Condition category
Cancer
Date applied
21/09/2000
Date assigned
21/09/2000
Last edited
04/02/2015
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Ms Louise Flanagan

ORCID ID

Contact details

Clinical Trials Research Unit
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 6441
l.m.flanagan@leeds.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

G0100132

Study information

Scientific title

Myelomatosis therapy trial for patients of all age groups

Acronym

MRC Myeloma IX

Study hypothesis

1. Therapeutic questions within the intensive pathway:
1. 1. To compare an oral induction regimen containing thalidomide with a standard infusional induction chemotherapy, CTD versus CVAD, with respect to overall/progression-free survival and response.
1.2. To investigate the effects of giving additional consolidation therapy in the form of a low intensity conditioning allogeneic stem cell transplantation on survival.

2. Therapeutic questions within the non-intensive pathway:
2.1. To compare attenuated C-Thal-Dex (CTDa) with standard MP with respect to overall/progression-free survival and response.

3. Therapeutic questions across both pathways:
3.1. To assess the value of low dose thalidomide in maintenance in improving overall and progression-free survival.
3.2. To compare an aminobisphosphonate, zoledronic acid, with standard clodronate on the severity of bone disease and in improving survival.
3.3. To investigate quality of life in the short-term (during induction chemotherapy/bisphosphonate treatment) and in the long-term (during maintenance therapy).
3.4. To investigate prognostic factors for outcome.

4. Biological objectives:
4.1. To determine the clinical relevance of genetic/cytogenetic changes present at presentation in the definition of prognostic groups.
4.2. To determine the relevance of cellular phenotypes at presentation and to subsequently use these data to monitor residual disease.
4.3. To evaluate serum free light chain (flc) measurement as a prognostic factor and in monitoring disease.

Ethics approval

Not provided at time of registration

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Multiple Myeloma

Intervention

There are two main pathways:
1. Intensive for 'younger/fitter' patients
2. Non-intensive for 'older/less fit' patients
There are three randomised comparisons within each pathway.

1. Intensive pathway
At diagnosis:
1.1. Cyclophosphamide, vincristine, adriamycin, dexamethasone (CVAD) versus cyclophosphamide, thalidomide, dexamethasone (CTD)
1.2. Clodronate versus Zoledronic acid
After high dose consolidation therapy (HDT):
1.3. Thalidomide versus no maintenance therapy
In addition, following standard high dose melphalan with autograft, patients with an available tissue-compatible sibling donor may be offered a reduced intensity conditioning allograft, if appropriate.

2. Non-intensive pathway
At diagnosis:
2.1. Melphalan, prednisolone (MP) versus cyclophosphamide, thalidomide, dexamethasone (attenuated) (CTDa)
2.2. Clodronate versus Zoledronic acid
After achievement of plateau state:
2.3. Thalidomide versus no maintenance therapy

Intervention type

Other

Phase

Not Specified

Drug names

Primary outcome measures

1. Overall survival
2. Progression-free survival
3. Response

Secondary outcome measures

1. Quality of Life
2. Skeletal related events
3. Toxicity
4. Thromboembolic events
5. Renal toxicity
6. Haematologic toxicity
7. Graft versus Host Disease (GvHD)

Overall trial start date

14/05/2003

Overall trial end date

31/07/2014

Reason abandoned

Eligibility

Participant inclusion criteria

1. Aged 18 years or greater
2. Newly diagnosed as having symptomatic multiple myeloma or non secretory multiple myeloma based on:
2.1. Paraprotein (M-protein) in serum and/or urine
2.2. Bone marrow clonal plasma cells or plasmacytoma
2.3. Related organ or tissue impairment
3. Written informed consent
4. Prepared to use contraception
5. Negative pregnancy test

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

1930

Participant exclusion criteria

1. Asymptomatic myeloma
2. Solitary plasmacytoma of bone
3. Extramedullary plasmacytoma (without evidence of myeloma)
4. Previous or concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas
5. Previous treatment for myeloma, except the following:
5.1. local radiotherapy to relieve bone pain or spinal cord compression
5.2. prior bisphosphonate treatment
5.3. low-dose corticosteroids (up to 12 mg/day dexamethasone or 80 mg/day prednisolone, for 14 days)
5.4. up to four single doses of corticosteroids (total dose 1 g methylperdnisolone, 200 mg dexamethasone, or 1.25 g prenisolone)
Caution is advised in patients with a past history of ischaemic heart disease or psychiatric disorders, but exclusion is essentially to be at the discretion of the treating clinician.
6. Acute renal failure (unresponsive to up to 72 h of rehydration characterised by creatine >500 µmol/l or urine output <400 ml/day or requirement for dialysis). These patients are not eligible for this study but may be eligible for inclusion in MERIT (Myeloma Renal Impairment Trial). NB Patients with serum creatinine >2 x upper limit or normal (or creatinine clearance <20 ml/min) are eligible for Myeloma IX, but bisphosphonates should not be administered until serum creatinine has decreased to <2 x upper limit of normal (or creatinine clearance >30 ml/min)

Recruitment start date

14/05/2003

Recruitment end date

31/07/2014

Locations

Countries of recruitment

New Zealand, South Africa, United Kingdom

Trial participating centre

Clinical Trials Research Unit
Leeds
LS2 9JT
United Kingdom

Sponsor information

Organisation

University of Leeds (UK)

