A randomised comparison of thalidomide and lenalidomide combinations in myeloma patients of all ages

ISRCTN	ISRCTN49407852
DOI	https://doi.org/10.1186/ISRCTN49407852
EudraCT/CTIS number	2009-010956-93
ClinicalTrials.gov number	NCT01554852
Secondary identifying numbers	HM09/8885

Submission date: 24/04/2009
Registration date: 29/06/2009
Last edited: 05/02/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Cancer Research UK plain English summary for the intensive pathway can be found here:
http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-lenalidomide-bortezomib-intensive-treatment-group-myeloma-XI

Cancer Research UK plain English summary for the non-intensive pathway can be found here:
http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-lenalidomide-bortezomib-myeloma-non-intensive-treatment-group-myeloma-XI

Study website

Contact information

Prof Graham Jackson
Scientific

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

Dr Catherine Olivier
Scientific

Head of Trial Management, Leeds Institute of Clinical Trials Research, Level 10 Worsley Building, Clarendon Way, University of Leeds
Leeds
LS2 9NL
United Kingdom

Email	ctru_myelomaxi@leeds.ac.uk

Study information

Study design	Randomized phase III multicentre open-label trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	Randomised comparisons, in myeloma patients of all ages, of thalidomide, lenalidomide, carfilzomib and bortezomib induction combinations, and of lenalidomide and combination lenalidomide plus vorinostat as maintenance
Study 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(s)	Oxfordshire REC A, 17/09/2009, ref:09/H0604/79
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
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Cyclophosphamide, thalidomide, dexamethasone, lenalidomide, melphalan, bortezomib, carfilzomib
Primary outcome measure	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	Current secondary outcome measures as of 21/10/2024: 1. Response including CR rate at the end of induction 2. Conversion rate to CR/VGPR for patients who undergo VCD randomisation 3. Toxicity 4. PFS2 5. Relevant biological endpoints 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. _____ Previous 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 study start date	01/10/2009
Overall study end date	31/12/2023

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	4400
Total final enrolment	4420
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 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 Added 21/10/2024: 3. Lactating or breastfeeding
Recruitment start date	25/05/2010
Recruitment end date	24/02/2016

Locations

Countries of recruitment

United Kingdom

Study participating centre

112 trial sites

-
United Kingdom

Sponsor information

University of Leeds (UK)
University/education

c/o Clare Skinner
Research Office
Room 10.110, Level 10 Worsley Building
Leeds
LS2 9JT
England
United Kingdom

Phone	+44 (0)113 343 4897
Email	governance-ethics@leeds.ac.uk
Website	http://www.leeds.ac.uk
"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Cancer Research UK (CRUK) (UK) (ref: CRUK/09/014)
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Celgene Ltd (UK)

No information available

Results and Publications

Intention to publish date	30/06/2025
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Peer reviewed scientific journals. Conference Presentations. Patients are informed that they can request the published results from their doctor.
IPD sharing plan	De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing and believes it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree on suitable requirements for release

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results for maintenance therapy with lenalidomide versus placebo	01/01/2019		Yes	No
Results article	response-adapted intensification treatment results	01/12/2019	21/10/2019	Yes	No
Results article	renal outcome results	24/11/2020	25/11/2020	Yes	No
Results article	results	01/12/2020	03/12/2020	Yes	No
Results article	results	11/01/2021	12/01/2021	Yes	No
Protocol file	version 9.0	02/11/2017	21/04/2023	No	No
HRA research summary			28/06/2023	No	No
Other publications	genetic profiling study	06/04/2023	14/01/2025	Yes	No
Results article	maintenance randomisation comparing combination lenalidomide-vorinostat and lenalidomide	21/12/2022	14/01/2025	Yes	No
Abstract results	Final Analysis of the Randomised UK MRA Myeloma XI+ Trial Examining Krdc (car.lzomib, lenalidomide, dexamethasone and cyclophosphamide) As Induction Therapy for Newly Diagnosed Multiple Myeloma Patients	05/11/2024	05/02/2025	No	No
Abstract results	MRD and Molecular Risk Status Help to De.ne Optimal Maintenance Delivery Strategies after ASCT: Long Term Outcomes of the UK MRA Myeloma XI Trial Comparing Lenalidomide to Observation	05/11/2024	05/02/2025	No	No
Abstract results	Optimising the Duration of Therapy for Newly Diagnosed Transplant Ineligible Patients - Analysis of Long Term Follow up Data from the UK MRA Myeloma XI Trial	05/11/2024	05/02/2025	No	No

Additional files

ISRCTN49407852_Protocol_v9.0_02Nov2017.pdf
ISRCTN49407852 Abstract 05Nov2024 blood-3518-main.pdf: Final Analysis of the Randomised UK MRA Myeloma XI+ Trial Examining Krdc (car.lzomib, lenalidomide, dexamethasone and cyclophosphamide) As Induction Therapy for Newly Diagnosed Multiple Myeloma Patients
ISRCTN49407852 Abstract 05Nov2024 blood-4734-main.pdf: Optimising the Duration of Therapy for Newly Diagnosed Transplant Ineligible Patients - Analysis of Long Term Follow up Data from the UK MRA Myeloma XI Trial
ISRCTN49407852 Abstract 05Nov2024 blood-6127-main.pdf: MRD and Molecular Risk Status Help to De.ne Optimal Maintenance Delivery Strategies after ASCT: Long Term Outcomes of the UK MRA Myeloma XI Trial Comparing Lenalidomide to Observation

Editorial Notes

05/02/2025: Publication references added.
14/01/2025: Publication reference added.
21/10/2024: The following changes were made to the trial record:
1. A contact was changed.
2. The secondary outcome measures were changed.
3. The exclusion criteria were updated.
4. The publication and dissemination plan was added.
5. The participant level data sharing statement was added.
6. The intention to publish date was added.
7. The total final enrolment was added.
05/03/2024: The overall study end date was changed from 01/12/2019 to 31/12/2023.
21/04/2023: Protocol file uploaded.
12/01/2021: Publication reference added.
03/12/2020: Publication reference added.
25/11/2020: Publication reference added.
21/10/2019: Publication reference added.
19/12/2018: Publication reference added.
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.