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

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.