Personalising treatment for myeloma patients based on initial response to NHS treatment and their overall fitness level

Approved 08/10/2025, South Central - Oxford C Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 207 104 8089; oxfordc.rec@hra.nhs.uk), ref: 25/SC/0279

Measured using eCRFs and patient records, unless otherwise indicated. If disease response is required, this is measured in accordance with the IMWG Uniform Response Criteria for Multiple Myeloma.

iFIT1: Progression-free survival, measured as the time from iFIT1 randomisation to progression or death from any cause. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.

iFIT2: Event-free survival, measured as the time from iFIT2 randomisation to the first of the following events: grade 4 haematological adverse events (AEs) (anaemia, neutropenia, thrombocytopenia), grade 3 and 4 non-haematological AEs (including secondary primary malignancies; SPMs), discontinuation of trial treatment, progression or death. Events will be graded according to NCI-CTCAE V5. Participants event-free at the time of analysis will be censored at their last date known to be alive and event-free.

iFIT3: iFIT3 has co-primary endpoints. Progression-free survival, measured as the time from iFIT3 randomisation to progression or death from any cause. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Participant-reported overall health and quality of life, measured using the EORTC QLQ-C30 global health status (GHS)/QoL scale score at 30 months after iFIT3 randomisation.

Measured using eCRFs and patient records, unless otherwise indicated. If disease response is required, this is measured in accordance with the IMWG Uniform Response Criteria for Multiple Myeloma.

1. Progression-free survival (iFIT2 only), measured from iFIT2 randomisation to progression or death from any cause. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.
2. Time to progression, measured from iFIT1/iFIT2/iFIT3 randomisation to first documented evidence of disease progression. Participants who died without progression will be censored at their date of death. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.
3. Time to second PFS event, measured from iFIT1/iFIT2/iFIT3 randomisation to the second documented evidence of PD or death from any cause. Participants alive and for whom a second progression has not been observed at the time of analysis will be censored at their last known date to be alive and second progression-free.
4. Overall survival, measured from iFIT1/iFIT2/iFIT3 randomisation to death from any cause. Participants alive at the time of analysis will be censored at their last known date to be alive.
5. Event-free survival (iFIT1 only), measured from iFIT1 randomisation to the first of the following events: grade 4 haematological AEs (anaemia, neutropenia, thrombocytopenia), grade 3 and 4 non-haematological AEs (including SPMs), discontinuation of trial treatment, progression, or death. Participants event-free at the time of analysis will be censored at their last date known to be alive and event-free.
6. Survival after progression, measured from first documented evidence of disease progression to death from any cause. Participants alive at the time of analysis will be censored at their last known date to be alive. This endpoint is only defined for those who experience progression.
7. Time to next treatment, measured from registration to the date of commencement of next 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.
8. Overall response rate, the disease response category (sCR, CR, VGPR, PR, MR, SD, or PD) measured at the end of standard of care induction DRd treatment, and further timepoints up to approximately 30 months post-iFIT1/iFIT2/iFIT3 randomisation, dependent on treatment pathway.
9. Attainment of ≥VGPR, the binary disease response category (≥VGPR: sCR, CR, VGPR vs. <VGPR: PR, MR, SD, PD) measured at the same timepoints as overall response rate.
10. Attainment of MRD negativity, the binary MRD status category (negative vs. positive) measured using flow cytometry at the same timepoints as overall response rate. MRD negativity is defined as at least a serological VGPR and MRD negative bone marrow aspirate at the 10^-5 threshold.
11. Maximum response, at any point after iFIT1/iFIT2/iFIT3 randomisation.
12. Time to improved response, measured from iFIT1/iFIT2/iFIT3 randomisation to first recorded improved response, where the baseline response is that recorded at the start of randomised treatment (iFIT1/iFIT2/iFIT3 cycle 1, day 1). Participants whose disease progresses or who die before an improved response is recorded will be censored at the time of progression or death, respectively. Participants alive with no improved response recorded at the time of analysis will be censored at their last known date to be alive.
13. Treatment compliance, including whether all cycles of treatment were completed, the number of cycles completed, the total dose of each trial medication received, the number and causes of dose omissions, dose delays, and dose reductions.
14. Toxicity and safety based on the adverse events reported as graded by NCI-CTCAE v5. Pregnancies will also be reported.
15. Incidence of secondary primary malignancies reported during standard of care induction DRd treatment and following iFIT1/iFIT2/iFIT3 randomisation.
16. Incidence, rate, and type of infections, measured using the proportion of participants experiencing an infection of any type or grade as graded by NCI-CTCAE v5 during standard of care induction DRd treatment and following iFIT1/iFIT2/iFIT3 randomisation.
17. Quality of life, measured using the EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-IL413 questionnaires at the start of DRd induction, end of DRd induction, and further timepoints up to 30 months post-randomisation. This will also be measured using the EORTC QLQ-IL414 questionnaire at the start and end of standard of care induction DRd and in iFIT1 only, and the Scale of Subjective Total Taste Acuity questionnaire at the end of standard of care induction DRd and in iFIT1 only.
18. Objective measures of function, measured using the 4 metre walk test and mini-cog assessments at the start of, after 3 cycles, and at the end of standard of care induction DRd.
19. Cost-utility, measured using costs, QALYs and net health benefit (QALYs below £20,000).

Exploratory endpoints include the following and are to be defined in the statistical analysis plan:
1. Bone therapy planned and prescribed
2. Dental assessment received during the trial
3. Bone disease (including skeletal-related events; SREs) experienced during the trial
4. Infection interactions and infection risk (iFIT1 only)

Translational endpoints are yet to be defined by the translational research teams.