Methods

• Design: Randomised open‐label trial conducted at the All India Institute of Medical Science, Delhi, India from Feb 2011 to Sep 2012.

• Sample size: N = 43 patients. Experimental arm (BD) = 22 patients. Control arm (CTD) = 21 patients.

Participants

• Patient Population: Multiple myeloma with light‐chain induced acute renal failure.

• Inclusion/Exclusion Criteria: Not reported.

• Baseline Characteristics: Not reported.

Interventions

• Experimental Arm (BD): IV bortezomib 1.3 mg/m², oral dexamethasone 40 mg both weekly, q 4 weekly.

• Control Arm (CTD): Oral cyclophosphamide 100 mg/m² for 7 days, oral thalidomide 100 mg daily and oral dexamethasone 40 mg/week, q 4 weekly.

• Additional Treatments: Not reported.

Outcomes

• Renal response and myeloma response according to IMWG Criteria.

Notes

• Sponsor/Funding: Not reported.

• Type of Publication (Full text or abstract only): Abstract only.

• Linked to other reports: None.

• IMWG = International Myeloma Working Group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study design described as 'randomised' in title however randomisation methods not reported.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective outcomes measured (e.g. response rate and progression according to IMWG guidelines, number of patients alive). Independent blinded outcomes assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Patient status reported at median follow‐up of 7.5 months.

Selective reporting (reporting bias)

High risk

Key eligibility criteria not reported. Baseline characteristics per arm not reported. Selected adverse events reported only.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 93 centres in the US, Canada, Europe and Israel from Jun 2002 to Oct 2003.

• Sample size: N = 669 patients. Experimental arm (bortezomib) = 333 patients. Control arm (high‐dose dexamethasone) = 336 patients.

• Cross‐over: Patients on the high‐dose dexamethasone were permitted to cross‐over to the bortezomib arm at disease progression.

Participants

• Patient Population: Multiple myeloma patients with measurable progressive disease after 1 to 3 previous treatments.

• Inclusion Criteria: KPS) ≥ 60%; platelets ≥ 50,000/mL³; haemoglobin ≥ 7.5g/dL; ANC ≥750/mL³; creatinine clearance 20 mL/min.

• Exclusion Criteria: Disease refractory to high‐dose dexamethasone; ≥ grade 2 peripheral neuropathy.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Experimental arm: IV bortezomib 1.3 mg/m² on days 1, 4, 8, 11 of cycles 1 to 8 (21‐day cycle) and days 1,8, 15, 22 of cycles 9 to 11 (35‐day cycle). Maximum treatment period = 273 days.

• Control arm: Oral dexamethasone 40 mg on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 to 4 (35‐day cycle) and days 1 to 4 of cycles 5 to 9 (28‐day cycles). Maximum treatment period = 280 days.

• Additional Treatments: Platelet and red‐cell transfusions, neutrophil growth factors and epoetin alfa. IV bisphosphonates unless clinically contraindicated.

Outcomes

• Primary: Time to disease progression.

• Secondary: Overall survival; 1‐year survival; response rate (complete plus partial response); duration of response; time to first evidence of confirmed response; time to first infection ≥ grade 3; incidence of ≥ grade 3 infection; time to first skeletal event; adverse events; health‐related quality of life.

Notes

• Sponsor/Funding: Millennium Pharmaceuticals.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Richardson, 2007 (extended follow‐up data).

• KPS = Karnofsky Performance Status.

• ANC = Absolute Neutrophil Count.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not specified. Central randomisation probably performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression by the European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Response data based on central laboratory analysis.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data for the final analyses of the time to disease progression and the response were censored. Full details of censoring reported.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

Not reported.

Methods

• Design: Exploratory, randomised, open‐label, phase II trial conducted at 10 centres in the US from May 2001 to Jan 2002.

• Sample size: N = 54 patients. Arm A (1.0 mg/m² bortezomib) = 28 patients. Arm B (1.3 mg/m² bortezomib) = 26 patients.

• Trial not designed to conduct formal statistical comparisons between groups.

Participants

• Patient Population: Multiple myeloma patients with relapsed/refractory disease who have received front‐line therapy only.

• Eligibility Criteria: Age ≥ 18 years; KPS) ≥ 60%; life expectancy > 3 months; platelets ≥ 30 x 10⁹/L; haemoglobin ≥ 8 g/dL; ANC ≥ 0.5 x 10⁹/L; creatinine clearance ≥ 30 mL/min; bilirubin ≤ 2 x ULN; AST or ALT ≤ 3 x ULN.

