Dynamic Frailty Assessment in Transplant Non-Eligible Newly Diagnosed Myeloma Patients: Initial Data from UK Myeloma Research Alliance (UK-MRA) Myeloma XIV (FiTNEss): A Frailty-Adjusted Therapy Study
Authors: Cook Gordon , Pawlyn Charlotte , Royle Kara-Louise , Senior Ethan R , Everritt Dax , Bird Jenny , Bowcock Stella J. , Dawkins Bryony , Drayson Mark , Gillson Sharon , Olivier Catherine , Chant Alan , Jenner Matthew W. , Jones John Robert , Kaiser Martin F. , Kishore Bhuvan , Meads David , Rabin Neil , Owen Roger , de Tute Ruth M , Parrish Christopher , Cairns David Allan , Jackson Graham 
Published: December 2023

Background

Multiple myeloma (MM) is a blood cancer that predominates in the older adult with significant morbidity and mortality. Frailty is increasingly recognized as a predictor for long- and short-term outcomes, with those who are frailer at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for frail older patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker for survival, but no evidence exists for its predictive biomarker potential. In addition, defining frailty at a single timepoint (baseline) by the IMWG FS may mask disease overlay and the improvements seen with therapy delivery. Understanding both improvements and deteriorations in frailty during treatment may have important implications for dynamic treatment delivery.

Study Design and Methods

The UKMRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for a stem cell transplant. The primary objectives of the study are 1) to compare early treatment cessation (within 60 days of randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, 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). Baseline revised IMWG FS (considering only those scoring &gt;=3 frail) and UKMRA Myeloma Risk Profile (MRP) were determined. Here we report the changes in IMWG FS for the patients recruited to the standard (toxicity-reactive) arm, including demographic data and the identification of an ultra-frail group.

Results

The FiTNEss trial opened on 04/08/2020 and at the time of data cut off (01/06/2023) recruitment is active at 84 sites, with 638 patients randomised. Baseline characteristics for the randomised patients are shown in Table 1. The median age of patients is 76 years (range 62, 93) with 34.8% aged 76-80 and 22.3% over 80. The IMWG FS at baseline for the full trial cohort was FIT 182/638 (28.5%), UNFIT 207/638 (32.4%) and FRAIL 249/638 (39.0%). Revised IMWG FS at baseline was Fit 28.5%, Unfit 56.0% and Frail 15.5% with MRP non-high risk (Fit or Unfit, nHR) in 64.3% and MRP HR (Frail) in 35.7% in patients with data available.

For descriptive analysis of FS dynamism, we assessed the impact on FS of delivery of IRD in the control arm (n=319), calculating the FS at 2, 4, 6 and 12 months. The majority of changes were seen at 2 months across the frailty categories. For Fit patients, 20.9% demonstrated a deterioration in FS score at any timepoint. For Unfit patients, 26.7% demonstrated a deterioration in FS score whilst 16.2% demonstrated an improvement in FS at any timepoint. For Frail patients, 15.4% demonstrated an improvement in FS at any timepoint (Figure 1). Of those who demonstrated a deterioration in FS, 59.1% experienced a treatment related safety event. In those who demonstrated an improvement in FS, 26.3% experienced a treatment related safety event. Of the 250 whose FS remained constant 34% experienced a treatment related safety event.

For frail patients, 119 could be stratified further and 57% were classified as Ultra-Frail (IMWG FS Frail and MRP HR).

Conclusion

The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The IMWG FS does demonstrate a dynamic biomarker potential both representing improved functionality in relation to disease response to therapy, as well as deterioration consequential to treatment-emergent toxicity. In addition, the concept of ultra-frail represents an exciting possibility to further stratify patients who may need additional support in order to improve their outcomes. Further work in these two areas is on-going as the trial dataset matures.