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673 IMWG Frailty Score-Adjusted Therapy Delivery Reduces the Early Mortality Risk in Newly Diagnosed Tne Multiple Myeloma: Results of the UK Myeloma Research Alliance (UK-MRA) Myeloma XIV Fitness Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Optimizing Therapy in Newly Diagnosed Myeloma and Beyond
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Sunday, December 8, 2024: 4:30 PM

Gordon Cook, PhD, DSc1,2*, Charlotte Pawlyn, PhD3, Kara-Louise Royle4*, Ethan R Senior5*, Dax Everritt6*, Jenny Bird7*, Stella Bowcock8*, Bryony Dawkins, MSc9*, Mark Drayson10*, Sharon Gillson, BSc5*, Catherine Olivier1*, Matthew W. Jenner11*, John Jones12*, Martin F Kaiser, MD13, Bhuvan Kishore14*, David Meads, PhD9*, Neil Rabin15*, Roger G Owen, MD, MRCP, FRCPath16*, Ruth M de Tute, MSc, PhD, FRCPath16*, Christopher Parrish, MBBChir, MRCP, FRCPath, MA, PhD4, Alan Chant17*, David A. Cairns, PhD4* and Graham Jackson, MD18*

1Leeds Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom
2CRUK Clinical Trials Unit, Leeds Institute of Clinical Tial Research, Leeds Myeloma Research Group and NIHR Leeds Biomedical Research Centre, Leeds, United Kingdom
3Institute of Cancer Research, Sutton, United Kingdom
4Cancer Research UK Clinical Trials Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom
5Leeds Institute of Clinical Trials Research, Cancer Research UK Clinical Trials Unit, Leeds, United Kingdom
6CRUK CTU, Leeds Insitute of Clinical Trial Research, University of Leeds, Leeds, United Kingdom
7Department of Haematology, University Hospitals Bristol NHS Foundation Trust, Cambridge, GBR
8King’s College Hospital, London, United Kingdom
9University of Leeds, Academic Unit of Health Economics, Leeds, United Kingdom
10University of Birmingham, Institute of Immunology and Immunotherapy, Birmingham, United Kingdom
11University Hospital Southampton, Southampton, United Kingdom
12East Sussex Healthcare NHS Trust, London, United Kingdom
13The Institute of Cancer Research, London, ENG, United Kingdom
14Heartofengland NHS FT, Birmingham, GBR
15Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
16HMDS, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
17Patient and Public Contributor, NA, United Kingdom
18University of Newcastle, Department of Haematology, Newcastle, United Kingdom

Background

Multiple myeloma (MM) predominates in the older adult with significant morbidity and mortality. Frailty (F) is increasingly recognized as a predictor for long- and short-term outcomes, with frailer patients at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for older/frail patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker, but no evidence exists for it as a predictive biomarker, and hence its capability to direct therapy decision-making. This is key to its impact on clinical practice.

Study Design and Methods

The UK-MRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for stem cell transplant. The primary objectives of the study are 1) to compare in unfit/frail patients early treatment cessation (within 60 days of randomisation) randomised to standard (RT: reactive) and frailty-adjusted (FA: F based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Here we report the final analysis of the first primary objective.

Results

The FiTNEss trial recruited patients between 04/08/2020 and 01/03/2024 from 84 UK sites. 733 patients were randomised. Median (range) age at randomisation was 77 years (62-93) with 35.2% aged 76-80 and 23.6% over 80. 55.7% were male sex. ISS was I in 20.7%, II in 46.4% and III in 32.6% with standard risk CA in 41.3%, high risk in 19.0% and unavailable in 39.7%. WHO performance status was 0-1 in 76.5%, 2 in 15.6% and 3+ in 7.2%. IMWG FS was FIT in 27.0%, UNFIT in 32.6% and FRAIL in 40.4%.

In the R1 ITT population (UNFIT and FRAIL; n=535) 115 patients stopped therapy in the first 60 days: 61/265 (23.0%) in the RT arm vs 54/270 (20%) in the FA arm (adjusted Odds Ratio [OR]: 1.21; 95%CI 0.80-1.84; p=0.368). Reasons for stopping therapy were: death (RT 29.5%, 18/61 vs FA 27.8%, 15/54), patient choice (RT 26.2%, 16/61 vs FA 25.9%, 14/54), clinician choice (RT 13.1%, 8/61 vs FA 20.4%, 11/54) and toxicity (RT 24.6%, 15/61 vs FA 20.4%, 11/54). There was a significant difference in early treatment cessation in the FRAIL (26.1%, n=295) versus the UNFIT (15.8%, n=240) group (adj. OR: 1.85; 95%CI 1.19-2.88; p=0.0061). Across all induction cycles delivered (n=5890 in 733 participants) dose modifications were higher in the RT arm vs FA (I 6.9% vs 5.8%, R 11.9% vs 10.0% and d 9.5% vs 7.2%). In the safety population (n=722), the total number of treatment emergent adverse events was similar between the arms. However, for treatment-emergent serious adverse reactions there were more infections in the RT arm (17%, 60/359 vs 13%, 47/363) and more GI toxicity in the FA arm (8%, 29/359 vs 10%, 36/363).

There was no clinically significant difference in the local response rate between the arms, >=VGPR in 42.2% of RT vs 37.8% in FA. Similarly, the 6- and 12-month MRD negative rate was similar (RT 9.9% and 9.3% vs FA 6.8% and 8.2%). 1-year PFS was 73.4% (95%CI 68.1-77.9) in the RT and 76.4% (95%CI 71.3-80.7) in the FA arms (Hazard Ratio [HR] 0.95, 95%CI 0.74-1.20; p=0.657). 136 patients have died, 81 (22.2%) in the RT and 55 (14.9%) in the FA arms. Causes of death were: PD (RT 30.9%, 25/81 vs FA 38.2%, 21/55), infection (RT 19.8%, 16/81 vs FA 9.1%, 5/55), cardiac (RT 7.4%, 6/81 vs FA 12.7%, 7/55) and respiratory (RT 9.9%, 8/81 vs FA 9.1%, 5/55). The 1-year OS was 83.2% (95%CI 78.5-86.9) in RT and 88.7% (95%CI 84.7-91.7) in FA arm (HR 1.45 95%CI 1.03-2.04; p=0.035).

Conclusion

The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The delivery of a frailty-adjusted dosing schedule whilst not improving early treatment cessation rate, did not compromise depth or durability of response and did reduce early mortality (1-year). Subgroup analysis will investigate where the greatest benefit is achieved. This analysis highlights the potential of the IMWG FS to be both a prognostic and predictive biomarker for early mortality in newly diagnosed TNE MM patients.

Disclosures: Cook: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Research Funding; Janssen-Cilag: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pawlyn: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Menarini Stemline: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; GSK: Honoraria; iTEOS Therapeutics: Honoraria. Drayson: Abingdon: Current equity holder in publicly-traded company. Kaiser: Regeneron: Consultancy; Roche: Consultancy; GSK: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; J&J/Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Pfizer: Consultancy, Honoraria; Poolbeg: Consultancy, Honoraria. Meads: Otsuka: Consultancy; Egetis: Consultancy.

OffLabel Disclosure: Ixazomib, in combination with lenalidomide and dexamethasone in newly diagnosed patents with multiple myeloma

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