• Baseline Characteristics: Some imbalances noted. More females, patients with IgG myeloma and patients with abnormal cytogenetics in 1.3 mg/m² group. More patients with platelets < 75 x 10⁹/L at baseline in 1.0 mg/m² group.

Interventions

• Arm A: Bortezomib 1.0 mg/m² IV days 1, 4, 8, 11 of 21‐day cycle up to 8 cycles.

• Arm B: Bortezomib 1.3 mg/m² IV days 1, 4, 8, 11 of 21‐day cycle up to 8 cycles.

• Additional Treatments: Patients with progressive disease after 2 cycles, or stable disease after 4 cycles were eligible to receive 20 mg oral dexamethasone on the day of, and day following bortezomib treatment.

Outcomes

• Primary: Overall response rate (ORR): sum of complete response (CR), partial response (PR) and minimal response (MR).

• Secondary: Response rate to bortezomib in combination with dexamethasone; time to progression on bortezomib alone and in combination with dexamethasone; overall survival; safety.

Notes

• Sponsor/Funding: Millennium Pharmaceuticals.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Jagannath, 2008 (extended follow‐up data).

• KPS = Karnofsky Performance Status.

• ANC = Absolute Neutrophil Count.

• AST = Aspartate aminotransferase.

• ALT = Alanine aminotransferase.

• IgG = Immunoglobulin G.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Randomisation envelopes at each centre selected based on stage of disease and front‐line chemo‐therapeutic regimen. Type of envelope used e.g. opaque and who had access to the envelopes not adequately reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression by the European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Response data assessed by independent review committee of 3 myeloma experts independent of trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Patient status at > 5‐year median follow‐up reported.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 66 centres in Spain from Apr 2006 to Aug 2009.

• Randomisation to one of 3 induction therapy arms (N = 386 patients):

1. Arm A = VTD (bortezomib, thalidomide, dexamethasone) = 127 patients

2. Arm B = TD (thalidomide, dexamethasone) = 130 patients

3. Arm C = VBMCP/VBAD/B (vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib) = 129 patients

• Post ASCT, randomisation to one of 3 maintenance therapy arms (N = 266 patients):

1. Arm A = TV (thalidomide, bortezomib) = 89 patients

2. Arm B = T (thalidomide only) = 87 patients

3. Arm C = alfa2‐IFN (Interferon alpha‐2b) = 90 patients

Participants

• Patient Population: Patients with newly diagnosed and untreated symptomatic multiple myeloma.

• Inclusion Criteria: Age ≤ 65 years; PS < 3; Platelets ≥ 50x10⁹/L; Haemoglobin ≥ 8 g/dL; ANC ≥ 1x10⁹/L; serum creatinine ≤ 2 mg/dL.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Induction Therapy (24 weeks):

1. Arm A: VTD: TD as per Arm B and IV bortezomib 1.3 mg/m² on D1, 4, 8 and 11 of each cycle.

2. Arm B: TD: Oral thalidomide 200 mg daily (escalating dose first cycle), oral dexamethasone 40 mg D1‐4 and 9‐12 for 6 cycles.

3. Arm C: VBMCP/VBAD/B: VBMCP and VBAD chemotherapy plus bortezomib for 4 cycles alternating VBMCP and VBAD.

• Maintenance Therapy (3 years):

1. Arm A: TV: Oral thalidomide 100 mg per day plus 1 cycle of bortezomib on D1,4,8 and 11 every 3 months.

2. Arm B: T: Oral thalidomide 100 mg per day.

3. Arm C: alfa2‐IFN: Interferon alpha‐2b SC 3MU 3 times per week.

• Additional Treatments: LMW heparin/aspirin for thromboprophylaxis for patients receiving thalidomide, zoledronic acid up to 2 years.

Outcomes

• Primary: Complete response rate after induction and after ASCT.

• Secondary: Progression‐free survival, overall survival and safety.

Notes

• Sponsor/Funding: PETHEMA Foundation supported by 2 grants from Janssen‐Cilag and Pharmion.

• Type of Publication (Full Text or abstract only): Full text.

• Linked to other reports: Rosinol, 2012 (maintenance data).

• PS = Performance Status.

• ANC = Absolute Neutrophil Count.

• LMW = Low molecular weight.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Patients were 'centrally randomised'.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate according to the European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Response data and toxicity monitored by an external contract research organisation and centrally reviewed by the principal investigators.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Acceptable rates of withdrawal during induction therapy reported.

