The efficacy of consolidation and maintenance in the context of salvage autologous haematopoietic stem-cell transplantation (HSCT) for relapsed multiple myeloma remains unclear. We aimed to assess whether consolidation after salvage autologous HSCT, using ixazomib, thalidomide, and dexamethasone, followed by maintenance with single agent ixazomib is superior to observation.
This is an interim analysis of Myeloma XII (ACCorD; referred to as ACCorD hereafter), an open-label, randomised, controlled, phase 3 trial done at 79 hospitals in the UK. Eligible patients were aged 18 years or older, had relapsed multiple myeloma with measurable disease, an ECOG performance status of 2 or less with adequate renal, hepatobiliary, pulmonary, and cardiac function, and required treatment for first progressive disease occurring at least 12 months after first autologous HSCT. In a first randomisation, patients were assigned (1:1) to receive either conventional autologous HSCT with melphalan or augmented autologous HSCT with melphalan and ixazomib. In the second randomisation, reported here, patients were assigned (1:1) to consolidation using ixazomib, thalidomide, and dexamethasone (oral ixazomib 4 mg per day on days 1, 8, and 15, oral thalidomide 100 mg per day on days 1-28, and oral dexamethasone 40 mg per day on days 1, 8, 15 and 22 of 28-day cycles), followed by maintenance with single agent ixazomib (oral ixazomib 4 mg per day on days 1, 8, and 15 of 28-day cycles until disease progression or intolerance), or observation. The primary endpoint was progression-free survival, analysed by intention-to-treat. Safety was analysed per-protocol. This study is registered with ISRCTN, ISRCTN10038996, and EudraCT, 2016-000905-35, and recruitment is complete.
Between Dec 12, 2017, and April 21, 2023, 206 patients entered the second randomisation (103 in the consolidation and maintenance group and 103 in the observation group). This prespecified interim analysis (data cutoff April 21, 2023), was done at a median follow-up of 27 months (IQR 13-38). Median progression-free survival was 20 months (95% CI 15-29) in the consolidation and maintenance group and 13 months (11-18) in the observation group (hazard ratio 0·55 [95% CI 0·39-0·78]; p=0·0006). Serious adverse events were reported in 29 (32%) of 92 patients in the consolidation and maintenance group compared with seven (7%) of 103 patients in the observation group. The most common serious adverse events were infections and infestations in both the consolidation and maintenance group and the observation group. The most common grade 3, 4, or 5 adverse events for patients in the consolidation and maintenance group were upper respiratory infection (seven [8%] of 92 patients). No deaths in the consolidation and maintenance group were deemed treatment related.
ACCorD provides evidence that an orally administered, deliverable, and tolerable post-salvage autologous HSCT treatment regimen can improve the durability of response for transplantation-eligible patients at first relapse. The findings are of relevance to patients who had durable disease control from autologous HSCT in the first line, representing a viable alternative to continuous parentally-administered relapse therapies.
Cancer Research UK, Takeda Oncology.
The Lancet. Haematology. 2024 Sep 06 [Epub ahead of print]
Gordon Cook, A John Ashcroft, Ethan Senior, Catherine Olivier, Anna Hockaday, Jeanine Richards, Jamie D Cavenagh, John A Snowden, Mark T Drayson, Ruth de Tute, Lesley Roberts, Roger G Owen, Kwee Yong, Mamta Garg, Kevin Boyd, Hamdi Sati, Sharon Gillson, Mark Cook, David A Cairns, Christopher Parrish, United Kingdom Myeloma Research Alliance
Department of Haematology, Leeds Cancer Centre, Leeds Teaching Hospitals Trust, Leeds, UK; Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK. Electronic address: ., Mid-Yorkshire NHS Trust, Wakefield, UK., Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK., Department of Haematology, Barts Health NHS Trust, London, UK., Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK., Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK., Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, Leeds Teaching Hospitals Trust, Leeds, UK., Leek, UK., University College London Hospitals, NHS Foundation Trust, London, UK., Leicester Royal Infirmary, Leicester, UK., Department of Haematology, Royal Marsden Hospital, London, UK., Department of Haematology, Singleton Hospital, Swansea, UK., Bristol-Myers Squibb, Boudry, Switzerland., Department of Haematology, Leeds Cancer Centre, Leeds Teaching Hospitals Trust, Leeds, UK; Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.