Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma
- Conditions
- Multiple Myeloma
- Registration Number
- NCT03720041
- Lead Sponsor
- University of Leeds
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 740
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Randomisation 1: Number of participants with early treatment cessation Within 60 days of Randomisation 1 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.
Randomisation 2: Progression-free survival (PFS-R2) 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 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.
- Secondary Outcome Measures
Name Time Method Deaths within 12 months of Randomisation 1 (R1) Within 12 months of Randomisation 1 Deaths within 12 months of Randomisation 1 is defined as a binary endpoint. Participants will be defined to have experienced an event if they die within 12 months of Randomisation 1.
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 PFS-R1 is defined as the time from R1 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.
Overall response rate (ORR) From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days) Overall response rate is defined as a categorical outcome consisting of whether a participant had Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) or Progressive Disease (PD) at the end of induction according to the IMWG Uniform Response Criteria for Multiple Myeloma.
Duration of response (DoR) The time from the date of the first observation of response ≥ Partial Response following Randomisation 1, to the date of first documented evidence of disease progression or death confirmed related to progression, up to 120 months Duration of response is defined as the time from the first observation of response ≥ Partial Response (PR), following Randomisation 1, to the time of first documented evidence of disease progression or death confirmed related to progression. Individuals who are lost to follow-up, or still alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Individuals whose cause of death is unrelated to disease progression will be censored at their date of death.
Overall survival (OS) The time from the date of randomisation to the date of death from any cause, up to 120 months Overall survival is defined separately for each randomisation. In each case it is the time from randomisation to the time of death from any cause. Individuals who are lost to follow-up or still alive at the time of analysis will be censored at their last known date to be alive.
Survival after progression The date of first documented evidence of disease progression to the date of death from any cause, up to 120 months Survival after progression is defined from the date of first documented evidence of disease progression to the date of death from any cause. Individuals who are lost to follow-up or alive at the time of analysis will be censored at their last known date to be alive following their first documented evidence of disease progression.
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 Time to disease progression is defined for both Randomisation 1 and Randomisation 2 as the time from randomisation to the date of first documented evidence of disease progression. Participants who die prior to documentation of disease progression will be censored in the analysis at their date of death. Participants not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Participants dying from causes not primarily due to progression will also be censored.
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 For both Randomisation 1 and Randomisation 2, progression-free survival two is defined as the time from randomisation to the time of the second documented disease progression. Individuals who are lost to follow-up or second progression-free at the time of analysis will be censored at their last known date to be alive and second progression-free.
Attainment of Minimal Residual Disease (MRD) negativity From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days); and 12 months after the date of Randomisation 2 Attainment of Minimal Residual Disease (MRD) negativity is defined as a binary endpoint. MRD negativity will be determined at the end of induction therapy and 12 months post Randomisation 2 according to the IMWG MRD criteria.
Treatment compliance and total amount of therapy delivered Number of induction and maintenance cycles a participant received (each cycle of induction or maintenance is 28 days), until disease progression, up to 120 months In the first instance treatment compliance is defined as a binary outcome i.e. did the participant receive 12 cycles of induction treatment. The total amount of therapy delivered will be first defined as the number of induction and maintenance cycles which the participant received. This may be extended to consider the percentage of protocol dose delivered. For each treatment (ixazomib, lenalidomide, dexamethasone) this will be defined as the total dose received in a cycle compared to the total dose the participant should have received in the cycle without modifications, averaged across all cycles of treatment.
EORTC QLQ-C30_questionnaire Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days) European Organization for the Research \& Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is used to measure patient-assessed quality of life (QoL) at R1, after cycles 2, 4, 6 \& 12 of induction, and after cycles 6 and 12 of maintenance (all cycles are 28 days).
The QLQ-C30 comprises multi-item scales \& single-item measures: 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, nausea \& vomiting), a global health status/QoL scale, \& 6 single items assessing additional symptoms (dyspnoea, loss of appetite, insomnia, constipation \& diarrhoea). All scales \& single-item measures range in score from 0 to 100. A high scale score represents a higher response level: a high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high quality of life, but a high score for a symptom scale/item represents a high level of symptomatology/problems.Attainment of ≥VGPR From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days) Attainment of ≥VGPR is defined as a binary outcome of whether a participant had ≥VGPR (VGPR, CR, sCR) or \<VGPR (PR, MR, SD, PD) at the end of induction, according to the IMWG Uniform Response Criteria for Multiple Myeloma.
Time to next treatment The time from the date of Randomisation 1 to the start date of the next line of treatment or death from any cause, up to 120 months Time to next treatment is defined as the time from Randomisation 1 to the start date of the next line of treatment or death from any cause.
Time to improved response The time from the date of Randomisation 2 to the date the response category is first improved, up to 120 months Time to improved response is defined as the time from the date of Randomisation 2 to the date the response category is first improved based on the Modified International Uniform Response Criteria for Multiple Myeloma. Subjects without any improvement of the baseline status at Randomisation 2 will be censored at the last date of response assessment.
EORTC QLQ-MY20_questionnaire Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days) The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module (EORTC QLQ-MY20) is used to measure patient-assessed quality of life (QoL) at Randomisation 1, after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days), and after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days).
