The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor

Samantha Hinsley,Mark Cook,Sadie Reed,Fiona Brudenell Straw,Sarah Brown,Debbie Sherratt,Bryony Dawkins,Martin F Kaiser,Sophie Mckee,Holger W Auner,Louise Flanagan,Gordon Cook,Lucy Bailey,David Meads,Katrina Walker

doi:10.1186/s13063-020-04739-8

Abstract

BackgroundMultiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD.MethodsMUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment.DiscussionDevelopment of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present.Trial registrationISRCTN number: ISRCTN58227268. Registered on 26 August 2015.

Highlights

Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year
Further investigation of the anti-tumour effect of this drug in refractory multiple myeloma (RRMM) patients is warranted, especially since no trials comparing cyclophosphamide and dexamethasone (CD) with in combination with cyclophosphamide and dexamethasone (ICD) have been completed at present
It is anticipated that the addition of ixazomib to CD (ICD), in RRMM patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor, may improve clinical efficacy by at least 50%, in terms of median progression-free survival (PFS)

Summary

Methods

Study aim The MUK eight study will evaluate the clinical effectiveness of ixazomib in combination with cyclophosphamide and dexamethasone (ICD), as compared to the combination of cyclophosphamide and dexamethasone alone (CD), in terms of progression-free survival (PFS): the time from. D1 differences between treatment arms (ICD vs CD), D2 differences between treatment arms (ICD vs ICD Switch after progression on CD), D3 differences between treatments (CD vs ICD Switch after progression on CD), NFT no formal statistical testing, HE health economic analysis, Cox PH Cox’s proportional hazards model, CIF cumulative incidence function curves for competing risk analysis may be carried out using methods such as multiple imputation, pattern-mixture multi-level models categorising participants into strata based on clinical information which is believed to represent the reasons for missing data (assuming MAR data conditional upon participants’ clinical data), and pattern mixture models for bivariate (baseline and 9 week) data fitted using a variety of restrictions reflecting the missing data pattern ranging from complete case missing variable restriction (MAR) to Brown’s protective restriction (assuming data are missing not at random (MNAR)). Further exploratory analyses, detailed, will be conducted for the switch phase of the trial, where patients on the CD arm may receive ICD treatment after confirmed progression on CD These will include PFS2, PFS Switch, treatment compliance, and safety and toxicity. Analyses relating to the switch phase of the study will take place after a minimum of 6 months follow-up after the last CD participant to switch treatments has started ICD treatment

Discussion

Background

Findings