The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)

A Phase III Study to Determine the Role of Ixazomib as an Augmented Conditioning Therapy in Salvage Autologous Stem Cell Transplant (ASCT) and as a Post-ASCT Consolidation and Maintenance Strategy in Patients With Relapsed Multiple Myeloma

Study design: Randomised, controlled, multi-centre, open-label, phase III trial (with a single intervention registration phase).

Primary Objectives

The primary objectives of this study are to determine:

• The impact on Depth of Response (DoR: less than VGPR versus VGPR or better) when salvage ASCT conditioning is augmented by the addition of a proteasome inhibitor
• The influence of a consolidation and maintenance strategy on the Durability of Response (DuR:PFS)

Secondary objectives

The secondary objectives of this study are to determine:

• Overall survival
• Time to disease progression
• The overall response rate following ixazomib, thalidomide and dexamethasone (ITD) re-induction
• Time to next treatment
• Progression-free survival 2 (PFS2)
• Duration of response
• Minimal Residual Disease (MRD) negative rate post re-induction, post-ASCT and conversion after ITD consolidation
• Engraftment kinetics
• Toxicity and safety
• Quality of life (QoL)

Participant population (refer to protocol section 9 for a full list of eligibility criteria).

• Relapsed MM (with measurable disease by IMWG criteria) previously treated with ASCT
• First progressive disease (PD) at least 12 months since first ASCT, requiring therapy.
• ECOG Performance Status 0-2
• Aged at least 18 years
• Adequate full blood count and renal, hepatobiliary, pulmonary and cardiac function
• Written informed consent

Interventions: All participants will be registered at trial entry and will receive re-induction therapy with 4-6, 28-day cycles of ixazomib, thalidomide and dexamethasone (ITD), in order to reach maximum response. Participants who achieve at least stable disease (SD) will be randomised on a 1:1 basis to receive either conventional ASCT (ASCTCon), using melphalan, or augmented ASCT (ASCTAug), using melphalan with ixazomib. All participants achieving or maintaining a minimal response (MR) or better following trial ASCT will undergo a second randomisation to consolidation and maintenance or no further treatment. Participants randomised to consolidation and maintenance will receive treatment as follows: consolidation with 2 cycles of ITD and maintenance with ixazomib until disease progression.

Number of participants: 406 participants will be registered into the trial to allow 284 participants to be randomised at the first randomisation (R1) and 248 participants to be randomised at the second randomisation (R2).

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction; Drug: Conventional autologous stem cell transplant (ASCT-con); Drug: ITD consolidation and ixazomib maintenance vs. No further therapy; Drug: Augmented autologous stem cell transplant (ASCT-aug)

