VELCADE-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Incorporated Into Double Autotransplantation for Untreated Multiple Myeloma (MM)

NCT ID: NCT01134484

Last Updated: 2012-07-20

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 480 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-31
• Study Completion Date: 2015-12-31

Brief Summary

Thalidomide-Dexamethasone (TD) is a standard induction therapy for Multiple Myeloma (MM). The present study is designed to compare TD with VELCADE-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan-based double autologous stem cell transplantation for previously untreated patients aged ≤65 years with symptomatic MM. Primary study endpoint is the rate of complete response (CR) plus near-complete response (nCR) to induction treatment. Secondary endpoints include the rate of CR plus nCR to double transplantation and subsequent consolidation therapy, time to progression (TTP), progression-free survival (PFS),overall survival (OS) and toxicity profile of both VTD and TD.

Detailed Description

This prospective phase 3 trial is aimed at evaluating whether, in comparison with standard TD, addition of Velcade to TD increases rate of CR and nCR from 15% to 30%, respectively. For this purpose, symptomatic patients aged 18-65 years with previously untreated MM and quantifiable M-protein in serum or urine are randomized (1:1) to receive induction therapy comprising three 3-week cycles of Velcade 1.3 mg/sqm, days 1, 4, 8, 11, thalidomide 100 mg, days 1-14, cycle 1, then 200 mg daily, and dexamethasone 40 mg, days 1, 2, 4, 5, 8, 9, 11, 12, or thalidomide and dexamethasone (same schedule and dosage as in VTD). Randomization to VTD or TD is stratified according to International Staging System disease stage at diagnosis. Following induction therapy, patients in both arms receive cyclophosphamide (4 g/sqm, day 0 and granulocyte colony-stimulating factor, 10 μcg/kg/day, from day +2) to collect autologous peripheral blood stem cells (minimum threshold CD34+ cells: 4 x 10^6/kg) and two subsequent courses of stem cell-supported high dose melphalan (200 mg/sqm), 3 to 6 months apart. Upon neutrophil (≥1 x 10^9/L) and platelet (≥75 x 10^9/L) recovery following the first autotransplantation, patients receive thalidomide (100 mg daily) and dexamethasone (40 mg, days 1-4 every 4 weeks) as bridge therapy until the day before the second transplantation.

Patients initially randomized to receive VTD or TD induction therapy are planned to receive two 5-week cycles of VTD (Velcade 1.3 mg/sqm, days 1, 8, 15, 22; thalidomide 100 mg daily; dexamethasone 40 mg, days 1, 2, 8, 9, 15, 16, 22, 23) or TD (thalidomide 100 mg daily; dexamethasone 40 mg, days 1-4 and 20-23) as consolidation therapy, starting 3 months after last transplant. Maintenance therapy comprise dexamethasone 40 mg, days 1-4, repeated monthly until relapse or progression.

Conditions

Multiple Myeloma

Keywords

autologous stem cell transplantation; complete remission; bortezomib; thalidomide; progression free survival; induction and consolidation therapy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

VTD

Group Type: EXPERIMENTAL

Velcade

Intervention Type: DRUG

• INDUCTION THERAPY: 1.3 mg/sqm as a bolus i.v. injection on days 1, 4, 8 and 11 (3 courses, 21 days each)
• REMISSION CONSOLIDATION THERAPY: 1.3 mg/sqm as a bolus i.v. injection on days 1, 8, 15 and 22 (2 courses, 35 days each)

Thalidomide

Intervention Type: DRUG

• INDUCTION THERAPY: 100 mg/d on days 1-14, 200 mg/d on days 15-63 (in case of delay of HD-CTX , Thalidomide will be continued until the day before Cyclophosphamide as priming therapy for PBSC collection)
• AFTER PBSC COLLECTION: 100 mg/d from day after last PBSC collection until the day before first course of MEL-200
• AFTER FIRST TRANSPLANTATION: 100 mg/d from recovery of hematopoiesis until the day before the second course of MEL-200
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation): 100 mg/d days 1-70

Dexamethasone

Intervention Type: DRUG

• INDUCTION THERAPY

1. VTD ARM: 40 mg/d days 1-2, 4-5, 8-9 and 11-12 (3 cycles, 21 days each)

2. TD ARM: 40 mg/d days 1-4 and 9-12 (3 cycles, 21 days each)

• AFTER PBSC COLLECTION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide)
• AFTER FIRST TRANSPLANTATION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide) and repeated every 28 days, for 3 months
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation)

1. VTD ARM: 40 mg/d days 1-2, 8-9, 15-16 and 22-23 (2 cycles, 35 days each)

2. TD ARM: 40 mg/d days 14 and 20-23 (2 cycles, 35 days each)

Peripheral Blood Stem Cell (PBSC) collection

Intervention Type: PROCEDURE

• Cyclophosphamide (CTX): 4 g/sqm given in a single day (day 0)
• G-CSF: 10 µcg/kg/d, starting on day +2 from CTX and continuing until completion of PBSC collection

