Clinical trial NCT03720041: Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Lenalidomide
Ixazomib
Dexamethasone
Revlimid
Ninlaro
Non-transplant eligible myeloma patients
Newly diagnosed myeloma
Double blind
Placebo
Frailty scoring
Frailty score-adjusted dosing
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: Takeda
name: Celgene
First posted: 2018-10-25
Enrollment: 740
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase III, multi-centre, randomised, parallel group trial
Primary purpose: TREATMENT

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.


Eligibility criteria: Eligibility criteria for Randomisation 1 (R1) Participants must meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion criteria for R1

1. Newly diagnosed as having MM according to the updated IMWG diagnostic criteria 2014 requiring treatment.
2. Not eligible for stem cell transplant.
3. Aged at least 18 years.
4. Meet all of the following blood criteria within 14 days before R1:

   Haematological:
   1. 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.
   2. 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.
   3. Haemoglobin ≥ 80 g/L. The use of red blood cell transfusions is permitted.

      Biochemical:
   4. Total bilirubin ≤ 3 x upper limit of normal (ULN).
   5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN.
5. Meet the pregnancy prevention requirements:

   Female participants who:
   1. Are not of childbearing potential, OR
   2. 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
   3. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)

   Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following:
   1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
   2. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception).

   Contraception for female and male participants must be in accordance with (and participants must consent to) the Celgene-approved Pregnancy Prevention Programme.

   If female and of childbearing potential, they must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Pregnancy Prevention Programme.
6. Able to provide written informed consent.

Exclusion criteria for R1

1. Smouldering MM, MGUS, solitary plasmacytoma of bone, or extramedullary plasmacytoma (without evidence of MM).
2. Received previous treatment for MM, with the exception of local radiotherapy to relieve bone pain or spinal cord compression, prior bisphosphonate treatment, or corticosteroids as long as the total dose does not exceed the equivalent of 160 mg dexamethasone.
3. Known resistance, intolerance or sensitivity to any component of the planned therapies.
4. Prior or concurrent invasive malignancies except the following:

   * Adequately treated basal cell or squamous cell skin cancer;
   * Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention;
   * Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention;
   * Any cancer from which the subject has been disease-free for at least 3 years.
5. Pregnant, lactating or breastfeeding female participants.
6. Major surgery within 14 days before randomisation. This would include surgical intervention for relief of cord compression but does not include vertebroplasty or kyphoplasty.
7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
8. Any concomitant drug therapy which, in the opinion of the investigator, may lead to an unacceptable interaction with any of the agents ixazomib, lenalidomide, dexamethasone, and that cannot be safely stopped prior to trial entry. Full details of interactions can be found in the SPCs.
9. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing.
10. ≥ Grade 2 peripheral neuropathy.
11. Known HIV positive or known hepatitis B surface antigen positive or hepatitis C antibody positive.
12. Active systemic infection.
13. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's participation in this study.

Eligibility criteria for Randomisation 2 (R2) Participants must meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion criteria for R2

1. Randomised into the FiTNEss (Myeloma XIV) trial and received induction chemotherapy with ixazomib and lenalidomide continued for 12 cycles.
2. Achieved at least MR at the end of IRD induction according to the IMWG Uniform Response Criteria for Multiple Myeloma, with no evidence of progression prior to R2.
3. Meet all of the following blood criteria within 14 days before R2:

Haematological:

1. 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.
2. Platelet count ≥ 50 x 10\^9/L. Please note: Platelet transfusions are not allowed ≤ 3 days prior to randomisation in order to meet these values.
3. Haemoglobin ≥ 80 g/L. The use of red blood cell transfusions is permitted.

   Biochemical:
4. Total bilirubin ≤ 3 x upper limit of normal (ULN).
5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 3 x ULN.

Exclusion criteria for R2

1. Received any anti-myeloma therapy other than their randomised trial treatment, with the exception of local radiotherapy to relieve bone pain (in the absence of disease progression), or bisphosphonate treatment.
2. SD or disease progression according to the IMWG Uniform Response Criteria for Multiple Myeloma.
3. Known resistance, intolerance or sensitivity to ixazomib or lenalidomide that required cessation of either agent during induction.
4. Developed any malignancy since R1 except the following:

   * Adequately treated basal cell or squamous cell skin cancer;
   * Incidental finding of low grade (Gleason 3+3 or less) prostate cancer requiring no intervention;
   * Adequately treated carcinoma in situ of the breast or cervix no longer requiring medical or surgical intervention.
5. Pregnant, lactating or breastfeeding female participants.
6. Major surgery within 14 days before randomisation. This does not include vertebroplasty or kyphoplasty.
7. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
8. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of trial treatment, including difficulty swallowing.
9. ≥ Grade 2 peripheral neuropathy, or grade 1 with pain.
10. Known HIV positive or known hepatitis B surface antigen positive or hepatitis C antibody positive.
11. Active systemic infection.
12. Any other medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's continued participation in this study.

