Contact information
Type
Scientific
Primary contact
Prof Pieter Sonneveld
ORCID ID
Contact details
Erasmus MC
Dept of Hematology
P.O. Box 2040
Rotterdam
3000 CA
Netherlands
p.sonneveld@erasmusmc.nl
Additional identifiers
EudraCT number
2004-000944-26
ClinicalTrials.gov number
Protocol/serial number
26866138MMY3003; HO65
Study information
Scientific title
Acronym
HOVON65/GMMG-HD4
Study hypothesis
Bortezomib combined with intensive chemotherapy and in maintenance therapy is superior in comparison with intensive therapy with vincristine followed by thalidomide maintenance in patients with previously untreated multiple myeloma, as measured by response rate and progression-free and overall survival.
Ethics approval
Ethics approval received from the local medical ethics committee
Study design
Prospective, multicentre, randomised, active controlled, parallel group trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Multiple myeloma
Intervention
Arm A: Standard Vincristine, Adriamycin and Dexamethasone (VAD) induction, followed by intensive chemotherapy with melphalan 200 mg/m^2 and autologous blood stem cell transplantation, followed by maintenance therapy with thalidomide.
Arm B: Induction chemotherapy with Bortezomib, Adriamycin and Dexamethasone (BAD) followed by intensive chemotherapy with melphalan 200 mg/m^2 and autologous blood stem cell transplantation, followed by maintenance with bortezomib.
Duration of treatment:
Expected duration of induction, stem cell collection and intensification (with or without Bortezomib) is six to seven months. Maintenance therapy with Bortezomib or Thalidomide will be given for two years.
Please note that the anticipated end date of this trial has been shortened to 22nd April 2007.
Intervention type
Drug
Phase
Phase III
Drug names
Bortezomib, vincristine, adriamycin, dexamethasone and melphalan
Primary outcome measure
Progression Free Survival (PFS), i.e. time from registration to progression, relapse or death from any cause.
Secondary outcome measures
1. Response (Partial Remission [PR], very Good Partial Remission [vGPR] and Complete Remission [CR])
2. Overall Survival (OS)
3. PFS from High-Dose Therapy (HDT) i.e. time from last High-Dose Melphalan (HDM) treatment to progression, relapse or death from any cause whichever occurs first for patients who received at least PR on HDT
4. Toxicity
5. PFS analysed as primary endpoint, but patients with an allogeneic transplant not censored. This primarily to check whether censoring has a major impact.
Overall trial start date
01/05/2005
Overall trial end date
30/09/2011
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients with a confirmed diagnosis of multiple myeloma stage II or III according to the Salmon and Durie criteria
2. Age 18 to 65 years inclusive
3. World Health Organisation (WHO) performance status zero to three (WHO = three is allowed only when caused by multiple myeloma and not by co-morbid conditions)
4. Negative pregnancy test at inclusion if applicable
5. Written informed consent
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
800
Participant exclusion criteria
1. Known intolerance of thalidomide or boron
2. Systemic AL amyloidosis
3. Non-secretory multiple myeloma
4. Previous chemotherapy or radiotherapy except two cycles of melphalan/prednisone or local radiotherapy in case of local myeloma progression
5. Severe cardiac dysfunction (New York Heart Association [NYHA] classification II - IV)
6. Significant hepatic dysfunction (serum bilirubin more than or equal to 30 µmol/l or transaminases more than or equal to 2.5 times normal level), unless related to myeloma
7. Patients known to be Human Immunodeficiency Virus (HIV) positive
8. Patients with active, uncontrolled infections
9. Patients with neuropathy, CTC grade two or higher
10. Patients with a history of active malignancy during the past five years with the exception of basal carcinoma of the skin or stage zero cervical carcinoma
11. Patients who will not give permission for collection of Bone Marrow (BM) aspirate at entry
12. Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women)
13. Patients 65 years or less with a Human Leukocyte Antigen (HLA) identical sibling who will undergo non-myeloablative AlloSCT
14. Lactating women
Recruitment start date
01/05/2005
Recruitment end date
30/09/2011
Locations
Countries of recruitment
Germany
Trial participating centre
Erasmus MC
Rotterdam
3000 CA
Netherlands
Sponsor information
Organisation
Dutch Haemato-oncology Association (Stichting Haemato-Oncologie voor Volwassenen Nederland [HOVON])
Sponsor details
VU Medisch Centrum
P.O. Box 7057
Amsterdam
1007 MB
Netherlands
f.barbieri@vumc.nl
Sponsor type
Research organisation
Website
Funders
Funder type
Industry
Funder name
Johnson & Johnson
Alternative name(s)
Johnson & Johnson, J&J
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United States of America
Funder name
Amgen
Alternative name(s)
Amgen Inc., Applied Molecular Genetics Inc.
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United States of America
Funder name
Chugai
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Novartis
Alternative name(s)
Novartis AG
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
Switzerland
Funder name
Roche
Alternative name(s)
F. Hoffmann-La Roche Ltd, F. Hoffmann-La Roche & Co, F. Hoffmann-La Roche AG
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
Switzerland
Funder name
German Federal Ministry of Education and Research
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2011 results in: http://www.ncbi.nlm.nih.gov/pubmed/21791469
2. 2011 results in: http://www.ncbi.nlm.nih.gov/pubmed/22160383
3. 2012 results in: http://www.ncbi.nlm.nih.gov/pubmed/23233657
4. 2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23996482
Publication citations
-
Results
Corthals SL, Kuiper R, Johnson DC, Sonneveld P, Hajek R, van der Holt B, Magrangeas F, Goldschmidt H, Morgan GJ, Avet-Loiseau H, Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients., Haematologica, 2011, 96, 11, 1728-1732, doi: 10.3324/haematol.2011.041434.
-
Results
Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H, Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p., Blood, 2012, 119, 4, 940-948, doi: 10.1182/blood-2011-09-379164.
-
Results
Broyl A, Kuiper R, van Duin M, van der Holt B, el Jarari L, Bertsch U, Zweegman S, Buijs A, Hose D, Lokhorst HM, Goldschmidt H, Sonneveld P, , , High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance., Blood, 2013, 121, 4, 624-627, doi: 10.1182/blood-2012-06-438101.
-
Results
Scheid C, Sonneveld P, Schmidt-Wolf IG, van der Holt B, el Jarari L, Bertsch U, Salwender H, Zweegman S, Blau IW, Vellenga E, Weisel K, Pfreundschuh M, Jie KS, Neben K, van de Velde H, Duehrsen U, Schaafsma MR, Lindemann W, Kersten MJ, Peter N, Hänel M, Croockewit S, Martin H, Wittebol S, Bos GM, van Marwijk-Kooy M, Wijermans P, Goldschmidt H, Lokhorst HM, Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial., Haematologica, 2014, 99, 1, 148-154, doi: 10.3324/haematol.2013.087585.