First Autologous Transplantation

Intervention Type: PROCEDURE

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

Second Autologous Transplantation

Intervention Type: PROCEDURE

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

TD

Group Type: ACTIVE_COMPARATOR

Thalidomide

Intervention Type: DRUG

• INDUCTION THERAPY: 100 mg/d on days 1-14, 200 mg/d on days 15-63 (in case of delay of HD-CTX , Thalidomide will be continued until the day before Cyclophosphamide as priming therapy for PBSC collection)
• AFTER PBSC COLLECTION: 100 mg/d from day after last PBSC collection until the day before first course of MEL-200
• AFTER FIRST TRANSPLANTATION: 100 mg/d from recovery of hematopoiesis until the day before the second course of MEL-200
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation): 100 mg/d days 1-70

Dexamethasone

Intervention Type: DRUG

• INDUCTION THERAPY

1. VTD ARM: 40 mg/d days 1-2, 4-5, 8-9 and 11-12 (3 cycles, 21 days each)

2. TD ARM: 40 mg/d days 1-4 and 9-12 (3 cycles, 21 days each)

• AFTER PBSC COLLECTION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide)
• AFTER FIRST TRANSPLANTATION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide) and repeated every 28 days, for 3 months
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation)

1. VTD ARM: 40 mg/d days 1-2, 8-9, 15-16 and 22-23 (2 cycles, 35 days each)

2. TD ARM: 40 mg/d days 14 and 20-23 (2 cycles, 35 days each)

Peripheral Blood Stem Cell (PBSC) collection

Intervention Type: PROCEDURE

• Cyclophosphamide (CTX): 4 g/sqm given in a single day (day 0)
• G-CSF: 10 µcg/kg/d, starting on day +2 from CTX and continuing until completion of PBSC collection

First Autologous Transplantation

Intervention Type: PROCEDURE

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

Second Autologous Transplantation

Intervention Type: PROCEDURE

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

Interventions

Velcade

• INDUCTION THERAPY: 1.3 mg/sqm as a bolus i.v. injection on days 1, 4, 8 and 11 (3 courses, 21 days each)
• REMISSION CONSOLIDATION THERAPY: 1.3 mg/sqm as a bolus i.v. injection on days 1, 8, 15 and 22 (2 courses, 35 days each)

Intervention Type: DRUG

Thalidomide

• INDUCTION THERAPY: 100 mg/d on days 1-14, 200 mg/d on days 15-63 (in case of delay of HD-CTX , Thalidomide will be continued until the day before Cyclophosphamide as priming therapy for PBSC collection)
• AFTER PBSC COLLECTION: 100 mg/d from day after last PBSC collection until the day before first course of MEL-200
• AFTER FIRST TRANSPLANTATION: 100 mg/d from recovery of hematopoiesis until the day before the second course of MEL-200
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation): 100 mg/d days 1-70

Intervention Type: DRUG

Dexamethasone

• INDUCTION THERAPY

1. VTD ARM: 40 mg/d days 1-2, 4-5, 8-9 and 11-12 (3 cycles, 21 days each)

2. TD ARM: 40 mg/d days 1-4 and 9-12 (3 cycles, 21 days each)

• AFTER PBSC COLLECTION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide)
• AFTER FIRST TRANSPLANTATION: 40 mg/d for 4 days (starting the same day of resumption of Thalidomide) and repeated every 28 days, for 3 months
• REMISSION CONSOLIDATION THERAPY (starting 3 months after the second autologous transplantation)

1. VTD ARM: 40 mg/d days 1-2, 8-9, 15-16 and 22-23 (2 cycles, 35 days each)

2. TD ARM: 40 mg/d days 14 and 20-23 (2 cycles, 35 days each)

Intervention Type: DRUG

Peripheral Blood Stem Cell (PBSC) collection

• Cyclophosphamide (CTX): 4 g/sqm given in a single day (day 0)
• G-CSF: 10 µcg/kg/d, starting on day +2 from CTX and continuing until completion of PBSC collection

Intervention Type: PROCEDURE

First Autologous Transplantation

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

Intervention Type: PROCEDURE

Second Autologous Transplantation

• HIGH-DOSE MELPHALAN (MEL-200): 200 mg/sqm, given as a single dose i.v. (day -2) followed by PBSC infusion 48 hours later (day 0)
• G-CSF: 5 µcg/kg daily starting from day +6 after grafting and continuing until the patient's ANC is more than 0.5x10^9/L for 3 consecutive days

Intervention Type: PROCEDURE

Other Intervention Names

Bortezomib; Talidomide; Soldesam

Eligibility Criteria

Inclusion Criteria

• Confirmed diagnosis of symptomatic MM based on standard criteria.
• No prior or current systemic therapy for MM, including steroids.
• At least 18 years and less than 65 years of age.
• Presence of quantifiable M protein in serum (e.g. greater than 1 g/dL for IgG MM, greater than 0.5 g/dL of IgA or IgD MM) or urine (e.g. greater than 200 mg/day for BJ MM).
• Karnofsky performance status (PS) at least 60%.
• Willing and able to comply with the protocol requirements.
• Agreement from both male and female patients to follow the risk management program established for the prevention of pregnancy, including double methods for contraception and beta-HCG tests for women of childbearing potential and contraception for males.
• Adequate organ function, including heart, liver, kidney (serum creatinine less than 2 mg/dL)
• Platelet count at least 70 x 10/mcL and absolute neutrophil count at least 1 x 10/mcl

