Personalising Treatment for Myeloma Patients Based on Initial Response to NHS Treatment and Their Overall Fitness Level

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.

The time from iFIT2 randomisation to the first of the following events: grade 4 haematological AEs, 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.

PFS: 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.

QoL: The GHS/QoL scale score of the EORTC QLQ-C30 questionnaire. The QoL primary endpoint is measured at 30 months (2.5 years) after iFIT3 randomisation.

The time 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.

The time 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.

The time from iFIT1/iFIT2/iFIT3 randomisation to the second documented evidence of progressive disease 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.

The time 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.

The time 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.

The time 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.

The time 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.

Overall response rate using the disease response category (sCR, CR, VGPR, PR, MR, SD, or PD).

Attainment of ≥VGPR using the binary disease response category (≥VGPR: sCR, CR, VGPR vs. <VGPR: PR, MR, SD, PD).

Attainment of MRD negativity using the binary MRD status category (negative vs. positive) measured using flow cytometry. MRD negativity is defined as at least a serological VGPR and MRD negative bone marrow aspirate at the 10^-5 threshold.

The maximum response attained.

The time 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.

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.

Toxicity and safety based on the adverse events reported as graded by NCI-CTCAE v5. Pregnancies will also be reported.

The number and details of all other cancers, defined as secondary primary malignancies.

Measured using the proportion of participants experiencing an infection of any type or grade as graded by NCI-CTCAE v5.

Measured using the EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-IL413 questionnaires. This will also be measured using the EORTC QLQ IL414 questionnaire and the Scale of Subjective Total Taste Acuity (STTA) at specified timepoints only.

Measured using the 4 metre walk test and mini-cog assessments.

Measured using costs, QALYs and net health benefit (QALYs below £20,000).

Observe and understand current UK bone therapy practice and investigate how it impacts on various bone and clinical myeloma outcomes, in order to generate hypotheses to inform future research in this area. This includes bone therapy planned and prescribed, dental assessment received, and bone disease (including SREs) experienced.

Certain genetic characteristics and medical history are suspected to influence the incidence and rate of infections. These will be investigated under this endpoint including iVIG usage and vaccination history. The ability to predict prospectively which participants are most at risk of infections could support the implementation of novel immunotherapies in practice. This will also be investigated under this endpoint.