Selective reporting (reporting bias)

Unclear risk

Benefits and harms reported, however selected adverse events reported only.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted in Spain.

• Overall sample size: N = 241 patients. Experimental arm (alternating scheme) = 120 patients. Control arm (sequential scheme) = 121 patients.

Participants

• Patient Population: Elderly patients with newly diagnosed multiple myeloma.

• Inclusion Criteria: Age > 65 years; ECOG PS ≤2; platelets ≥ 75 x 10⁹/L; haemoglobin ≥ 8 g/dL; ANC ≥ 1.0 x 10⁹/L; serum bilirubin ≤ 1.5 mg/dL; alkaline phosphatase, AST, ALT ≤ 2.5 x ULN; serum creatinine ≤ 2.5 mg/dL.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; prior bortezomib or lenalidomide.

• Baseline Characteristics: Not known.

Interventions

• Sequential scheme: 9 cycles of VMP (IV bortezomib 1.3 mg/m² twice weekly for 1 six‐week cycle followed by once weekly for 8 four‐weeks cycles, oral melphalan 9 mg/m², prednisone 60 mg/m² once daily on days 1‐4 of each cycle) followed by 9 cycles of Rd (oral lenalidomide 25 mg daily on days 1‐21, dexamethasone 40 mg weekly).

• Alternating scheme: One cycle of VMP alternating with one cycle of Rd (half of patients started VMP and half by Rd) for up to 18 cycles.

Outcomes

• Primary: Time to progression; toxicity (safety and tolerability).

• Secondary: Response; genomics analysis; duration of response; progression‐free survival, time to next therapy; overall survival.

Notes

• Sponsor/Funding: PETHEMA Foundation.

• Type of Publication (Full text or abstract only): Abstract only.

• Linked to other reports: None.

• ECOG PS = Eastern Coooperative Oncology Group Performance Status.

• ANC = Absolute Neutrophil Count.

• AST = Aspartate aminotransferase.

• ALT = Alanine aminotransferase.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not known. Central randomisation probably performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective endpoints measured (e.g. response rate according to the European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Not known if blinded/independent outcomes assessment conducted.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not clear if any patients lost to follow‐up, withdrawn etc (abstract only).

Selective reporting (reporting bias)

Unclear risk

Not clear (abstract only). Benefits and harms reported.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 61 centres in Italy from May 2006 to Jan 2009.

• Overall sample size: N = 511 patients. Experimental arm (VMPT‐VT) = 254 patients. Control arm (VMP) = 257 patients.

Participants

• Patient Population: Patients with newly diagnosed transplant ineligible multiple myeloma.

• Inclusion Criteria: Age ≥ 65 years; not candidates for high‐dose therapy plus stem cell transplantation due to age or co‐existing co‐morbidities; KPS ≥ 60%.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; renal insufficiency (creatinine ≥ 25 mg/mL); psychiatric disease; uncontrolled/severe cardiovascular disease; other malignancy within 5 years.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Experimental arm (VMPT‐VT): Induction therapy with nine 6‐weekly cycle of IV bortezomib 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, 32 of cycles 1to 4 and on days 1, 8, 22, 29 of cycles 5‐9, oral melphalan 9 mg/m² on days 1 to 4, oral prednisone 60 mg/m² on days 1 to 4, oral thalidomide 50 mg/day continuously. Maintenance therapy with IV bortezomib 1.3 mg/m² every 14 days and oral thalidomide 50mg/day for 2 years or until progression.

• Control arm (VMP): Standard induction therapy with nine 6‐weekly cycles of VMP at same doses and no maintenance therapy.

• Post safety analysis of 139 patients, induction changed to nine 5‐week cycles and weekly bortezomib cycles 1 to 9 to reduce neuropathy.

• Additional Treatments: Thromboprophylaxis for VMPT‐VT patients.

Outcomes

• Primary: Progression‐free survival.

• Secondary: Response rate, time to first response, overall survival, incidence of ≥ grade 3 adverse events.

Notes

• Sponsor/Funding: Fondazione Neoplasie Sangue Onlus.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Palumbo 2014 (updated follow‐up).

• KPS = Karnofsky Performance Status.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not reported. Multi‐centre trial, therefore probably centrally randomised.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective endpoints measured (e.g. response rate and progression according to International Uniform Response Criteria, overall survival) however independent blinded outcomes assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart accounting for all patients. Acceptable rates of withdrawal/lost to follow‐up.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 73 centres in Italy from May 2006 to Apr 2008.

