Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma
FiTNEss
Myeloma XIV: A Phase III Trial to Compare Standard and Frailty-adjusted Induction Therapy With Ixazomib, Lenalidomide and Dexamethasone (IRD) and Maintenance Lenalidomide (R) to Lenalidomide Plus Ixazomib (R+I)
1 other identifier
interventional
740
1 country
110
Brief Summary
Trial Title: FiTNEss (UK-MRA Myeloma XIV) - Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma Overview: A phase III, multi-centre, randomised controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomised on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose-modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomisation on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians will be blinded to maintenance allocation. Participant population:
- Newly diagnosed as having Multiple Myeloma (MM) according to the updated IMWG diagnostic criteria 2014 (see Appendix 1 for criteria)
- Not eligible for stem cell transplant
- Aged at least 18 years
- Able to provide written informed consent Number of participants: 740 participants will be entered into the trial at Randomisation 1 (R1), with 478 participants at Randomisation 2 (R2). Objectives: The primary objectives of this study are to determine:
- Early treatment cessation (within 60 days of randomisation) for standard versus frailty-adjusted up-front dosing
- Progression-free survival (PFS, from maintenance randomisation) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (R+I) The secondary objectives of this study are to assess progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, time to progression, time to 2nd PFS event (PFS2), overall survival (OS), survival after progression, deaths within 12 months of R1, overall response rate (ORR), attainment of ≥VGPR, attainment of MRD negativity, duration of response, time to improved response, time to next treatment, treatment compliance and total amount of therapy delivered, toxicity \& safety including the incidence of SPMs, Quality of Life (QoL), cost effectiveness of standard versus frailty-adjusted up-front dosing of IRD and cost-effectiveness of R + I versus R. Exploratory objectives are prospective validation of a novel frailty risk score (UK-MRA Myeloma Risk Profile - MRP), usefulness of Karnofsky Performance Status (PS), and association of molecular subgroups with response, PFS and OS.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 multiple-myeloma
Started Aug 2020
110 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 17, 2018
CompletedFirst Posted
Study publicly available on registry
October 25, 2018
CompletedStudy Start
First participant enrolled
August 4, 2020
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
December 1, 2024
CompletedJune 15, 2021
December 1, 2020
4.3 years
October 17, 2018
June 10, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Randomisation 1: Number of participants with early treatment cessation
Early treatment cessation is defined as a binary endpoint. Participants will be defined to have experienced an event if they die, progress, or are withdrawn from treatment (by a treating clinician) or withdraw consent for trial treatment, within 60 days of Randomisation 1.
Within 60 days of Randomisation 1
Randomisation 2: Progression-free survival (PFS-R2)
PFS-R2 is defined as the time from Randomisation 2 to the time of first documented evidence of disease progression or death from any cause. Individuals who are lost to follow-up or progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Disease progression is defined according to the IMWG Uniform Response Criteria for Multiple Myeloma.
The time from the date of Randomisation 2 to the date of first documented evidence of disease progression or death from any cause, up to 120 months
Secondary Outcomes (17)
Progression-free survival (PFS-R1)
The time from the date of Randomisation 1 to the date of first documented evidence of disease progression or death from any cause, up to 120 months
Time to disease progression
The time from the date of randomisation to the date of first documented evidence of disease progression, up to 120 months
Progression-free survival two (PFS2)
The time from the date of randomisation to the date of the second documented disease progression, up to 120 months
Overall survival (OS)
The time from the date of randomisation to the date of death from any cause, up to 120 months
Survival after progression
The date of first documented evidence of disease progression to the date of death from any cause, up to 120 months
- +12 more secondary outcomes
Other Outcomes (2)
Novel frailty risk score (UK-MRA MRP)_composite measure
Through study completion, up to 120 months
Usefulness of Karnofsky PS_composite measure
Through study completion, up to 120 months
Study Arms (4)
R1: IRD induction therapy (reactive)
ACTIVE COMPARATORIn the reactive arm at Randomisation 1, participants will receive IRD induction therapy with standard up-front dosing, with toxicity assessed at each cycle and doses adjusted in accordance with the guidelines given in the trial protocol.
