NCT07649525 - Personalising Treatment for Myeloma Patients Based on Initial Response to NHS Treatment and Their Overall Fitness Level | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Eligibility criteria for registration: Inclusion criteria for registration: 1. Newly diagnosed as having symptomatic MM, plasma cell leukaemia or non-secretory MM according to IMWG diagnostic criteria 2014. 2. Considered not suitable to receive autologous stem cell transplant as part of their first line therapy by the treating clinician, 3. Planned for treatment with Daratumumab, Lenalidomide and dexamethasone (DRd) as first line therapy as standard of care, 4. Aged 18 years or greater, 5. Able to provide full informed consent, and 6. Prepared to comply with pregnancy prevention plan. Exclusion criteria for registration: 1. Smouldering myeloma (SMM), primary amyloidosis, solitary plasmacytoma of bone or extramedullary plasmacytoma (without additional evidence of myeloma), 2. Pregnant, breastfeeding, plans to become pregnant, or plans to father a child whilst enrolled in the study or within 3 months after the last dose, 3. Previous treatment for myeloma, except as specified in the protocol, 4. Active systemic viral, fungal or bacterial infection requiring systemic therapy. Criteria for specific chronic infections clarified in the protocol, or 5. Participation in any other interventional study for myeloma that involves an IMP during treatment and active monitoring. Additional eligibility criteria for randomisation into iFIT1/iFIT2/iFIT3 pathways, as follows: Inclusion criteria for randomisation into all iFIT1/iFIT2/iFIT3 pathways: * Completed 6 cycles of DRd induction therapy after registering within the iFIT study, * Able to provide full informed consent, and * Prepared to comply with pregnancy prevention plan. Inclusion criteria specific to randomisation pathways: * Dexamethasone may have been stopped due to toxicity and the participant will remain eligible (iFIT1 and iFIT3), * Planned to continue on at least daratumumab (monthly) and lenalidomide (at any dose level) (iFIT1 and iFIT3), * Planned to continue on all three DRd medications (dose reductions are allowed) (iFIT2), * Achieved a partial response (PR) biochemically (irrespective of MRD status) or achieved a ≥VGPR and are MRD positive, as confirmed by HMDS (central laboratory) (iFIT1 and iFIT2), * Achieved a ≥VGPR and are MRD negative, as confirmed by HMDS (central laboratory) (iFIT3), * Categorised as FIT or UNFIT according to the IMWG frailty index (iFIT1), * Categorised as FRAIL according to the IMWG frailty index (iFIT2), and * Meet the blood criteria specified in the protocol within 14 days before randomisation (haematological and biochemical) (iFIT1). Exclusion criteria for randomisation into all iFIT1/iFIT2/iFIT3 pathways: * Received systemic anti-myeloma therapy other than DRd prior to randomisation. Steroids given (by any route) for reasons other than myeloma disease control are allowed, * Received a stem cell transplant, * Participation in any other interventional study for myeloma that involves an IMP during treatment and active monitoring, and * Pregnant, breast feeding, plans to become pregnant, or plans to father a child whilst enrolled in the study or within a specified period after the last dose. Exclusion criteria specific to randomisation pathways: * Stable disease (SD) or progressive disease (PD) as per IMWG response criteria (iFIT1 and iFIT2), * Partial response (PR), stable disease (SD) or progressive disease (PD) as per IMWG response criteria (iFIT3), and * Further exclusion criteria related to safety of interventions (iFIT1). Full inclusion and exclusion criteria are listed in the protocol.

Outcomes

Primary Outcomes

iFIT1: Progression-free survival (PFS)

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.

Time frame: From iFIT1 randomisation to PFS event, assessed up to a maximum of 10.5 years post-randomisation.

iFIT2: Event-free survival (EFS)

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.

Time frame: From iFIT2 randomisation to EFS event, assessed up to a maximum of 6.5 years post-randomisation.

iFIT3: Progression-free survival (PFS) and participant-reported overall health and quality of life (QoL) - co-primary outcomes

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.

Time frame: PFS: from iFIT3 randomisation to PFS event, assessed up to a maximum of 10.5 years post-randomisation. QoL: measured at the start of cycle 1 and after 6 28-day cycles of DRd induction, and further timepoints up to 30 months post-iFIT3 randomisation.

Secondary Outcomes

Progression-free survival (PFS; iFIT2 only)

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.

Time frame: From iFIT2 randomisation to PFS event, assessed up to a maximum of 10.5 years post-randomisation.

Time to progression (TTP)

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.

Time frame: From iFIT1/iFIT2/iFIT3 randomisation to TTP event, assessed up to a maximum of 10.5 years post-randomisation.

Time to second PFS event (PFS2)

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.

Time frame: From iFIT1/iFIT2/iFIT3 randomisation to PFS2 event, assessed up to a maximum of 10.5 years post-randomisation.

Overall survival (OS)

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.

Time frame: From iFIT1/iFIT2/iFIT3 randomisation to OS event, assessed up to a maximum of 10.5 years post-randomisation.

Event-free survival (EFS; iFIT1 only)

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.

Time frame: From iFIT1 randomisation to EFS event, assessed up to a maximum of 6.5 years post-randomisation.

Survival after progression

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.

Time frame: From disease progression to death, assessed up to a maximum of 10.5 years post-randomisation.

Time to next treatment (TTNT)

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.

Time frame: From registration to TTNT event, assessed up to a maximum of 10.5 years post-randomisation.

Overall response rate (ORR)

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

Time frame: Measured after 6 28-day cycles of standard of care induction DRd treatment, and further timepoints up to approximately 30 months post-iFIT1/iFIT2/iFIT3 randomisation, dependent on treatment pathway.

Attainment of ≥VGPR

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

Attainment of MRD negativity

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.

Maximum response

The maximum response attained.

Time frame: From iFIT1/iFIT2/iFIT3 randomisation up to a maximum of 6.5 years post-randomisation.

Time to improved response

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.

Time frame: From iFIT1/iFIT2/iFIT3 randomisation to first recorded improved response, up to a maximum of 6.5 years post-randomisation.

Treatment compliance

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.

Time frame: From registration to the end of trial treatment, up to a maximum of 7 years post-registration.

Toxicity and safety as graded by NCI-CTCAE v5

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

Time frame: From registration up to a maximum of 11 years post-registration. SAEs may be reported up to 60 days post-last dose of protocol treatment/cycle of active monitoring.

Incidence of secondary primary malignancies

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

Time frame: Measured during standard of care induction DRd treatment and following iFIT1/ iFIT2/iFIT3 randomisation, up to a maximum of 11 years post-registration.

Incidence, rate, and type of infections as graded by NCI-CTCAE v5

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

Time frame: Measured during standard of care induction DRd treatment and following iFIT1/iFIT2/iFIT3 randomisation, up to a maximum of 7 years post-registration.

Quality of life using questionnaires

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.

Time frame: Measured at the start of cycle 1 and after 6 28-day cycles of DRd induction, and timepoints up to 30 months post-randomisation. The IL414 is measured at the induction timepoints and in iFIT1, and the STTA after 6 28-day cycles of induction and in iFIT1.

Objective measures of function

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

Time frame: Measured at the start of cycle 1, after 3 28-day cycles, and after 6 28-day cycles of standard of care induction DRd.

Cost-utility

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

Time frame: Measured at the start of cycle 1 of DRd induction, after 6 28-day cycles of DRd induction, and further timepoints up to 30 months post-iFIT1/iFIT2/iFIT3 randomisation.

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

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts