Condition category
Cancer
Date applied
24/04/2009
Date assigned
29/06/2009
Last edited
03/06/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Prof Graham Jackson

ORCID ID

Contact details

Northern Centre for Cancer Care
Freeman Hospital
Freeman Road
Newcastle-upon-Tyne
NE7 7DN
United Kingdom

Type

Scientific

Additional contact

Dr Gwen Jacques

ORCID ID

Contact details

Senior Trial Coordinator for Myeloma XI
Clinical Trials Research Unit
University of Leeds
71-75 Clarendon Road
Leeds
LS2 9PH
United Kingdom
-
ctru_myelomaxi@leeds.ac.uk

Additional identifiers

EudraCT number

2009-010956-93

ClinicalTrials.gov number

NCT01554852

Protocol/serial number

HM09/8885

Study information

Scientific title

Randomised comparisons, in myeloma patients of all ages, of thalidomide, lenalidomide, carfilzomib and bortezomib induction combinations, and of lenalidomide and combination lenalidomide vorinostat as maintenance

Acronym

Myeloma XI

Study hypothesis

Current hypothesis as of 03/06/2016:
Myeloma XI has two treatment pathways; an intensive pathway for younger/fitter patients where intensive high-dose therapy (HDT) with stem cell support is considered appropriate, and a non-intensive pathway for older/less fit patients. The trial aims to answer three main questions at induction, consolidation and maintenance:
1. Is cyclophosphamide-lenalidomide-dexamethasone (RCD) or a 4-drug regimen including both lenalidomide and carfilzomib (CCRD) given to maximum response, a better induction regimen than the current UK gold standard of cyclophosphamide-thalidomide-dexamethasone (CTD)?
2. For patients achieving a sub-optimal response to induction across both treatment pathways (less than very good partial response [VGPR]), can the use of bortezomib, cyclophosphamide and dexamethasone (VCD) improve responses and does this translate into improved progression-free survival (PFS) and overall survival (OS)?
3. Can lenalidomide at maintenance improve PFS and OS when compared to the use of no maintenance?

Previous hypothesis:
Myeloma XI has two treatment pathways; an intensive pathway for younger/fitter patients where intensive high-dose therapy (HDT) with stem cell support is considered appropriate, and a non-intensive pathway for older/less fit patients. The trial aims to answer three main questions at induction, consolidation and maintenance:
1. Is cyclophosphamide-lenalidomide-dexamethasone (RCD) given to maximum response, a better induction regimen than the current UK gold standard of cyclophosphamide-thalidomide-dexamethasone (CTD)?
2. For patients achieving a sub-optimal response to induction across both treatment pathways (less than very good partial response [VGPR]), can the use of bortezomib, cyclophosphamide and dexamethasone (VCD) improve responses and does this translate into improved progression-free survival (PFS) and overall survival (OS)?
3. Can lenalidomide at maintenance improve PFS and OS when compared to the use of no maintenance?

Ethics approval

Oxfordshire REC A, 17/09/2009, ref:09/H0604/79

Study design

Randomised phase III multicentre open-label trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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

Condition

Myeloma

Intervention

Intensive pathway: current interventions as of 02/06/2016:
Patients will be initially randomised to receive either CTD (cyclophosphamide, thalidomide, and dexamethasone), RCD (cyclophsphamide, lenalidomide, and dexamethasone), or CCRD (carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone), and will receive a minimum of 4 cycles of induction chemotherapy to maximum response or patient intolerance.
All patients showing a complete response (CR) or very good partial response (VGPR) to CTD/RCD/CCRD will proceed to peripheral blood stem cell harvest and standard high-dose melphalan (HDM) with supporting autologous peripheral blood stem cell transplant (ASCT).
Patients showing a partial response (PR) or minimal response (MR) to CTD/ RCD/CCRD will be randomised to receive consolidation bortezomib plus cyclophosphamide and dexamethasone (VCD) to maximum response or intolerance (up to 8 cycles), or proceed straight to peripheral blood stem cell harvest and standard HDM with supporting ASCT. Once randomised patients have received VCD, they will proceed with harvest, HDM and ASCT.
Patients showing progressive disease (PD) or no change (NC) during induction chemotherapy (CTD, RCD, or CCRD) will all receive consolidation VCD (i.e. will not undergo the VCD vs nothing randomisation) to maximum response or intolerance (up to 8 cycles), then proceed to peripheral blood stem cell harvest and standard HDM with supporting ASCT.
Following HDM/ASCT, all patients who are disease progression-free (except those who demonstrated PD or NC during RCD) will undergo maintenance randomisation to either lenalidomide maintenance or no maintenance treatment. Patients randomised to lenalidomide maintenance will commence lenalidomide approximately 100 days post HDM/ASCT. In the absence of toxicity, lenalidomide maintenance will continue (21 days out of every 28) until disease progression.

