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
Authors: Cook Gordon , Pawlyn Charlotte , Royle Kara-Louise , Senior Ethan R , Everritt Dax , Bird Jenny , Bowcock Stella , Dawkins Bryony , Drayson Mark , Gillson Sharon , Olivier Catherine , Jenner Matthew W. , Jones John , Kaiser Martin F , Kishore Bhuvan , Meads David , Rabin Neil , Owen Roger G , de Tute Ruth M , Parrish Christopher , Chant Alan , Cairns David A. , Jackson Graham 
Published: December 2024

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, &gt;=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.