• Study Type: Interventional
• Enrollment (Anticipated): 406
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gwen Jacques, Senior Trial Coordinator; Phone Number: 0044 113 343 1159; Email: ctru-myelomaxii@leeds.ac.uk
• Study Contact Backup: Name: Trial Management Assistant; Phone Number: 0044 113 343 5476; Email: ctru-myelomaxii@leeds.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom
    • Recruiting
    • Aberdeen Royal Infirmary
    • Contact: Jane Tighe
  • Airdrie, United Kingdom
    • Recruiting
    • Monklands Hospital
    • Contact: Iain Singer
  • Ayr, United Kingdom
    • Recruiting
    • University Hospital Ayr
    • Contact: Paul Micallef-Eynaud
  • Barnsley, United Kingdom
    • Recruiting
    • Barnsley Hospital
    • Contact: Youssef Sorour
  • Basingstoke, United Kingdom
    • Recruiting
    • Basingstoke & North Hampshire Hospital
    • Contact: Noel Ryman
  • Bath, United Kingdom
    • Recruiting
    • Royal United Hospital
    • Contact: Sally Moore
  • Birmingham, United Kingdom
    • Recruiting
    • Queen Elizabeth Hospital
    • Contact: Mark Cook
  • Birmingham, United Kingdom
    • Recruiting
    • Good Hope Hospital
    • Contact: Anand Lokare
  • Birmingham, United Kingdom
    • Recruiting
    • Heartlands Hospital
    • Contact: Anand Lokare
  • Blackpool, United Kingdom
    • Recruiting
    • Blackpool Victoria Hospital
    • Contact: Mark Grey
  • Boston, United Kingdom
    • Recruiting
    • Pilgrim Hospital
    • Contact: Charlotte Kallmeyer
  • Bournemouth, United Kingdom
    • Recruiting
    • Royal Bournemouth Hospital
    • Contact: Rachel Hall
  • Bradford, United Kingdom
    • Recruiting
    • Bradford Royal Infirmary
    • Contact: Anshu Garg
  • Bristol, United Kingdom
    • Recruiting
    • Southmead Hospital
    • Contact: Alistair Whiteway
  • Bristol, United Kingdom
    • Recruiting
    • Bristol Haematology & Oncology Centre
    • Contact: James Griffin
  • Burton Upon Trent, United Kingdom
    • Recruiting
    • Queen's Hospital
    • Contact: Humayun Ahmad
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrooke's Hospital
    • Contact: Charles Crawley
  • Carshalton, United Kingdom
    • Recruiting
    • St Helier Hospital
    • Contact: Simon Stern
  • Cheltenham, United Kingdom
    • Recruiting
    • Cheltenham General Hospial
    • Contact: Michael Shields
  • Chester, United Kingdom
    • Recruiting
    • Countess of Chester Hospital
    • Contact: Salah Tueger
  • Chesterfield, United Kingdom
    • Recruiting
    • Chesterfield Royal Hospital
    • Contact: Rowena Faulkner
  • Chichester, United Kingdom
    • Recruiting
    • St Richards Hospital
    • Contact: Jamie Wilson
  • Coventry, United Kingdom
    • Recruiting
    • University Hospital Coventry
    • Contact: Beth Harrison
  • Derby, United Kingdom
    • Recruiting
    • Royal Derby Hospital
    • Contact: David Allotey
  • Dewsbury, United Kingdom
    • Recruiting
    • Dewsbury Hospital
    • Contact: John Ashcroft
  • Dudley, United Kingdom
    • Recruiting
    • Russells Hall Hospital
    • Contact: Rupert Hipkins
  • Dundee, United Kingdom
    • Recruiting
    • Ninewells Hospital
    • Contact: Duncan Gowans
  • East Kilbride, United Kingdom
    • Recruiting
    • Hairmyres Hospital
    • Contact: Iain Singer
  • Edinburgh, United Kingdom
    • Recruiting
    • Western General Hospital
    • Contact: Huw Roddie
  • Glasgow, United Kingdom
    • Recruiting
    • Beatson Cancer Centre
    • Contact: Grant McQuaker
  • Glasgow, United Kingdom
    • Recruiting
    • New Victoria Hospital
    • Contact: Ian MacDonald
  • Gloucester, United Kingdom
    • Recruiting
    • Gloucestershire Royal Hospital
    • Contact: Michael Shields
  • Grantham, United Kingdom
    • Recruiting
    • Grantham and District Hospital
    • Contact: Charlotte Kallmeyer
  • Grimsby, United Kingdom
    • Recruiting
    • Diana Princess of Wales Hospital
    • Contact: Sanjeev Jalihal
  • Halifax, United Kingdom
    • Recruiting
    • Calderdale Royal Hospital
    • Contact: Sylvia Feyler
  • Harrogate, United Kingdom
    • Recruiting
    • Harrogate District Hospital
    • Contact: Tharani Balasubramaniam
  • Huddersfield, United Kingdom
    • Recruiting
    • Huddersfield Royal Infirmary
    • Contact: Sylvia Feyler
  • Hull, United Kingdom
    • Recruiting
    • Castle Hill Hospital
    • Contact: Senthilkumar Durairaj
  • Inverness, United Kingdom
    • Recruiting
    • Raigmore Hospital
    • Contact: Peter Forsyth
  • Ipswich, United Kingdom
    • Recruiting
    • Ipswich Hospital
    • Contact: Debo Ademokun
  • Kidderminster, United Kingdom
    • Recruiting
    • Kidderminster Hospital
    • Contact: Saleem Shafik
  • Kilmarnock, United Kingdom
    • Recruiting
    • University Hospital Crosshouse
    • Contact: Paul Micallef-Eynaud
  • Leeds, United Kingdom
    • Recruiting
    • St James's University Hospital
    • Contact: Gordon Cook
  • Leicester, United Kingdom
    • Recruiting
    • Leicester Royal Infirmary
    • Contact: Mamta Garg
  • Lincoln, United Kingdom
    • Recruiting
    • Lincoln County Hospital
    • Contact: Charlotte Kallmeyer
  • Liverpool, United Kingdom
    • Recruiting
    • Royal Liverpool University Hospital
    • Contact: Stephen Hawkins
  • Liverpool, United Kingdom
    • Recruiting
    • University Hospital Aintree
    • Contact: Lynny Young
  • London, United Kingdom
    • Recruiting
    • Royal Marsden Hospital
    • Contact: Kevin Boyd
  • London, United Kingdom
    • Recruiting
    • Kings College Hospital
    • Contact: Majid Kazmi
  • London, United Kingdom
    • Recruiting
    • University College London Hospital
    • Contact: Kwee Yong
  • London, United Kingdom
    • Recruiting
    • Guys and St Thomas's Hospital
    • Contact: Majid Kazmi
  • London, United Kingdom
    • Recruiting
    • St Barts Hospital
    • Contact: Jamie Cavenagh
  • Maidstone, United Kingdom
    • Recruiting
    • Maidstone Hospital
    • Contact: Lolita Banerjee
  • Manchester, United Kingdom
    • Recruiting
    • Manchester Royal Infirmary
    • Contact: Alberto Rocci
  • Manchester, United Kingdom
    • Recruiting
    • The Christie
    • Contact: Samar Kulkarni
  • Melrose, United Kingdom
    • Recruiting
    • Borders General Hospital
    • Contact: Jennifer Buxton
  • Middlesbrough, United Kingdom
    • Recruiting
    • James Cook University Hospital
    • Contact: Marianna David
  • Milton Keynes, United Kingdom
    • Recruiting
    • Milton Keynes General Hospital
    • Contact: Moez Dungarwalla
  • Newcastle, United Kingdom
    • Recruiting
    • Freeman Hospital
    • Contact: Graham Jackson
  • North Shields, United Kingdom
    • Recruiting
    • North Tyneside General Hospital
    • Contact: Mari Kilner
  • Norwich, United Kingdom
    • Recruiting
    • Norfolk & Norwich University Hospital
    • Contact: Kristian Bowles
  • Nottingham, United Kingdom
    • Recruiting
    • Nottingham City Hospital
    • Contact: Jenny Byrne
  • Oldham, United Kingdom
    • Recruiting
    • Royal Oldham Hospital
    • Contact: Hayley Greenfield
  • Oxford, United Kingdom
    • Recruiting
    • Churchill Hospital
    • Contact: Jam Kothari
  • Paisley, United Kingdom
    • Recruiting
    • Royal Alexandra Hospital
    • Contact: Alison Sefcick
  • Plymouth, United Kingdom
    • Recruiting
    • Derriford Hospital
    • Contact: Hannah Hunter
  • Pontefract, United Kingdom
    • Recruiting
    • Pontefract Hospital
    • Contact: John Ashcroft
  • Prescot, United Kingdom
    • Recruiting
    • Whiston Hospital
    • Contact: Toby Nicholson
  • Reading, United Kingdom
    • Recruiting
    • Royal Berkshire Hospital
    • Contact: Henri Grech
  • Redditch, United Kingdom
    • Recruiting
    • Redditch Hospital
    • Contact: Saleem Shafik
  • Salford, United Kingdom
    • Recruiting
    • Salford Royal Hospital
    • Contact: Sonya Ravenscroft
  • Salisbury, United Kingdom
    • Recruiting
    • Salisbury Hospital
    • Contact: Jonathan Cullis
  • Scunthorpe, United Kingdom
    • Recruiting
    • Scunthorpe General Hospital
    • Contact: Sanjeev Jalihal
  • Sheffield, United Kingdom
    • Recruiting
    • Royal Hallamshire Hospital
    • Contact: John Snowden
  • Southampton, United Kingdom
    • Recruiting
    • Southampton General Hospital
    • Contact: Matthew Jenner
  • St Helens, United Kingdom
    • Recruiting
    • St Helens Hospital
    • Contact: Toby Nicholson
  • Stafford, United Kingdom
    • Recruiting
    • Stafford County Hospital
    • Contact: Kamaraj Karunanithi
  • Stockport, United Kingdom
    • Recruiting
    • Stepping Hill Hospital
    • Contact: Montaser Haj
  • Stoke-on-Trent, United Kingdom
    • Recruiting
    • Royal Stoke University Hospital
    • Contact: Kamaraj Karunanithi
  • Sunderland, United Kingdom
    • Not yet recruiting
    • Sunderland Royal Hospital
    • Contact: Victoria Hervey
  • Sutton In Ashfield, United Kingdom
    • Recruiting
    • King's Mill Hospital
    • Contact: Tim Moorby
  • Swansea, United Kingdom
    • Recruiting
    • Singleton Hospital
    • Contact: Hamdi Sati
  • Taunton, United Kingdom
    • Recruiting
    • Musgrove Park Hospital
    • Contact: Simon Bolam
  • Tooting, United Kingdom
    • Recruiting
    • St George's Hospital
    • Contact: Fenella Willis
  • Tunbridge Wells, United Kingdom
    • Recruiting
    • Tunbridge Wells Hospital
    • Contact: Lolita Banerjee
  • Wakefield, United Kingdom
    • Recruiting
    • Pinderfields General Hospital
    • Contact: John Ashcroft
  • Winchester, United Kingdom
    • Recruiting
    • Royal Hampshire County Hospital
    • Contact: Noel Ryman
  • Wishaw, United Kingdom
    • Recruiting
    • Wishaw Hospital
    • Contact: Iain Singer
  • Wolverhampton, United Kingdom
    • Recruiting
    • New Cross Hospital
    • Contact: Supratik Basu
  • Worcester, United Kingdom
    • Recruiting
    • Worcestershire Royal Hospital
    • Contact: Saleem Shafik
  • Worthing, United Kingdom
    • Recruiting
    • Worthing Hospital
    • Contact: Jamie Wilson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) previously treated with ASCT).
2. First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3).
4. Aged at least 18 years.