Exclusion Criteria

• Diagnosis of asymptomatic MM or of MGUS based on standard criteria.
• Diagnosis of non-secretory MM.
• Diagnosis of AL Amyloidosis.
• Prior or current systemic therapy for MM, including steroids (with exception of bisphosphonates).
• Patient has received other investigational drugs within 30 days before enrollment.
• Female subjects pregnant or breastfeeding
• Patient has Grade 2 or higher peripheral neuropathy (NCI criteria).
• Patient has a prior history of thrombosis or venous thromboembolism or pulmonary embolism.
• Patient has a previous diagnosis of antiphospholipid antibodies or lupus anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin, protein C or S deficiency.
• Patient has a clear indication to receive a specific other anti-platelet therapy (e.g. clopidogrel, ticlopidine).
• Patient has a clear indication to receive long-term anticoagulant therapy (e.g. prosthetic heart valve, atrial fibrillation).
• Active bleeding or high risk of bleeding (gastrointestinal bleeding within the past 12 months; endoscopic diagnosis of peptic ulcer disease or ulcerative esophagitis within the past 6 months unless there is documented endoscopic evidence of healing; intracranial bleeding within the past year; amyloidosis; known bleeding diathesis).
• Seropositive for HIV, or active hepatitis A, B or C infection.
• Poorly controlled hypertension or diabetes mellitus (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before the start of therapy) or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study.
• Patient has hypersensitivity to bortezomib, boron or mannitol.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Previous or concurrent malignancies at other sites, with the exception of appropriately treated localized epithelial skin or cervical cancer. Patients with remote histories (>5 years) of other cured tumors may be entered.
• Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks before enrolment.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen-Cilag S.p.A.

INDUSTRY

Sponsor Role: collaborator

Michele Cavo

OTHER

Sponsor Role: lead

Responsible Party

Michele Cavo

MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Michele Cavo, MD

Role: PRINCIPAL_INVESTIGATOR

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Locations

AOU di Bologna Policlinico S.Orsola-Malpighi, UO di Ematologia

Bologna, , Italy

Countries

Italy

References

Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. doi: 10.1016/S2352-3026(20)30323-9.

Reference Type: DERIVED

PMID: 33242443 (View on PubMed)

Zamagni E, Nanni C, Dozza L, Carlier T, Bailly C, Tacchetti P, Versari A, Chauvie S, Gallamini A, Gamberi B, Caillot D, Patriarca F, Macro M, Boccadoro M, Garderet L, Barbato S, Fanti S, Perrot A, Gay F, Sonneveld P, Karlin L, Cavo M, Bodet-Milin C, Moreau P, Kraeber-Bodere F. Standardization of 18F-FDG-PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Jan 10;39(2):116-125. doi: 10.1200/JCO.20.00386. Epub 2020 Nov 5.

Reference Type: DERIVED

PMID: 33151787 (View on PubMed)

Jamet B, Morvan L, Nanni C, Michaud AV, Bailly C, Chauvie S, Moreau P, Touzeau C, Zamagni E, Bodet-Milin C, Kraeber-Bodere F, Mateus D, Carlier T. Random survival forest to predict transplant-eligible newly diagnosed multiple myeloma outcome including FDG-PET radiomics: a combined analysis of two independent prospective European trials. Eur J Nucl Med Mol Imaging. 2021 Apr;48(4):1005-1015. doi: 10.1007/s00259-020-05049-6. Epub 2020 Oct 2.

Reference Type: DERIVED

PMID: 33006656 (View on PubMed)

Pezzi A, Cavo M, Biggeri A, Zamagni E, Nanni O. Inverse probability weighting to estimate causal effect of a singular phase in a multiphase randomized clinical trial for multiple myeloma. BMC Med Res Methodol. 2016 Nov 9;16(1):150. doi: 10.1186/s12874-016-0253-9.

Reference Type: DERIVED

PMID: 27829371 (View on PubMed)

Sonneveld P, Goldschmidt H, Rosinol L, Blade J, Lahuerta JJ, Cavo M, Tacchetti P, Zamagni E, Attal M, Lokhorst HM, Desai A, Cakana A, Liu K, van de Velde H, Esseltine DL, Moreau P. Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013 Sep 10;31(26):3279-87. doi: 10.1200/JCO.2012.48.4626. Epub 2013 Jul 29.

Reference Type: DERIVED

PMID: 23897961 (View on PubMed)

Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. doi: 10.1182/blood-2012-02-408898. Epub 2012 Apr 12.

Reference Type: DERIVED

PMID: 22498745 (View on PubMed)

Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. doi: 10.1016/S0140-6736(10)61424-9. Epub 2010 Dec 9.

Reference Type: DERIVED

PMID: 21146205 (View on PubMed)

Other Identifiers

2005-003723-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

26866138-MMY-3006

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

MM-BO2005

Identifier Type: -

Identifier Source: org_study_id