• Overall sample size: N = 480 patients. Experimental arm (VTD: bortezomib, thalidomide, dexamethasone) = 241 patients. Control Arm (TD: thalidomide, dexamethasone) = 239 patients.

Participants

• Patient Population: Patients with newly diagnosed and untreated symptomatic multiple myeloma.

• Inclusion Criteria: Age 18‐65 years; KPS ≥ 60%; Platelets ≥ 70 x 10⁹/L; ANC ≥ 1 x 10⁹/L; serum creatinine ≤ 176 µmol/L.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; history of venous thromboembolism; diagnosis of thrombophylic alterations.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Experimental Arm (VTD): Induction: IV bortezomib 1.3 mg/m² on days 1, 4, 8, 11 with TD for 3 x 21‐day cycles. Consolidation: IV bortezomib 1.3mg/m² on Days 1, 8, 15 and 22 with TD for 2 x 35‐day cycles.

• Control Arm (TD): Induction: oral thalidomide 100 mg daily first 14 days, 200 mg daily thereafter and dexamethasone 40 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. Consolidation: oral thalidomide 100 mg daily and oral dexamethasone 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23.

• Additional Treatments: Double ASCT 3‐6 months apart following induction therapy and stem cell mobilisation.

Outcomes

• Primary: Complete response rate plus near complete response after induction.

• Secondary: Complete response rate plus near complete response rate to double transplantation and consolidation therapy, time to progression or relapse, progression‐free survival, overall survival and safety.

Notes

• Sponsor/Funding: Seràgnoli Institute of Haematology at the University of Bologna. Janssen‐Cilag provided bortezomib.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Cavo 2012 (median follow‐up 43 months); Cavo 2012 (abstract only, median follow‐up 52 months).

• KPS = Karnofsky Performance Status.

• ANC = Absolute Neutrophil Count.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Patients were randomised via 'web‐based system' at central coordinating centre.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression according to the European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Responses monitored by external contract research organisation and centrally reassessed by central coordinating team.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart accounting for all patients. Acceptable rates of withdrawal/lost to follow‐up.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

Not reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted in Belgium, Netherlands and Germany from May 2005 to May 2008.

• Overall sample size: N = 827 patients. Experimental arm (PAD ) = 413 patients. Control arm (VAD) = 414 patients.

Participants

• Patient Population: Patients with newly diagnosed symptomatic multiple myeloma.

• Inclusion Criteria: Age 18‐65 years; Performance Status 0‐2.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; serum bilirubin ≥ 30 µmol/L; amino transferases ≥ 2.5 normal level.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Experimental arm (PAD): Induction chemotherapy with bortezomib, Adriamycin and dexamethasone (PAD) followed by intensive chemotherapy with melphalan 200 mg/m² and ASCT, followed by maintenance therapy with bortezomib for 2 years. PAD = 3 cycles of IV bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, IV doxorubicin 9 mg/m²/day on days 1 to 4, oral dexamethasone 40 mg/day on days 1 to 4, 9 to 12, 17 to 20 every 28 days. Maintenance IV bortezomib = 1.3 mg/m² every 2 weeks for 2 years.

• Control arm (VAD): Induction chemotherapy with vincristine, Adriamycin and dexamethasone (VAD) followed by intensive chemotherapy with melphalan 200 mg/m² and ASCT, followed by maintenance therapy with thalidomide for 2 years. VAD = 3 cycles of IV vincristine 0.4 mg/day on days 1 to 4, IV doxorubicin 9 mg/m²/day on days 1 to 4, oral dexamethasone 40 mg/day on days 1 to 4, 9 to 12, 17 to 20 every 28 days. Maintenance oral thalidomide = 50 mg/day for 2 years.

Outcomes

• Primary: Progression‐free survival.

• Secondary: Response rate; progression‐free survival without censoring patients with ASCT; progression‐free survival from last high‐dose melphalan; overall survival; safety; toxicity.

Notes

• Sponsor/Funding: Dutch‐Belgian Hemato‐Oncology Cooperative Group and the German Multicenter Myeloma Group (GMMG). Supported by Dutch Cancer Foundation, German Federal Ministry of Education and Research, Janssen‐Cilag‐Ortho Biotech, Novartis, Amgen, Chugai, and Roche.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Sonneveld 2013 (abstract only, median follow‐up 67 months).

