Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma

Summary

Trial Title:

FiTNEss (UK-MRA Myeloma XIV) - Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma

Overview:

A phase III, multi-centre, randomised controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (R+I) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant.

All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomised on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose-modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomisation on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians will be blinded to maintenance allocation.

Participant population:

* Newly diagnosed as having Multiple Myeloma (MM) according to the updated IMWG diagnostic criteria 2014 (see Appendix 1 for criteria)
* Not eligible for stem cell transplant
* Aged at least 18 years
* Able to provide written informed consent

Number of participants:

740 participants will be entered into the trial at Randomisation 1 (R1), with 478 participants at Randomisation 2 (R2).

Objectives:

The primary objectives of this study are to determine:

* Early treatment cessation (within 60 days of randomisation) for standard versus frailty-adjusted up-front dosing
* Progression-free survival (PFS, from maintenance randomisation) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (R+I)

The secondary objectives of this study are to assess progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, time to progression, time to 2nd PFS event (PFS2), overall survival (OS), survival after progression, deaths within 12 months of R1, overall response rate (ORR), attainment of ≥VGPR, attainment of MRD negativity, duration of response, time to improved response, time to next treatment, treatment compliance and total amount of therapy delivered, toxicity \& safety including the incidence of SPMs, Quality of Life (QoL), cost effectiveness of standard versus frailty-adjusted up-front dosing of IRD and cost-effectiveness of R + I versus R.

Exploratory objectives are prospective validation of a novel frailty risk score (UK-MRA Myeloma Risk Profile - MRP), usefulness of Karnofsky Performance Status (PS), and association of molecular subgroups with response, PFS and OS.

Conditions

• Multiple Myeloma

Interventions

DRUG

R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - reactive arm

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.

DRUG

R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - adaptive arm

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.

DRUG

R2: Lenalidomide plus placebo maintenance

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.

DRUG

R2: Lenalidomide + ixazomib maintenance

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.

Sponsors & Collaborators

• Cancer Research UK

  collaborator OTHER

• Takeda

  collaborator INDUSTRY

• Celgene

  collaborator INDUSTRY

• University of Leeds

  lead OTHER

Principal Investigators

• Gordon Cook, MD · University of Leeds

• Graham Jackson, MD · Freeman Hospital, Newcastle-Upon-Tyne

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-08-04

Primary Completion

2024-12-31

Completion

2024-12-31

Countries

• United Kingdom

Study Locations