5. Participants must have the following blood results within 14 days before registration:

   1. Absolute neutrophil count (ANC) ≥1x109/L
   2. Platelet count ≥75x109/L. If the participant has ≥50% bone marrow infiltration a platelet count of ≥50x109/L is allowed.

   Platelet transfusions are not allowed within 3 days before registration in order to meet these values.

6. Adequate renal function within 14 days before registration:

   a. Creatinine clearance ≥30ml/min (calculated according to the Cockcroft-Gault equation or other locally approved formula)

7. Adequate hepatobiliary function within 14 days before registration:

   1. Total bilirubin <2 x upper limit of normal (ULN)
   2. ALT <2 x ULN

8. Adequate pulmonary function within 14 days before registration:

   a. Adequate respiratory functional reserve (delineated by KCO/DLCO (carbon monoxide diffusion in the lung) of ≥50%). No evidence of a history of pulmonary disease. If a significant history, then a review by a respiratory medicine physician is required.

9. Adequate cardiac function within 12 weeks before registration

   a. Left ventricular ejection fraction (LVEF) ≥40%. Note: repeat confirmation of cardiac function is needed if treatment is given between this assessment and registration.

10. Female participants who:

    1. Are not of childbearing potential (Appendix 8), OR
    2. If they are of childbearing potential (Appendix 8), agree to practice 2 effective methods of contraception (Appendix 8), 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 consent to) the Celgene-approved Thalidomide Pregnancy Prevention Programme.
11. If female and of childbearing potential (see Appendix 8), must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Thalidomide Pregnancy Prevention Programme.
12. Patients agree not to receive other clinical trials treatment, including investigational medicinal products (IMPs) not included in this trial, within 30 days of trial registration and throughout the duration of the trial, until disease progression.
13. Able to provide written informed consent.

Exclusion Criteria:

1. Received prior second line therapy for their relapsed disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone (up to a maximum of 200mg is allowed but not within 30 days prior to registration). Radiotherapy sufficient to alleviate or control pain of local invasion is permitted, but must not be within 14 days before registration. Patients who have received hemi-body radiation or similar since relapse will not be eligible.
2. ≥Grade 2 peripheral neuropathy within 14 days before registration.
3. Known HIV seropositivity.
4. Known resistance, intolerance or sensitivity to any component of the planned therapies.
5. Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's participation in this study.
6. Previous or concurrent malignancies at other sites (excluding completely resected non-melanoma skin cancer or carcinoma in situ of any type, such as cervical cancer).
7. Pregnant, lactating or breast feeding female participants.
8. Failure to have fully recovered (i.e.Grade 1 or less toxicity) from the reversible effects of prior chemotherapy.
9. Major surgery within 14 days before registration.
10. Central nervous system involvement with myeloma.
11. Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration.
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
13. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
14. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing.
15. Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.
16. Participant has current or prior hepatitis B or C infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Conventional Autologous Stem Cell Transplant (ASCT); Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0	Drug: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction; 4 - 6 ITD 28-day cycles as follows: Ixazomib 4mg capsule on days 1, 8 and 15; Thalidomide 100mg capsule on days 1-28; Dexamethasone 40mg tablets on days 1, 8, 15 and 22; Drug: Conventional autologous stem cell transplant (ASCT-con); Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0.; Drug: ITD consolidation and ixazomib maintenance vs. No further therapy; Participants will be randomised to either 'no further therapy' or 'ITD consolidation and ixazomib maintenance'. Participants randomised to 'no further treatment' will not receive any further treatment but will be followed up at 8 weeks post randomisation 2 and at 3-monthly clinic visits until disease progression. Participants randomised to ITD consolidation and ixazomib maintenance will receive: Two 28-day cycles of ITD consolidation (same doses as in ITD re-induction). This will be followed by ixazomib maintenance as follows: Ixazomib 4mg capsule on days 1, 8 and 15 of each 28-day cycle until disease progression.
Experimental: Augmented Autologous Stem Cell Transplant (ASCT); Melphalan 100mg/m2 IV infusion on Day -3 and -2 plus ixazomib 4mg capsules on Day -4 and -1. ASCT will then be given on Day 0.	Drug: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction; 4 - 6 ITD 28-day cycles as follows: Ixazomib 4mg capsule on days 1, 8 and 15; Thalidomide 100mg capsule on days 1-28; Dexamethasone 40mg tablets on days 1, 8, 15 and 22; Drug: ITD consolidation and ixazomib maintenance vs. No further therapy; Participants will be randomised to either 'no further therapy' or 'ITD consolidation and ixazomib maintenance'. Participants randomised to 'no further treatment' will not receive any further treatment but will be followed up at 8 weeks post randomisation 2 and at 3-monthly clinic visits until disease progression. Participants randomised to ITD consolidation and ixazomib maintenance will receive: Two 28-day cycles of ITD consolidation (same doses as in ITD re-induction). This will be followed by ixazomib maintenance as follows: Ixazomib 4mg capsule on days 1, 8 and 15 of each 28-day cycle until disease progression.; Drug: Augmented autologous stem cell transplant (ASCT-aug); Melphalan 100mg/m2 IV infusion on Day -3 and Day -2 plus ixazomib 4mg capsules on Day -4 and Day -1. ASCT will then be given on Day 0.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Overall response rate following ASCT will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma. This endpoint will be defined as a binary dichotomization of response (≥VGPR vs <VGPR) at an assessment 100 days after the date of stem cell transplant.	100 days post-ASCT
Progression-free survival	The influence of a consolidation and maintenance strategy on the Durability of Response (DuR: PFS)	From date of registration to date of disease progression, up to 120 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival is defined as the time from randomisation to the consolidation/maintenance part of the trial post-ASCT to death from any cause or last follow-up.	From date of R2 to date of death, up to 120 months
Time to disease progression	Time to disease progression is defined as time from randomisation to the consolidation/maintenance part of the trial post-ASCT to first documented evidence of disease progression. Participants who die without disease progression will be censored in the analysis.	From date of registration until date of disease progression, up to 120 months
Overall response rate to ITD re-induction	Overall response rate following re-induction will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma.	At the end of re-induction - after 4-6 re-induction cycles (each cycle is 28 days)
Upgrade in response after two cycles of ITD consolidation	Upgrade in response after 2 cycles of ITD consolidation - response rate following ITD consolidation will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma. This endpoint will be defined as a binary dichotomization of response (≥VGPR vs <VGPR).	After 2 cycles of ITD consolidation (each cycle is 28 days)
