The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial

Abstract

Background: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance.

Methods/design: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression.

Discussion: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM.

Trial registration: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016.

Keywords: ASCT; Augmented ASCT; Depth of response; Haematology; Multiple myeloma; Randomised.

Conflict of interest statement

Ethics approval and consent to participate

The trial has been approved by a main Research Ethics Committee (Main REC) and the appropriate local R&D department for each participating centre prior to opening to participant recruitment into the trial. Ethical approval has been obtained from the National Research Ethics Service Committee - North West, Greater Manchester (reference 16/NW/0517).

The trial will be performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, amended at the 52nd World Medical Association General Assembly, Edinburgh, Scotland, 2000, principles of Good Clinical Practice in clinical trials, as applicable under UK regulations, the NHS Research Governance Framework (and Scottish Executive Health Department Research Governance Framework for Health and Social Care 2006 for studies conducted in Scotland) and through adherence to CTRU Standard Operating Procedures (SOPs). Additionally, CTRU and the Sponsor have systems in place to ensure that serious breaches of GCP or the trial protocol are picked up and reported.

Informed written consent will be obtained from the participants prior to registration into the trial. The right of a participant to refuse participation without giving reasons must be respected. The participant must remain free to withdraw at any time from the trial without giving reasons and without prejudicing his/her further treatment.

Consent for publication

Consent for publication is not applicable, as an individual person’s data is not part of the ACCoRd study.

Competing interests

AJA provides consultancy for Celgene, Janssen, Takeda; receives honoraria from Celgene, Amgen, Janssen, Takeda; is part of the Speakers Bureau for Celgene, Amgen, Janssen, Takeda; AH has research funding from Takeda, Celgene, Janssen, Amgen, Merck Sharp & Dohme; AS has research funding from Takeda, Celgene, Janssen, Amgen, Merck Sharp & Dohme; CW receives honoraria from Takeda, Janssen, Celgene, Amgen, Novartis; is part of the Speakers Bureau for Takeda, Celgene, Janssen, Amgen; receives travel support from Takeda, Janssen, Celgene; DC has research funding from Takeda, Celgene, Janssen, Amgen, Merck Sharp & Dohme; GC provides consultancy for Takeda, Janssen, Sanofi, Amgen, Glycomimetics; receives research funding from Takeda, Celgene, Janssen; is part of the Speakers Bureau for Takeda, Janssen, Sanofi, Amgen; GJ has research funding from Takeda, Celgene, Janssen, Amgen, Merck Sharp & Dohme; JC is involved with honoraria/Speakers Bureau for Celgene, Janssen, Novartis, Amgen; JS provides consultancy for Kiadis; receives honoraria from Sanofi-Genzyme, Jazz; KB has research funding from Takeda, Celgene, Janssen, Amgen, Merck Sharp & Dohme; KY has research funding from Janssen, Amgen; receives honoraria from Janssen, Amgen; MC has research funding from Celgene, Janssen; is involved with honoraria/Speakers Bureau for Takeda, Celgene, Janssen, Amgen, Chugai; MD is a consultant to and shareholder of Abingdon Health Limited; RO receives honoraria from Takeda, Celgene; has research funding from Celgene; provides consultancy for Celgene, Janssen; receives travel support from Takeda, Janssen.

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Figures

Fig. 1

ACCoRd study flowchart

Fig. 2

Schedule of enrolment, interventions and assessments