Study: NCT03720041

Intervention type: DRUG
Group type: ACTIVE_COMPARATOR
Intervention: R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - reactive arm
Description: In the reactive arm at Randomisation 1, participants will receive IRD induction therapy with standard up-front dosing, with toxicity assessed at each cycle and doses adjusted in accordance with the guidelines given in the trial protocol. All participants will be given the following starting doses:~Ixazomib: 4mg/day on days 1, 8 and 15, taken orally~Lenalidomide: 25mg/day on days 1-21, taken orally~Dexamethasone: 40mg on days 1, 8, 15 and 22 for participants aged ≤75 years, or 20mg on days 1, 8, 15 and 22 for participants aged \> 75 years; taken orally~Participants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - adaptive arm
Description: In the adaptive arm at Randomisation 1, participants will receive IRD induction therapy with up-front dose reductions adjusted according to their frailty score: fit, unfit, or frail. The starting doses for each frailty category are described below:~1. Fit category:~   Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 25mg on days 1-21, taken orally Dexamethasone: 40mg on days 1, 8, 15 and 22, taken orally~2. Unfit category:~   Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 15mg on days 1-21, taken orally Dexamethasone: 20mg on days 1, 8, 15 and 22, taken orally~3. Frail category:~Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 10mg on days 1-21, taken orally Dexamethasone: 10mg on days 1, 8, 15 and 22, taken orally~Participants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.

Intervention type: DRUG
Group type: ACTIVE_COMPARATOR
Intervention: R2: Lenalidomide plus placebo maintenance
Description: Participants randomised to receive lenalidomide plus placebo maintenance at Randomisation 2 will receive the following starting doses:~Lenalidomide: 10mg\*/day on days 1-21, taken orally Placebo: 4mg\*/day on days 1, 8 and 15~\* or final dose administered at the end of induction treatment if lower.~This dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days.~Randomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.

Intervention type: DRUG
Group type: EXPERIMENTAL
Intervention: R2: Lenalidomide + ixazomib maintenance
Description: Participants randomised to receive lenalidomide plus ixazomib maintenance at Randomisation 2 will receive the following starting doses:~Lenalidomide: 10mg\*/day on days 1-21, taken orally Ixazomib: 4mg\*/day on days 1, 8 and 15~\* or final dose administered at the end of induction treatment if lower.~This dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days.~Randomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.