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

NCT01134484 | Unknown Phase 3 DMC

• 3 other identifiers: MM-BO20052005-003723-3926866138-MMY-3006
• Study Type: interventional
• Target: 480
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Myeloma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Rate of CR+nCR to induction treatment

  Responses to induction therapy were reported by study investigators and centrally reassessed by study coordinator(s). Criteria are those initially proposed by the European Group for Blood and Marrow Transplantation (EBMT), with the addition of nCR (100% M-protein reduction by electrophoresis, but immunofixation-positive) and very good partial response (VGPR) (at least 90% serum and urine M-protein reduction) categories. Comparisons of response rates between treatment arms are performed using Fisher's exact test.

  63 days after the start day of either TD or VTD as induction therapy

Secondary Outcomes (5)

• Rate of CR+nCR to autotransplantation(s) and subsequent consolidation therapy

  90 days after the second autologous transplantation and 70 days after the beginning of either TD or VTD as consolidation therapy

• Time To Progression (TTP)

  Average time period between the start day of either TD or VTD as induction therapy and the day of relapse or progression

• Progression-Free Survival (PFS)

  Average time period between the start day of either TD or VTD as induction therapy and the day of relapse or progression or death, whichever occurs firstly

• Overall Survival (OS)

  Average time period between the start day of either TD or VTD as induction therapy and the day of death, due to any cause

• Safety

  Average time period between the start day of either TD or VTD as induction therapy and the day of any toxicity/adverse event(s) recorded during and after study drug administration

Study Arms (2)

VTD

EXPERIMENTAL

Drug: Velcade; Drug: Thalidomide; Drug: Dexamethasone; Procedure: Peripheral Blood Stem Cell (PBSC) collection; Procedure: First Autologous Transplantation; Procedure: Second Autologous Transplantation

TD

ACTIVE COMPARATOR

Drug: Thalidomide; Drug: Dexamethasone; Procedure: Peripheral Blood Stem Cell (PBSC) collection; Procedure: First Autologous Transplantation; Procedure: Second Autologous Transplantation

Interventions

Velcade 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)

Also known as: Bortezomib

VTD

Thalidomide 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

Also known as: Talidomide

TD; VTD

Dexamethasone 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)

Also known as: Soldesam

TD; VTD

Peripheral Blood Stem Cell (PBSC) collection 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

TD; VTD

First Autologous Transplantation 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; VTD

Second Autologous Transplantation 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; VTD

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Michele Cavo: lead
• Janssen-Cilag S.p.A.: collaborator

Study Sites (1)

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

Bologna, 40138, Italy

Location

Related Publications (7)

• 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.

  PMID: 33242443 DERIVED

• 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.

  PMID: 33151787 DERIVED

• 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.

  PMID: 33006656 DERIVED

• 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.

  PMID: 27829371 DERIVED

• 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.

  PMID: 23897961 DERIVED

• 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.

  PMID: 22498745 DERIVED

• 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.

  PMID: 21146205 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Pathologic Complete Response

Interventions

Bortezomib; Thalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Progression; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Michele Cavo, MD

  IRCCS Azienda Ospedaliero-Universitaria di Bologna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: May 28, 2010
• First Posted: June 2, 2010
• Study Start: May 1, 2006
• Primary Completion: August 1, 2008
• Study Completion: December 1, 2015
• Last Updated: July 20, 2012

Record last verified: 2012-07

Locations

IT (1)