Primary outcomes:
measure: Randomisation 1: Number of participants with early treatment cessation
timeFrame: Within 60 days of Randomisation 1
measure: Randomisation 2: Progression-free survival (PFS-R2)
timeFrame: 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:
measure: Progression-free survival (PFS-R1)
timeFrame: 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
measure: Time to disease progression
timeFrame: The time from the date of randomisation to the date of first documented evidence of disease progression, up to 120 months
measure: Progression-free survival two (PFS2)
timeFrame: The time from the date of randomisation to the date of the second documented disease progression, up to 120 months
measure: Overall survival (OS)
timeFrame: The time from the date of randomisation to the date of death from any cause, up to 120 months
measure: Survival after progression
timeFrame: The date of first documented evidence of disease progression to the date of death from any cause, up to 120 months
measure: Deaths within 12 months of Randomisation 1 (R1)
timeFrame: Within 12 months of Randomisation 1
measure: Overall response rate (ORR)
timeFrame: From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days)
measure: Attainment of ≥VGPR
timeFrame: From the date of Randomisation 1 to the end of 12 cycles of induction treatment (each induction cycle is 28 days)
measure: Attainment of Minimal Residual Disease (MRD) negativity
timeFrame: 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
measure: Duration of response (DoR)
timeFrame: 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
measure: Time to improved response
timeFrame: The time from the date of Randomisation 2 to the date the response category is first improved, up to 120 months
measure: Time to next treatment
timeFrame: 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
measure: Treatment compliance and total amount of therapy delivered
timeFrame: 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
measure: Incidence of treatment-emergent adverse events (Toxicity and safety, including incidence of second malignancies)
timeFrame: 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
measure: EORTC QLQ-C30_questionnaire
timeFrame: 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)
measure: EORTC QLQ-MY20_questionnaire
timeFrame: 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)
measure: EQ-5D-3L_questionnaire
timeFrame: 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)
Other outcomes:
measure: Novel frailty risk score (UK-MRA MRP)_composite measure
timeFrame: Through study completion, up to 120 months
measure: Usefulness of Karnofsky PS_composite measure
timeFrame: Through study completion, up to 120 months
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Abergavenny
country: United Kingdom
facility: Nevill Hall Hospital
city: Appley Bridge
country: United Kingdom
facility: Wrightington Hosptial
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
city: Barnstaple
country: United Kingdom
facility: North Devon District Hospital
city: Barrow In Furness
country: United Kingdom
facility: Furness General Hospital
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bolton
country: United Kingdom
facility: Royal Bolton Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Burton Upon Trent
country: United Kingdom
facility: Queen's Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Chelmsford
country: United Kingdom
facility: Chelmsford & Essex Hospital
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Chichester
country: United Kingdom
facility: St Richard's Hospital
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Croydon
country: United Kingdom
facility: Croydon University Hospital
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Grantham
country: United Kingdom
facility: Grantham and District Hospital
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales Hospital
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
city: Haverfordwest
country: United Kingdom
facility: Withybush General Hospital
city: Hereford
country: United Kingdom
facility: Hereford County Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Keighley
country: United Kingdom
facility: Airedale Hospital
city: Kendal
country: United Kingdom
facility: Westmorland General Hospital
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
city: Kidderminster
country: United Kingdom
facility: Kidderminster Hospital & Treatment Centre
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
city: Lancaster
country: United Kingdom
facility: Royal Lancaster Infirmary
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital Greenwich
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: London
country: United Kingdom
facility: University Hospital Lewisham
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham Hospital
city: Orpington
country: United Kingdom
facility: Princess Royal University Hospital
city: Peterborough
country: United Kingdom
facility: Peterborough City Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Prescot
country: United Kingdom
facility: Whiston Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Redditch
country: United Kingdom
facility: Alexandra Hospital
city: Rhyl
country: United Kingdom
facility: Glan Clwyd Hospital
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
city: Scarborough
country: United Kingdom
facility: Scarborough General Hospital
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Shrewsbury
country: United Kingdom
facility: Royal Shrewsbury Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: St Helens
country: United Kingdom
facility: St Helens Hospital
city: Stafford
country: United Kingdom
facility: Stafford County Hospital
city: Stockport
country: United Kingdom
facility: Stepping Hill Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton Coldfield
country: United Kingdom
facility: Good Hope Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Tooting
country: United Kingdom
facility: St George's Hospital
city: Torquay
country: United Kingdom
facility: Torbay District General Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Tunbridge Wells
country: United Kingdom
facility: Tunbridge Wells Hospital
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
city: Warwick
country: United Kingdom
facility: Warwick Hospital
city: West Bromwich
country: United Kingdom
facility: Sandwell General Hospital
city: Wigan
country: United Kingdom
facility: Royal Albert Edward Infirmary
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
city: York
country: United Kingdom
facility: York Hospital
Study officials:
affiliation: University of Leeds
name: Gordon Cook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Freeman Hospital, Newcastle-Upon-Tyne
name: Graham Jackson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.