R1: IRD induction therapy (adaptive)
EXPERIMENTALIn the adaptive arm at Randomisation 1, participants will receive IRD induction therapy with up-front dose reductions adjusted according to their frailty score: fit, unfit, or frail.
R2: Lenalidomide plus placebo maintenance
ACTIVE COMPARATORParticipants randomised to this arm at Randomisation 2 will receive lenalidomide plus placebo maintenance.
R2: Lenalidomide + ixazomib maintenance
EXPERIMENTALParticipants randomised to this arm at Randomisation 2 will receive lenalidomide plus ixazomib maintenance.
Interventions
In the reactive arm at Randomisation 1, participants will receive IRD induction therapy with standard up-front dosing, with toxicity assessed at each cycle and doses adjusted in accordance with the guidelines given in the trial protocol. All participants will be given the following starting doses: Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 25mg/day on days 1-21, taken orally Dexamethasone: 40mg on days 1, 8, 15 and 22 for participants aged ≤75 years, or 20mg on days 1, 8, 15 and 22 for participants aged \> 75 years; taken orally Participants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.
In the adaptive arm at Randomisation 1, participants will receive IRD induction therapy with up-front dose reductions adjusted according to their frailty score: fit, unfit, or frail. The starting doses for each frailty category are described below: 1. Fit category: Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 25mg on days 1-21, taken orally Dexamethasone: 40mg on days 1, 8, 15 and 22, taken orally 2. Unfit category: Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 15mg on days 1-21, taken orally Dexamethasone: 20mg on days 1, 8, 15 and 22, taken orally 3. Frail category: Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 10mg on days 1-21, taken orally Dexamethasone: 10mg on days 1, 8, 15 and 22, taken orally Participants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.
Participants randomised to receive lenalidomide plus placebo maintenance at Randomisation 2 will receive the following starting doses: Lenalidomide: 10mg\*/day on days 1-21, taken orally Placebo: 4mg\*/day on days 1, 8 and 15 \* or final dose administered at the end of induction treatment if lower. This dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days. Randomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.
Participants randomised to receive lenalidomide plus ixazomib maintenance at Randomisation 2 will receive the following starting doses: Lenalidomide: 10mg\*/day on days 1-21, taken orally Ixazomib: 4mg\*/day on days 1, 8 and 15 \* or final dose administered at the end of induction treatment if lower. This dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days. Randomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.
Eligibility Criteria
You may not qualify if:
- Newly diagnosed as having MM according to the updated IMWG diagnostic criteria 2014 requiring treatment.
- Not eligible for stem cell transplant.
- Aged at least 18 years.
- Meet all of the following blood criteria within 14 days before R1:
- Haematological:
- Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L. Unless the participant has a known/suspected diagnosis of familial or racial neutropenia in which case an ANC ≥ 0.75 x 10\^9/L is allowed. The use of growth factor support is permitted.
- Platelet count ≥ 50 x 10\^9/L, or, in the case of heavy bone marrow infiltration (≥ 50%) which in the opinion of the investigator is the cause of the thrombocytopenia and provided appropriate supportive measures and patient monitoring are in place, platelet count ≥ 30 x 10\^9/L is permitted. Please note: Platelet transfusions are not allowed ≤ 3 days prior to randomisation in order to meet these values.
- Haemoglobin ≥ 80 g/L. The use of red blood cell transfusions is permitted.
- Biochemical:
- Total bilirubin ≤ 3 x upper limit of normal (ULN).
- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN.