Sponsor details

c/o Clinical Trials Research Unit (CTRU)
University of Leeds
17 Springfield Mount
Leeds
LS2 9NG
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Research council

Funder name

Medical Research Council (MRC) (UK)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

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. 2005 interim results in: http://www.ncbi.nlm.nih.gov/pubmed/16166766
2. 2010 results on homozygous deletion mapping in myeloma samples in: http://www.ncbi.nlm.nih.gov/pubmed/20215539
3. 2010 results on genomic profiling of multiple myeloma in: http://www.ncbi.nlm.nih.gov/pubmed/20616218
4. 2010 results on XBP1s levels in multiple myeloma in: http://www.ncbi.nlm.nih.gov/pubmed/20421453
5. 2011 results on CTD initial therapy in: http://www.ncbi.nlm.nih.gov/pubmed/21652683
6. 2011 results on secondary outcomes in: http://www.ncbi.nlm.nih.gov/pubmed/21771568
7. 2011 results and meta-analysis in: http://www.ncbi.nlm.nih.gov/pubmed/22021371
8. 2011 results in: http://www.ncbi.nlm.nih.gov/pubmed/22058209
9. 2011 results in: http://www.ncbi.nlm.nih.gov/pubmed/21856767
10. 2012 results in: http://www.ncbi.nlm.nih.gov/pubmed/22573403
11. 2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23995858
12. 2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23974194
13. 2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/24733348
14. 2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25645353

Publication citations

  1. Interim results

    Child JA, Russell N, Sonneveld P, Schey S, Future directions in multiple myeloma treatment., Acta Haematol., 2005, 114 Suppl 1, 8-13, doi: 10.1159/000087038.

  2. Results on homozygous deletion mapping in myeloma samples

    Dickens NJ, Walker BA, Leone PE, Johnson DC, Brito JL, Zeisig A, Jenner MW, Boyd KD, Gonzalez D, Gregory WM, Ross FM, Davies FE, Morgan GJ, Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome., Clin. Cancer Res., 2010, 16, 6, 1856-1864, doi: 10.1158/1078-0432.CCR-09-2831.

  3. Results on genomic profiling of multiple myeloma

    Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, Johnson DC, Gonzalez D, Dagrada GP, Protheroe RK, Konn ZJ, Stockley DM, Gregory WM, Davies FE, Ross FM, Morgan GJ, A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value., Blood, 2010, 116, 15, e56-65, doi: 10.1182/blood-2010-04-279596.

  4. Results on CTD initial therapy

    Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA, , Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation., Blood, 2011, 118, 5, 1231-1238, doi: 10.1182/blood-2011-02-338665.

  5. Results

    Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA, , Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results., Haematologica, 2012, 97, 3, 442-450, doi: 10.3324/haematol.2011.043372.

  6. Results

    Wu P, Walker BA, Brewer D, Gregory WM, Ashcroft J, Ross FM, Jackson GH, Child AJ, Davies FE, Morgan GJ, A gene expression-based predictor for myeloma patients at high risk of developing bone disease on bisphosphonate treatment., Clin. Cancer Res., 2011, 17, 19, 6347-6355, doi: 10.1158/1078-0432.CCR-11-0994.

  7. Results

    Walker BA, Wardell CP, Melchor L, Hulkki S, Potter NE, Johnson DC, Fenwick K, Kozarewa I, Gonzalez D, Lord CJ, Ashworth A, Davies FE, Morgan GJ, Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma., Blood, 2012, 120, 5, 1077-1086, doi: 10.1182/blood-2012-03-412981.

  8. Results

    Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA, Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment., Clin. Cancer Res., 2013, 19, 21, 6030-6038, doi: 10.1158/1078-0432.CCR-12-3211.

  9. Results

    Larocca A, Child JA, Cook G, Jackson GH, Russell N, Szubert A, Gregory WM, Brioli A, Owen RG, Drayson MT, Wu P, Palumbo A, Boccadoro M, Davies FE, Morgan GJ, The impact of response on bone-directed therapy in patients with multiple myeloma., Blood, 2013, 122, 17, 2974-2977, doi: 10.1182/blood-2013-04-498139.

  10. Results

    Brioli A, Giles H, Pawlyn C, Campbell JP, Kaiser MF, Melchor L, Jackson GH, Gregory WM, Owen RG, Child JA, Davies FE, Cavo M, Drayson MT, Morgan GJ, Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome., Blood, 2014, 123, 22, 3414-3419, doi: 10.1182/blood-2013-12-542662.

  11. Bagratuni T, Wu P, Gonzalez de Castro D, Davenport EL, Dickens NJ, Walker BA, Boyd K, Johnson DC, Gregory W, Morgan GJ, Davies FE, XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments., Blood, 2010, 116, 2, 250-253, doi: 10.1182/blood-2010-01-263236.

  12. Morgan GJ, Child JA, Gregory WM, Szubert AJ, Cocks K, Bell SE, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross FM, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Wu P, Davies FE, , Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial., Lancet Oncol., 2011, 12, 8, 743-752, doi: 10.1016/S1470-2045(11)70157-7.

  13. Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA, , The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis., Blood, 2012, 119, 1, 7-15, doi: 10.1182/blood-2011-06-357038.

  14. Results

    Rawstron AC, Gregory WM, de Tute RM, Davies FE, Bell S, Drayson MT, Cook G, Jackson GH, Morgan GJ, Child JA, Owen RG, Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction, Blood, 2015 .

Additional files

Editorial Notes