomib thalidomide dexamethasone compared with bortezomib dexamethasone and with bortezomib melphalan prednisone in newly diagnosed elderly patients | ||
| Niesvizky et al., 200975 (abs.) | Interim analysis | |
| Niesvizky et al., 201176 (abs.) | Patient-reported qol | |
| Orlowski | Orlowski et al., 201283 (abs.) | |
| Efficacy and safety: siltuximab plus bortezomib compared with bortezomib plus placebo in relapsed or refractory disease | ||
| pethema/gem05 | Rosinol et al., 201284 (abs.) | |
| Effectiveness: thalidomide–dexamethasone compared with bortezomib–thalidomide–dexamethasone and with vbmcp/vbad/bortezomib in newly diagnosed disease; presents data on time to progression | ||
| Rosinol et al., 200973 (abs.) | Interim analysis | |
| Rosinol et al., 201174 (abs.) | Data on response rate and time to progression | |
| panorama1 | San Miguel et al., 201285 (abs.) | |
| Reports a blinded safety analysis from a randomized controlled trial: panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone in relapsed or refractory disease | ||
| San-Miguel et al., 201177 (abs.) | Update on 273 patients | |
| Systematic reviews | ||
| Palumbo | Palumbo et al., 20095 | |
| Systematic review of evidence for an update to a previous guideline for the management of multiple myeloma | ||
| Palumbo | Palumbo and Rajkumar 201012 | |
| Review of novel agents and discussion of the role of asct | ||
| Kumar | Kumar et al., 201110 | |
| Indirect comparison of melphalan–prednisone–thalidomide and melphalan–prednisone–bortezomib | ||
| hta | Picot et al., 201111 | |
| Review 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; includes a systematic review and an economic evaluation | ||
| Piro | Piro et al., 201113 | |
| Systematic review of bortezomib in patients with renal impairment | ||
| Wang | Wang et al., 201214 | |
| Systematic review and meta-analysis of randomized controlled trials of novel agents bortezomib, lenalidomide, and thalidomide in newly diagnosed disease before asct; subgroup analyses were conducted by type of new agent | ||
| Guidelines | ||
| Bird | Bird et al., 20118 | |
| Guidelines for the diagnosis and management of multiple myeloma | ||
| nice technology appraisal guidance 228 | Doss et al., 20119 | |
| Guidelines for the use of bortezomib and thalidomide for first-line treatment of multiple myeloma | ||
| sie, sies, gitmo | Barosi et al., 20127 | |
| Guidelines on the use of thalidomide, bortezomib, and lenalidomide for multiple myeloma | ||
qol = quality of life; abs. = abstract; os = overall survival; asct = autologous stem-cell transplantation; pfs = progression-free survival; vbmcp = vincristine (1.2 mg/m2 intravenously day 1), carmustine (20 mg/m2 intravenously day 1), melphalan 8 mg/m2 orally days 1–4), cyclophosphamide (400 mg/m2 intravenously day 1), prednisone (40 mg/m2 orally days 1–7); vbad= vincristine, carmustine, doxorubicin, and high-dose dexamethasone; nice= U.K. National Institute for Health and Care Excellence.