The EORTC QLQ-MY20 comprises 20 questions that address four myeloma-specific QoL domains: Disease Symptoms, Side Effects of Treatment, Future Perspectives, and Body Image. Disease Symptoms, Side Effects of Treatment, and Future Perspectives are all multi-item scales, and Body Image is a single-item scale. Domain scores are averaged and transformed linearly to a score ranging from 0-100. A high score for Disease Symptoms and Side Effects of Treatment represents a high level of symptomatology or problems, whereas a high score for Future Perspective and Body Image represents better outcomes.Incidence of treatment-emergent adverse events (Toxicity and safety, including incidence of second malignancies) Baseline, end of each induction cycle (each induction cycle is 28 days), end of each maintenance cycle (each maintenance cycle is 28 days), until disease progression, up to 120 months Toxicity \& safety, including incidence of second malignancies Toxicity and safety will be reported based on the adverse events, as graded by CTCAE V5 and determined by routine clinical assessments at each centre. The number of SAEs will be reported according to MedDRA System Organ Class. All second primary malignancies will be reported based on information collected on the Case Report Form.
EQ-5D-3L_questionnaire Randomisation 1; after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days); after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days) The EuroQol 5 Dimension 3 Level questionnaire (EQ-5D-3L) will be used to measure participant-assessed quality of life at Randomisation 1, after cycles 2, 4, 6 and 12 of induction treatment (each induction cycle is 28 days), and after cycles 6 and 12 of maintenance treatment (each maintenance cycle is 28 days).
The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
Trial Locations
- Locations (109)
North Devon District Hospital
🇬🇧Barnstaple, United Kingdom
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Wrightington Hosptial
🇬🇧Appley Bridge, United Kingdom
Furness General Hospital
🇬🇧Barrow In Furness, United Kingdom
Dorset County Hospital
🇬🇧Dorchester, United Kingdom
Colchester General Hospital
🇬🇧Colchester, United Kingdom
Ninewells Hospital
🇬🇧Dundee, United Kingdom
Royal United Hospital
🇬🇧Bath, United Kingdom
Basingstoke and North Hampshire Hospital
🇬🇧Basingstoke, United Kingdom
Pilgrim Hospital
🇬🇧Boston, United Kingdom
Royal Bolton Hospital
🇬🇧Bolton, United Kingdom
St Richard's Hospital
🇬🇧Chichester, United Kingdom
Russells Hall Hospital
🇬🇧Dudley, United Kingdom
Medway Maritime Hospital
🇬🇧Gillingham, United Kingdom
Royal Surrey County Hospital
🇬🇧Guildford, United Kingdom
Withybush General Hospital
🇬🇧Haverfordwest, United Kingdom
Salford Royal Hospital
🇬🇧Salford, United Kingdom
Scarborough General Hospital
🇬🇧Scarborough, United Kingdom
Scunthorpe General Hospital
🇬🇧Scunthorpe, United Kingdom
Sunderland Royal Hospital
🇬🇧Sunderland, United Kingdom
Good Hope Hospital
🇬🇧Sutton Coldfield, United Kingdom
St George's Hospital
🇬🇧Tooting, United Kingdom
Singleton Hospital
🇬🇧Swansea, United Kingdom
Tunbridge Wells Hospital
🇬🇧Tunbridge Wells, United Kingdom
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
Nevill Hall Hospital
🇬🇧Abergavenny, United Kingdom
Ysbyty Gwynedd
🇬🇧Bangor, United Kingdom
Belfast City Hospital
🇬🇧Belfast, United Kingdom
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Royal Blackburn Hospital
🇬🇧Blackburn, United Kingdom
Blackpool Victoria Hospital
🇬🇧Blackpool, United Kingdom
Bradford Royal Infirmary
🇬🇧Bradford, United Kingdom
Royal Bournemouth Hospital
🇬🇧Bournemouth, United Kingdom
Bristol Haematology and Oncology Centre
🇬🇧Bristol, United Kingdom
Southmead Hospital
🇬🇧Bristol, United Kingdom
Queen's Hospital
🇬🇧Romford, 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
University Hospital Coventry
🇬🇧Coventry, United Kingdom
Croydon University Hospital
🇬🇧Croydon, United Kingdom
Royal Derby Hospital
🇬🇧Derby, United Kingdom
Western General Hospital
🇬🇧Edinburgh, United Kingdom
Royal Devon & Exeter Hospital
🇬🇧Exeter, United Kingdom
Gloucestershire Royal Hospital
🇬🇧Gloucester, United Kingdom
Grantham and District Hospital
🇬🇧Grantham, United Kingdom
Diana Princess of Wales Hospital
🇬🇧Grimsby, United Kingdom
Calderdale Royal Hospital
🇬🇧Halifax, United Kingdom
Harrogate District Hospital
🇬🇧Harrogate, United Kingdom
Hereford County Hospital
🇬🇧Hereford, United Kingdom
Huddersfield Royal Infirmary
🇬🇧Huddersfield, 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
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
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Maidstone Hospital
🇬🇧Maidstone, 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
Salisbury District Hospital
🇬🇧Salisbury, 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
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
Guy's Hospital
🇬🇧London, United Kingdom
Castle Hill Hospital
🇬🇧Hull, United Kingdom