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Patients were randomised via 'web‐based' system.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective endpoints measured (e.g. response rate and progression according to modified European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival), however, independent/blinded outcomes assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart accounting for all patients included.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 89 centres in France, Belgium and Switzerland from Aug 2005 to Jan 2008.

• Overall sample size: N = 482 patients:

1. Arm A1 (VAD induction + no consolidation) = 121 patients.

2. Arm A2 (VAD induction + DCEP consolidation) = 121 patients.

3. Arm B1 (BD induction + no consolidation) = 121 patients.

4. Arm B2 (BD induction + DCEP consolidation) = 119 patients.

• VAD induction (A1 + A2) = 242 patients.

• BD induction (B1 + B2) = 240 patients.

Participants

• Patient Population: Patients with newly diagnosed untreated symptomatic multiple myeloma.

• Inclusion Criteria: Age ≤ 65 years; Performance Status ≤ 2; adequate renal, haematologic, and hepatic function.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; HIV positive; uncontrolled diabetes.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• VAD: 4 cycles of vincristine 0.4 mg/day on days 1 to 4, doxorubicin 9 mg/m²/day by continuous infusion on days 1 to 4, oral dexamethasone 40 mg/day on days 1 to 4 (all cycles), 9 to 12, 17 to 20 (cycles 1 and 2) every 28 days.

• BD: 4 cycles of IV bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, oral dexamethasone 40 mg/day on days 1 to 4 (all cycles), days 9 to 12 (cycles 1 and 2) every 21 days.

• DCEP: 2 cycles of dexamethasone 40 mg/day on days 1 to 4, cyclophosphamide 400 mg/m², etoposide 40 mg/m², cisplatin 15 mg/m²/day by continuous infusion on days 1 to 4 every 28 days.

• Additional treatments: Bisphosphonates, antibiotics, anti‐fungal and anti‐viral therapies according to local practice.

Outcomes

• Primary: Post‐induction Complete Response/near Complete Response (CR/nCR) rate.

• Secondary: Post‐induction overall response rate; CR/nCR rate with and without DCEP consolidation; CR/nCR and at least VGPR rates post first transplantation; proportion of patients requiring second transplantation; safety and toxicity.

Notes

• Sponsor/Funding: Investigator‐initiated trial.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: None.

• HIV = human immunodeficiency virus.

• CR/nCR = Complete Response/near Complete Response.

• VGPR = Very Good Partial Response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Patients were 'centrally randomly assigned'.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression according to modified European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Responses confirmed by independent review committee.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart accounting for all patients included. Acceptable rates of withdrawal.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 50 centres in France from Mar 2008 to Jan 2009.

• Overall sample size: N = 199 patients. Experimental arm (vtD) = 100 patients. Control arm (VD) = 99 patients.

Participants

• Patient Population: Patients with newly diagnosed untreated symptomatic multiple myeloma.

• Inclusion Criteria: Age ≤ 65 years; Performance Status ≤ 2; adequate renal function.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; HIV positive; uncontrolled diabetes; amyloidosis; history of other cancer (except basal cell carcinoma and cervix cancer in situ).

• Baseline Characteristics: No significant imbalance apparent or reported except difference in proportion of patients with t(4;14) and/or del (17p) higher in vtD arm than VD arm.

Interventions

• vtD: 4 cycles of IV bortezomib 1.0 mg/m² on days 1, 4, 8 and 11, oral thalidomide 100 mg/day and oral dexamethasone 40 mg/day on days 1 to 4 (all cycles), days 9 to 12 (cycles 1 and 2) every 21 days. In case of < PR after cycle 2, bortezomib increased to 1.3 mg/m² and thalidomide to 200 mg/day.

• VD: 4 cycles of IV bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, oral dexamethasone 40 mg/day on days 1 to 4 (all cycles), days 9 to 12 (cycles 1 and 2) every 21 days.

• Additional treatments: Bisphosphonates, antibiotics and anti‐viral therapies according to local practice.

Outcomes

• Primary: Post‐induction CR rate.

• Secondary: CR plus VGPR rates after cycle 2, after induction and after ASCT; overall response rates (≥ PR) after cycle 2, after induction and after ASCT; safety and toxicity.

Notes

• Sponsor/Funding: Investigator‐initiated trial by the Intergroupe Francophone du Myelome (IFM).

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: None.

• CR = Complete Response.

• VGPR = Very Good Partial Response.

• PR = Partial Response.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Patients were 'centrally randomised'.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression according to International Myeloma Working Group Uniform Criteria, overall survival). Laboratory samples to evaluate response data were centrally evaluated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart accounting for all patients included. Acceptable rates of withdrawal.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase II trial conducted at 1 centre in US from October 2006 to September 2007.