- Meet the pregnancy prevention requirements:
- Female participants who:
- Are not of childbearing potential, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR
- +49 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of Leedslead
- Cancer Research UKcollaborator
- Takedacollaborator
- Celgenecollaborator
Study Sites (110)
Aberdeen Royal Infirmary
Aberdeen, United Kingdom
Nevill Hall Hospital
Abergavenny, United Kingdom
Wrightington Hosptial
Appley Bridge, United Kingdom
Ysbyty Gwynedd
Bangor, United Kingdom
North Devon District Hospital
Barnstaple, United Kingdom
Furness General Hospital
Barrow in Furness, United Kingdom
Basingstoke and North Hampshire Hospital
Basingstoke, United Kingdom
Royal United Hospital
Bath, United Kingdom
Belfast City Hospital
Belfast, United Kingdom
Birmingham Heartlands Hospital
Birmingham, United Kingdom
Queen Elizabeth Hospital
Birmingham, United Kingdom
Royal Blackburn Hospital
Blackburn, United Kingdom
Blackpool Victoria Hospital
Blackpool, United Kingdom
Royal Bolton Hospital
Bolton, United Kingdom
Pilgrim Hospital
Boston, United Kingdom
Royal Bournemouth Hospital
Bournemouth, United Kingdom
Bradford Royal Infirmary
Bradford, United Kingdom
Bristol Haematology and Oncology Centre
Bristol, United Kingdom
Southmead Hospital
Bristol, United Kingdom
Queen's Hospital
Burton-on-Trent, United Kingdom
Kent and Canterbury Hospital
Canterbury, United Kingdom
Chelmsford & Essex Hospital
Chelmsford, United Kingdom
Cheltenham General Hospital
Cheltenham, United Kingdom
Countess of Chester Hospital
Chester, United Kingdom
St Richard's Hospital
Chichester, United Kingdom
Colchester General Hospital
Colchester, United Kingdom
University Hospital Coventry
Coventry, United Kingdom
Croydon University Hospital
Croydon, United Kingdom
Royal Derby Hospital
Derby, United Kingdom
Dorset County Hospital
Dorchester, United Kingdom
Russells Hall Hospital
Dudley, United Kingdom
Ninewells Hospital
Dundee, United Kingdom
Western General Hospital
Edinburgh, United Kingdom
Royal Devon & Exeter Hospital
Exeter, United Kingdom
Medway Maritime Hospital
Gillingham, United Kingdom
Gloucestershire Royal Hospital
Gloucester, United Kingdom
Grantham and District Hospital
Grantham, United Kingdom
Diana Princess of Wales Hospital
Grimsby, United Kingdom
Royal Surrey County Hospital
Guildford, United Kingdom
Calderdale Royal Hospital
Halifax, United Kingdom
Harrogate District Hospital
Harrogate, United Kingdom
Withybush General Hospital
Haverfordwest, United Kingdom
Hereford County Hospital
Hereford, United Kingdom
Huddersfield Royal Infirmary
Huddersfield, United Kingdom
Castle Hill Hospital
Hull, United Kingdom
Raigmore Hospital
Inverness, United Kingdom
Ipswich Hospital
Ipswich, United Kingdom
Airedale Hospital
Keighley, United Kingdom
Westmorland General Hospital
Kendal, United Kingdom
Kettering General Hospital
Kettering, United Kingdom
Kidderminster Hospital & Treatment Centre
Kidderminster, United Kingdom
Victoria Hospital
Kirkcaldy, United Kingdom
Royal Lancaster Infirmary
Lancaster, United Kingdom
St James's University Hospital
Leeds, United Kingdom
Leicester Royal Infirmary
Leicester, United Kingdom
Lincoln County Hospital
Lincoln, United Kingdom
Aintree University Hospital
Liverpool, United Kingdom
Royal Liverpool Hospital
Liverpool, United Kingdom
Guy's Hospital
London, United Kingdom
King's College Hospital
London, United Kingdom
Queen Elizabeth Hospital Greenwich
London, United Kingdom
