Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

ABSTRACT

Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation (<60 days from randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG score) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associa ed exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. [Formula presented] Disclosures Cook Amgen Consultancy, Honoraria, Research Funding;BMS Consultancy, Honoraria, Research Funding;Sanofi Consultancy, Honoraria;Karyopharm Consultancy, Honoraria;Roche Consultancy, Honoraria;Pfizer Consultancy, Honoraria;Oncopeptides Consultancy, Honoraria;Takeda Consultancy, Honoraria, Research Funding;Janssen Consultancy, Honoraria, Research Funding. Pawlyn Sanofi Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene / BMS Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen Honoraria. Royle BMS Research Funding;Merck Sharpe and Dohme Research Funding;Amgen Research Funding;Takeda Research Funding. Coulson BMS / Celgene Honoraria;Merck Sharpe and Dohme Research Funding;Amgen Research Funding;Takeda Research Funding. Jenner BMS/Celgene Consultancy, Honoraria, Speakers Bureau;Janssen Consultancy, Honoraria, Speakers Bureau;Pfizer Consultancy;Takeda Consultancy. Kishore Sanofi Other Attending fees;Celgene Other Attending fees;Takeda Other Attending fees;Jannsen Other Attending fees. Rabin BMS / Celgene Consultancy, Honoraria, Other Travel support for meetings;Takeda Consultancy, Honoraria, Other Travel support for meetings;Janssen Consultancy, Honoraria, Other Travel support for meetings. Best BMS/Celgene Research Funding;Merck Sharpe and Dohme Research Funding;Amgen Research Funding;Takeda Research Funding. Gillson BMS / Celgene Research Funding;Meck Sharpe and Dohme Research Funding;Amgen Research Funding;Takeda Research Funding. Henderson Takeda Research Funding;Amgen Research Funding;Merck Sharpe and Dohme Research Funding;BMS / Celgene Research Funding. Olivier Merck Sharpe and Dohme Research Funding;Takeda Research Funding;Amgen Research Funding;Celgene / BMS Research Funding. Kaiser AbbVie Consultancy;GSK Consultancy;Karyopharm Consultancy, Research Funding;Pfizer Consultancy;Amgen Honoraria;Seattle Genetics Consultancy;Takeda Consultancy, Other Educational support;Janssen Consultancy, Other Educational support, Research Funding;BMS/Celgene Consultancy, Other Travel support, Research Funding. Drayson Abingdon Health Current holder of individual stocks in a privately-held company. Jones Janssen Honoraria;BMS/Celgene Other Conference fees. Cairns Merck Sharpe and Dohme Research Funding;Amgen Research Funding;Takeda Research Funding;Celgene / BMS Other travel support, Research Funding. Jackson celgene BMS Consultancy, Honoraria, Research Funding, Speakers Bureau;amgen Consultancy, Honoraria, Speakers Bureau;takeda Consultancy, Honoraria, Research Funding, Speakers Bureau;GSK Consultancy, Honoraria, Speakers Bureau;J and J Consultancy, Honoraria, Speakers Bureau;oncopeptides Consultancy;Sanofi Honoraria, Speakers Bureau. OffLabel Disclosure Frailty-score adapted dosing strategies