• Overall sample size: N = 60 patients. Randomised to 1 of 3 groups (N = 20 per group).

• Group 1 Control Arm: No bortezomib + Melphalan (Mel) + Ascorbic Acid (AA) +Arsenic Trioxide (ATO).

• Group 2 Treatment Arm: Bortezomib 1.0 mg/m² + Mel + AA +ATO.

• Group 3 Treatment Arm: Bortezomib 1.5 mg/m²+ Mel + AA +ATO.

Participants

• Patient Population: Patients with newly diagnosed multiple myeloma undergoing ASCT.

• Inclusion Criteria: Age ≤ 75 years; PS < 2; serum bilirubin < 2 x ULN; SGPT < 4 x ULN.

• Baseline Characteristics: No significant imbalances apparent or reported.

Interventions

• Group 1 Control Arm: Mel (100 mg/m² IV days ‐4, ‐3), AA (100 mg/m² IV days ‐9 to ‐3), ATO (0.25 mg/kg IV days ‐9 to ‐3).

• Group 2 Treatment Arm: Bortezomib 1.0 mg/m² IV days ‐9, ‐6, ‐3 + Mel + AA +ATO.

• Group 3 Treatment Arm: Bortezomib 1.5 mg/m² IV days ‐9, ‐6, ‐3 + Mel + AA +ATO.

• Additional treatments: Supportive care according to established guidelines.

Outcomes

• Primary: Complete response, time to grade IV toxicity and death.

• Secondary: Response rate, progression‐free survival, overall survival and safety.

Notes

• Sponsor/Funding: Sponsored by M.D. Anderson Cancer Center. Part supported by grant from Cephalon Oncology.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: None.

• PS = Performance Status.

• ULN = Upper Normal Limit.

• SGPT = Serum glutamic pyruvic transaminase.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not specified.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate, overall survival).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 patients withdrew early (from group 1 and group 3). No lost to follow‐up patients reported.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 60 centres in 9 countries in Europe and Israel from Jan 2006 to Jul 2010.

• Overall sample size: N = 269 patients. Experimental Arm A (VTD: bortezomib + thalidomide + dexamethasone) = 135 patients. Control Arm (TD: thalidomide + dexamethasone Alone) = 134 patients.

Participants

• Patient Population: Patients with relapsed multiple myeloma following ASCT.

• Inclusion Criteria: KPS > 50%; platelets ≥ 40,000/µL; ANC ≥ 1,000/µL; creatinine clearance ≥ 30 mL/min.

• Exclusion Criteria: ≥ grade 2 peripheral neuropathy; prior allogeneic SCT.

• Baseline Characteristics: No significant imbalances apparent or reported.

Interventions

• Experimental Arm (VTD): IV bortezomib 1.3 mg/m² on days 1, 4, 8, 11 of 21 day cycle for 8 cycles (6 months), followed by IV bortezomib 1.3 mg/m² on days 1, 8, 15 and 22 of 42 day cycle for 4 cycles (6 months) with TD. Total duration = 1 year.

• Control Arm (TD): Oral thalidomide 200 mg daily and oral dexamethasone 40 mg on 4 days every 3 weeks. Total duration = 1 year.

Outcomes

• Primary: Time to disease progression.

• Secondary: Progression‐free survival; overall survival; overall response rate (complete plus partial); adverse events.

Notes

• Sponsor/Funding: European Group for Blood and Marrow Transplantation.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: None.

• KPS = Karnofksy Performance Status.

• ANC = Absolute Neutrophil Count.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not specified. Central randomisation most probably performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective endpoints measured (e.g. response rate and progression according to European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Independent outcomes assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Flow chart with all randomised patients accounted for. Low rate of lost to follow‐up. All patients included in intention‐to‐treat Analysis.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III non‐inferiority trial conducted at 53 centres in 10 countries in Europe, Asia and South America from Jul 2008 to Feb 2010.

• Overall sample size: N = 222 patients. 2 : 1 allocation. Experimental arm (SC bortezomib) = 148 patients. Control arm (IV bortezomib) = 74 patients.

Participants

• Patient Population: Multiple myeloma patients with measurable progressive disease.

• Inclusion Criteria: Age ≥ 18 years; KPS ≥ 70%; 1 to 3 prior lines of therapy; adequate haematologic, hepatic and renal function.