Progression-free survival 2 (PFS2)	Progression-free survival 2 is defined as the time from second randomisation to the consolidation/maintenance part of the trial post-ASCT to second documented disease progression (or the start of next line anti-myeloma treatment), or death from any cause, whichever occurs first. Participants alive and for whom a second progression after second randomisation has not been observed will be censored at the last day they were known to be alive and second progression-free.	Date of R2 to date of second disease progression, up to 120 months
Time to next treatment	Time to next line treatment is defined as the time from the date of randomisation to the date of commencement of next line treatment. Participants who do not receive next line treatment will be censored at the date of the last assessment or follow-up visit where they are known to have received no new therapy.	Date of registration to start date of new therapy, up to 120 months
Duration of response	Duration of response to protocol treatment is defined from the time of achieving at least a partial response to the date of first documented evidence of disease progression. Participants who die prior to documentation of disease progression will be censored at the date of death. Participants dying from causes not primarily due to progression will also be censored at the 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.	Date of achieving at least partial response to date of disease progression, up to 120 months
Proportion of patients Minimal Residual Disease negative	Proportion of patients Minimal Residual Disease negative is defined as the proportion of participants with minimal residual disease (MRD) negative as assessed by flow cytometry will be assessed at various points in trial protocol treatment.	Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; After 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-randomisation 2; 12 months post-randomisation 2
Continuous Minimal Residual Disease (MRD)	Continuous Minimal Residual Disease (MRD) measurements as assessed by flow cytometry will be assessed at various points in trial protocol treatment.	Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; After 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-randomisation 2; 12 months post-randomisation 2
Engraftment kinetics_test	Engraftment kinetics will be summarised based on summaries of stem cell remobilisation protocol and success of remobilisation and stem cell harvest after the completion of ASCT for all participants.	Stem cell harvest; 100 days post-ASCT
Incidence of treatment-emergent adverse events (Toxicity and safety)	Toxicity and safety will be reported based on adverse events, as graded by CTCAE V4.03 and determined by routine clinical assessments at each centre.	Baseline; End of each re-induction cycle (each cycle is 28 days); 100 days post-ASCT; End of 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-R2; 3 monthly post-R2 until disease progression; Disease progression, up to 120 months
EORTC QLQ-C30_questionnaire	The EORTC QLQ-C30 questionnaire will be used to measure participant-assessed quality of life at registration, post re-induction, 100 days post-ASCT and annually post second randomisation until 24 months post second randomisation, or until disease progression whichever is earlier.	Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2
EORTC QLQ-MY20_questionnaire	The EORTC QLQ-MY20 questionnaire will be used to measure participant-assessed quality of life at registration, post re-induction, 100 days post-ASCT and annually post second randomisation until 24 months post second randomisation, or until disease progression whichever is earlier.	Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2
EQ-5D_questionnaire	The EQ-5D questionnaire will be used to measure participant-assessed quality of life at registration, post re-induction, 100 days post-ASCT and annually post second randomisation until 24 months post second randomisation, or until disease progression whichever is earlier.	Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytogenetics_composite measure	Cytogenetic subgroups will be analysed to explore a number of specific hypotheses, including the effect on PFS, OS, TTP and response (≥VGPR vs. <VGPR). Some examples of what will be studied include chromosome 14 translocations and abnormalities of chromosome 1p, 1q, 13q and 17p. In addition, other regions considered to be of interest will be analysed according to the statistical analysis plan. Other subgroup and exploratory analyses may also be carried out and will be described in the statistical analysis plan or separate analyses plans related to translational work.	Through study completion, up to 120 months

Collaborators and Investigators

• Sponsor: University of Leeds
• Collaborators: Takeda; Cancer Research UK
• Investigators: Study Director: Head of Trial Management, Univeristy of Leeds, CTRU

Publications and helpful links

General Publications

• Striha A, Ashcroft AJ, Hockaday A, Cairns DA, Boardman K, Jacques G, Williams C, Snowden JA, Garg M, Cavenagh J, Yong K, Drayson MT, Owen R, Cook M, Cook G. The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial. Trials. 2018 Mar 7;19(1):169. doi: 10.1186/s13063-018-2524-8.

Helpful Links

• Myeloma XII protocol paper

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Anticipated): March 1, 2026
• Study Completion (Anticipated): March 1, 2027

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: June 7, 2018
• First Posted (Actual): June 19, 2018

Study Record Updates

• Last Update Posted (Actual): June 19, 2018
• Last Update Submitted That Met QC Criteria: June 7, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Glycine Agents; Dexamethasone; Thalidomide; Ixazomib; Glycine
• Other Study ID Numbers: HM16/047; 2016-000905-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No