Intensive pathway: previous interventions
Patients will be initially randomised to receive either CTD (cyclophosphamide, thalidomide and dexamethasone) or RCD (cyclophsphamide, lenalidomide and dexamethasone) and will receive a minimum of 4 cycles of induction chemotherapy to maximum response or patient intolerance.
All patients showing a complete response (CR) or very good partial response (VGPR) to RCD/CTD will proceed to peripheral blood stem cell harvest and standard high-dose melphalan (HDM) with supporting autologous peripheral blood stem cell transplant (ASCT).
Patients showing a partial response (PR) or minimal response (MR) to RCD/CTD will be randomised to receive consolidation bortezomib plus cyclophosphamide and dexamethasone (VCD) to maximum response or intolerance (up to 8 cycles), or proceed straight to peripheral blood stem cell harvest and standard HDM with supporting ASCT. Once randomised patients have received VCD, they will proceed with harvest, HDM and ASCT.
Patients showing progressive disease (PD) or no change (NC) during induction chemotherapy (RCD or CTD) will all receive consolidation VCD (ie will not undergo the VCD vs nothing randomisation) to maximum response or intolerance (up to 8 cycles), then proceed to peripheral blood stem cell harvest and standard HDM with supporting ASCT.
Following HDM/ASCT, all patients who are disease progression-free (except those who demonstrated PD or NC during RCD) will undergo maintenance randomisation to either lenalidomide maintenance or no maintenance treatment. Patients randomised to lenalidomide maintenance will commence lenalidomide approximately 100 days post HDM/ASCT. In the absence of toxicity, lenalidomide maintenance will continue (21 days out of every 28) until disease progression.

Non-intensive pathway
Patients will be randomised to RCDa (RCD with a reduced dose of dexamethasone) or CTDa (CTD with a reduced dose of dexamethasone and lower starting dose of thalidomide) and will receive a minimum 6 cycles of their randomised induction treatment regimen to maximum response.
All patients showing CR or VGPR will proceed to maintenance randomisation (lenalidomide or no maintenance). Patients showing PR or MR to RCDa/CTDa will be randomised to receive consolidation VCD to maximum response or intolerance (up to 8 cycles), or proceed to maintenance randomisation. Once randomised patients have received VCD, they will proceed with maintenance randomisation.
Patients showing progressive disease (PD) or NC during induction chemotherapy (RCDa or CTDa) will all receive consolidation VCD (i.e., will not undergo the VCD versus nothing randomisation) to maximum response or intolerance (up to 8 cycles).
Following RCD/CTD/VCD, all patients who are disease progression-free (except those who demonstrated PD or NC during RCDa) will undergo maintenance randomisation to either lenalidomide maintenance or no maintenance treatment. In the absence of toxicity, lenalidomide maintenance will continue (21 days out of every 28) until disease progression.

Intervention type

Drug

Phase

Phase III

Drug names

Cyclophosphamide, thalidomide, dexamethasone, lenalidomide, melphalan, bortezomib, carfilzomib

Primary outcome measures

1. Overall survival
2. Progression-free survival

Interim analyses will be presented to the DMEC at approximately yearly intervals and the trial will have a formal interim analysis when half the total number of deaths has been observed. No other formal analyses are planned until after the trial is closed to accrual.

Secondary outcome measures

1. Response
2. Conversion rate to CR/VGPR for patients who undergo VCD randomisation
3. Toxicity

Interim analyses will be presented to the DMEC at approximately yearly intervals and the trial will have a formal interim analysis when half the total number of deaths has been observed. No other formal analyses are planned until after the trial is closed to accrual.

Overall trial start date

01/10/2009

Overall trial end date

01/12/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Aged 18 years or greater, either sex
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 and/or symptoms considered by the clinician to be myeloma related
3. Provide written informed consent
4. Women of childbearing potential and male patients whose partner is a woman of child bearing potential must be prepared to use contraception in accordance with (and consent to) the Celgene approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention, or commit to absolute and continuous abstinence
5. Women of child bearing potential must have a negative pregnancy test in accordance with the Celgene approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

4400

Participant exclusion criteria

1. Asymptomatic myeloma
2. Solitary plasmacytoma of bone (patients with previous solitary plasmacytoma that have now progressed to symptomatic or non-secretory myeloma are eligible)
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. Patients with remote histories (greater than 5 years) of other cured malignancies may be entered.
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. Corticosteroids within the last 3 months
6. Known history of allergy contributable to compounds containing boron or mannitol
7. Grade 2 or greater (National Cancer Institute [NCI] criteria) peripheral neuropathy
8. Caution is advised in patients with a past history of ischaemic heart disease, pericardial disease, acute diffuse infiltrative pulmonary disease or psychiatric disorders, evidence of impaired marrow function or elevated liver function tests, but exclusion is essentially to be at the discretion of the treating clinician
9. Acute renal failure (unresponsive to up to 72 hours of rehydration, characterised by creatinine greater than 500 µmol/l or urine output less than 400 ml/day or requirement for dialysis)

Added 02/06/2016:
1. Documented diagnosis of Myelodysplastic Syndrome (MDS) that meets International Prognostic Scoring System (IPSS) criteria for high-risk disease
2. Patient has active or prior hepatitis C

Recruitment start date

25/05/2010

Recruitment end date

24/02/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

112 trial sites
-
United Kingdom

Sponsor information

Organisation

University of Leeds (UK)

Sponsor details

c/o Clare Skinner
Research Office
Room 10.110
Level 10 Worsley Building
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 4897
governance-ethics@leeds.ac.uk

Sponsor type

University/education

Website

http://www.leeds.ac.uk

Funders

Funder type

Charity

Funder name

Cancer Research UK (CRUK) (UK) (ref: CRUK/09/014)

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Celgene Ltd (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

To be confirmed at a later date

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

On 13/04/2016 the following changes were made to the trial record: 1. The scientific title was changed from 'Thalidomide and lenalidomide combinations in newly diagnosed patients with symptomatic myeloma: a randomised, phase III, multi-centre, open-label trial' to 'Randomised comparisons, in myeloma patients of all ages, of thalidomide, lenalidomide, carfilzomib and bortezomib induction combinations, and of lenalidomide and combination lenalidomide vorinostat as maintenance' 2. The overall trial end date was changed from 30/09/2017 to 01/12/2019. 3. The target number of participants was changed from 1865 to 4400.