Condition category
Cancer
Date applied
13/09/2005
Date assigned
03/11/2005
Last edited
03/09/2013
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

http://www.hovon.nl

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 measures

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

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, JNJ

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

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

corporate

Location

United States of America

Funder name

Chugai

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Novartis

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

Switzerland

Funder name

Roche

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

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

Results - basic reporting

Publication summary

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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

Additional files

Editorial Notes