• Exclusion Criteria: Prior bortezomib therapy; ≥ grade 2 peripheral neuropathy or neuropathic pain; anti‐neoplastic, experimental, corticosteroid (> 10 mg/day prednisone or equivalent) therapy within 3 weeks of randomisation.

• Baseline Characteristics: No significant imbalance apparent or reported except: higher number of patients in SC group with KPS < 80%, creatinine clearance < 60 mL/min and from Eastern Europe; higher number of male patients and patients with high‐risk cytogenetics in IV group.

Interventions

• Experimental Arm: Bortezomib 1.3 mg/m² by SC injection on days 1, 4, 8, 11 of 21‐day cycle up to 8 cycles.

• Control Arm: Bortezomib 1.3 mg/m² by IV infusion on days 1, 4, 8, 11 of 21‐day cycle up to 8 cycles.

• Patients with suboptimal response (< CR, without disease progression) at end of cycle 4 could additionally receive oral dexamethasone from cycle 5 onwards. Patients with stable disease or PR as best response at end of cycle 8, evolving steadily to late PR or CR, respectively, could receive two additional cycles.

• Additional Treatments: Concomitant supportive care therapies allowed except systemic steroids and anti‐neoplastic therapies with anti‐myeloma effects. Bisphosphonates permitted.

Outcomes

• Primary: Overall response rate (complete plus partial response) after 4 cycles.

• Secondary: CR, nCR and VGPR rates after 4 cycles; ORR after 8 cycles; time to response; duration of response; time to progression; progression‐free survival; 1‐year overall survival; safety and tolerability; pharmacokinetics and pharmacodynamics.

Notes

• Sponsor/Funding: Millennium Pharmaceuticals.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Arnulf, 2012 (extended follow‐up data).

• KPS = Karnofksy Performance Status.

• CR/nCR = Complete Response/near Complete Response.

• VGPR = Very Good Partial Response.

• ORR = Overall Response Rate.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised', employing a 'computer‐generated randomisation schedule' based on 'permuted blocks'.

Allocation concealment (selection bias)

Low risk

Central randomisation using an 'interactive voice response system' (IVRS).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression by European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Response data based on central laboratory analysis and blinded response evaluation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart with all randomised patients accounted for. No lost to follow‐up patients reported.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 23 centres in Denmark, Estonia, Finland, Iceland, Norway and Sweden from Oct 2005 to Apr 2009.

• Overall sample size: N = 370 patients. Experimental arm (bortezomib consolidation therapy) = 187 patients. Control arm (No consolidation therapy) = 183 patients.

Participants

• Patient Population: Patients with newly diagnosed multiple myeloma following ASCT.

• Exclusion Criteria: > grade 2 peripheral neuropathy; severe heart disease or heart failure; history of hypotension; prior exposure to bortezomib.

• Baseline Characteristics: No significant imbalances apparent or reported.

Interventions

• Experimental Arm: Consolidation therapy with IV bortezomib 1.3 mg/m² on days 1, 4, 8, 11 of 21‐day cycle for 2 cycles, followed by IV bortezomib 1.3 mg/m² on Days 1, 8, 15 of 28‐day cycle for 4 cycles.

• Control Arm: No consolidation therapy.

• Additional Treatments: No steroids permitted except < 50 mg prednisone for 1 week for other medical conditions. Bisphosphonates allowed.

Outcomes

• Primary: Progression‐free survival.

• Secondary: Response rate; overall survival; health‐related quality of life; tolerability.

Notes

• Sponsor/Funding: Nordic Myeloma Study Group.

• Type of Publication (Full Text or abstract only): Full Text.

• Linked to other reports: None.

• ASCT = Autologous Stem Cell Transplant.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Central computer randomisation performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. response rate and progression according to European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Independent outcomes assessment not reported but data monitored by independent contract research organization.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Clear flow chart with all randomised patients accounted for. No lost to follow‐up reported. All patients included in intention‐to‐treat analysis.

Selective reporting (reporting bias)

Unclear risk

Benefits and harms reported however selected adverse events reported (peripheral neuropathy and neuropathic pain) only. 2 secondary malignancies reported (1 on treatment arm; 1 on control arm).

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 29 centres in Norway, Sweden and Denmark from Oct 2007 to Sep 2010.

• Overall sample size: N = 131 patients. Trial prematurely closed due to low accrual.

• Experimental arm (bortezomib + dexamethasone) = 64 patients. Control arm (thalidomide + dexamethasone) = 67 patients.