St Bartholomew's Hospital
London, United Kingdom
University College Hospital
London, United Kingdom
University Hospital Lewisham
London, United Kingdom
Maidstone Hospital
Maidstone, United Kingdom
Manchester Royal Infirmary
Manchester, United Kingdom
James Cook University Hospital
Middlesbrough, United Kingdom
Freeman Hospital
Newcastle, United Kingdom
Royal Gwent Hospital
Newport, United Kingdom
North Tyneside General Hospital
North Shields, United Kingdom
Nottingham City Hospital
Nottingham, United Kingdom
Royal Oldham Hospital
Oldham, United Kingdom
Princess Royal University Hospital
Orpington, United Kingdom
Peterborough City Hospital
Peterborough, United Kingdom
Derriford Hospital
Plymouth, United Kingdom
Whiston Hospital
Prescot, United Kingdom
Royal Preston Hospital
Preston, United Kingdom
Royal Berkshire Hospital
Reading, United Kingdom
Alexandra Hospital
Redditch, United Kingdom
Glan Clwyd Hospital
Rhyl, United Kingdom
Queen's Hospital
Romford, United Kingdom
Tunbridge Wells Hospital
Royal Tunbridge Wells, United Kingdom
Salford Royal Hospital
Salford, United Kingdom
Salisbury District Hospital
Salisbury, United Kingdom
Scarborough General Hospital
Scarborough, United Kingdom
Scunthorpe General Hospital
Scunthorpe, United Kingdom
Royal Hallamshire Hospital
Sheffield, United Kingdom
Royal Shrewsbury Hospital
Shrewsbury, United Kingdom
Southampton General Hospital
Southampton, United Kingdom
St Helens Hospital
St Helens, United Kingdom
Stafford County Hospital
Stafford, United Kingdom
Stepping Hill Hospital
Stockport, United Kingdom
Royal Stoke University Hospital
Stoke-on-Trent, United Kingdom
Sunderland Royal Hospital
Sunderland, United Kingdom
Good Hope Hospital
Sutton Coldfield, United Kingdom
Singleton Hospital
Swansea, United Kingdom
St George's Hospital
Tooting, United Kingdom
Torbay District General Hospital
Torquay, United Kingdom
Royal Cornwall Hospital
Truro, United Kingdom
Hillingdon Hospital
Uxbridge, United Kingdom
Pinderfields General Hospital
Wakefield, United Kingdom
Warwick Hospital
Warwick, United Kingdom
Sandwell General Hospital
West Bromwich, United Kingdom
Royal Albert Edward Infirmary
Wigan, United Kingdom
Royal Hampshire County Hospital
Winchester, United Kingdom
New Cross Hospital
Wolverhampton, United Kingdom
Worcestershire Royal Hospital
Worcester, United Kingdom
Worthing Hospital
Worthing, United Kingdom
Wrexham Maelor Hospital
Wrexham, United Kingdom
York Hospital
York, United Kingdom
Related Publications (1)
Coulson AB, Royle KL, Pawlyn C, Cairns DA, Hockaday A, Bird J, Bowcock S, Kaiser M, de Tute R, Rabin N, Boyd K, Jones J, Parrish C, Gardner H, Meads D, Dawkins B, Olivier C, Henderson R, Best P, Owen R, Jenner M, Kishore B, Drayson M, Jackson G, Cook G. Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial. BMJ Open. 2022 Jun 2;12(6):e056147. doi: 10.1136/bmjopen-2021-056147.
PMID: 35654466DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Gordon Cook, MD
University of Leeds
- PRINCIPAL INVESTIGATOR
Graham Jackson, MD
Freeman Hospital, Newcastle-Upon-Tyne
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- Randomisation 1 is open label Randomisation 2 is double-blind, placebo-controlled
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 17, 2018
First Posted
October 25, 2018
Study Start
August 4, 2020
Primary Completion
December 1, 2024
Study Completion
December 1, 2024
Last Updated
June 15, 2021
Record last verified: 2020-12