• Cross‐over: Patients offered cross‐over to other arm at disease progression: 39 patients received bort‐dex after failure on thal‐dex, 33 received thal‐dex after failure on bort‐dex.

Participants

• Patient Population: Patients with refractory multiple myeloma.

• Inclusion Criteria: Any age; refractory to prior melphalan treatment.

• Exclusion Criteria: Former treatment with thalidomide, bortezomib, lenalidomide; ≥ grade 3 sensory neuropathy; ≥ grade 2 neuropathic pain; platelets < 25 x 10⁹/L; severe co‐morbidity.

• Baseline Characteristics: Signficantly more females on control arm (thal‐dex); no prognostic importance on univariate analysis. All other characteristics balanced.

Interventions

• Experimental Arm (bort‐dex); Bortezomib 1.3 mg/m² IV on days 1, 4, 8, 11 of 21‐day cycle. Dexamethasone 20 mg oral on days 1‐2, 4‐5, 8‐9, 11‐12 of 21‐day cycle.

• Control Arm (thal‐dex): Thalidomide 50 mg oral daily, escalated by 50 mg every 3 weeks to a maximum of 200 mg. Dexamethasone 40 mg oral on days 1 to 4 every 3 weeks.

• Additional Treatments: Anti‐thrombotic prophylaxis and acyclovir prophylaxis used routinely.

Outcomes

• Primary: Progression‐free survival.

• Secondary: Response rate; duration of response; toxicity; health‐related quality of life; time to next treatment; overall survival.

Notes

• Sponsor/Funding: Nordic Myeloma Study Group.

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: None.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Low risk

Central web‐based randomisation performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Objective endpoints measured (e.g. response rate and progression according to International Myeloma Working Group (IMWG) guidelines, overall survival). Independent outcomes assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart for randomised patients included. Acceptable rates of withdrawal, no lost to follow‐up patients reported. All patients included in intention‐to‐treat analysis.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.

Methods

• Design: Randomised, open‐label, phase III trial conducted at 151 centres in 22 countries in Europe, North and South America and Asia from Dec 2004 to Sep 2006.

• Overall sample size: N = 682 patients. Experimental arm A (VMP: melphalan + prednisone + bortezomib) = 344 patients. Control arm (MP: melphalan + prednisone alone) = 338 patients.

Participants

• Patient Population: Newly diagnosed, untreated, symptomatic, measurable multiple myeloma patients not candidates for high‐dose therapy plus stem‐cell transplantation.

• Inclusion Criteria: Age ≥ 65 years; measurable disease.

• Exclusion Criteria: Serum creatinine > 2 mg/dL; ≥ grade 2 peripheral neuropathy or neuropathic pain.

• Baseline Characteristics: No significant imbalance apparent or reported.

Interventions

• Experimental Arm: VMP: Nine 6‐weekly cycles of melphalan 9 mg/m²and prednisone at 60 mg/m²on days 1 to 4 of each cycle with IV bortezomib. 1.3 mg/m² on Days 1, 4, 8, 11, 22, 25, 29 and 32 during cycles 1 to 4 and on days 1, 8, 22 and 29 during cycles 5 to 9.

• Control Arm: MP: Nine 6‐weekly cycles of melphalan 9 mg/m²and prednisone at 60 mg/m²on days 1 to 4 alone.

• Additional Treatments: Bisphosphonates for patients with myeloma‐associated bone disease.

Outcomes

• Primary: Time to disease progression.

• Secondary: Progression‐free survival, complete plus partial response rate, complete response rate, duration of response; time to subsequent myeloma therapy, overall survival, adverse events, health‐related quality of life.

Notes

• Sponsor/Funding: Millennium Pharmaceuticals/Johnson & Johnson Pharmaceutical Research & Development

• Type of Publication (Full text or abstract only): Full text.

• Linked to other reports: Mateos 2010, San Miguel 2013, Delforge 2013, Spicka 2011.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study design described as 'randomised'.

Allocation concealment (selection bias)

Unclear risk

Not specified. Central randomisation most probably performed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study.

Blinding of outcome assessment (detection bias) for OS

Low risk

Low risk of bias for OS.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Objective endpoints measured (e.g. e.g. response rate and progression according to European Group for Blood and Bone Marrow Transplant (EBMT) criteria, overall survival). Response data based on central laboratory analysis of blood and urine samples.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Detailed flow chart. Low numbers lost to follow‐up/excluded from analysis.

Selective reporting (reporting bias)

Low risk

Benefits and harms reported.

Other bias

Unclear risk

None reported.