Functional Geriatric Assessment Tests Predict Toxicity Rates in Functional High Risk Myeloma Patients Treated with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone in a Prospective Clinical Trial
Authors: Shmuel Ronit , Tellem Rotem , Gatt Moshe E , Lavi Noa , Ganzel Chezi , Luttwak Efrat , Chubar Evgeni , Rouvio Ory , Vaxman Iuliana , Pasvolsky Oren , Ballan Mouna , Tadmor Tamar , Nemets Anatoly , Jarchowcky Osnat , Shvetz Olga , Lieba Merav , Shpilberg Ofer , Lowenton-Spier Noa , Dally Najib , Avivi Mazza Irit , Cohen Yael C. 
Published: December 2024

Background
Frailty has been shown to have a major impact on treatment outcomes in myeloma patients (pts), yet prospective data on the effects of functional and cognitive assessments on treatment outcomes and their dynamics throughout therapy course, are scarce. We aimed to investigate the clinical utility of functional geriatric assessment and quality of life (QoL) measures in comparison with the commonly used International Myeloma Working Group (IMWG) frailty score, in a sub-study of the Kydar phase 2 prospective clinical trial, which investigated salvage of functional high risk (FHR) pts with a quadruple salvage regimen.
Methods
Forty-one FHR myeloma pts who failed to respond or experienced early (&lt;18 months [mo] from treatment start) relapse after a bortezomib-containing induction enrolled to receive second line treatment in eighteen 28-day (d) cycles (C) or until disease progression/ unacceptable toxicity. Carfilzomib: 56 mg/m2 IV d 1,8,15 (C 1-9), d 1,15 (C 10-18). Lenalidomide (LEN): 25 mg (Frail: 15mg) d1-21; Dexamethasone (DEX) 40mg (Frail: 20mg) weekly; Daratumumab (DARA): IV 16mg/Kg weekly (C 1-2), q14d (C 3-6), q28d. After 18 cycles, pts continued to receive DARA/LEN/DEX.
Here we focus on functional and geriatric sub-study of the above, evaluating IMWG frailty score and functional geriatric assessment examination at baseline and C4, including: European Organization for Research and Treatment of Cancer [EORTC] QoL Questionnaire Core Module [QLQ-C30] and multiple myeloma module [QLQ-MY20], frailty status (Activities of daily living [ADL], Instrumental activities of daily living [IADL], Charlson comorbidity index), cognition (MINI-COG), depression screening (Patient health questionnaire-2 [PHQ-2]), and physical assessment associated with frailty (Handgrip test [HG], 4-meter walking speed test [4MW]). Scales for analysis of test results were based on reported thresholds.
Tests dynamics were assessed over time as were their effects on QoL, and their correlation with hematological response and the occurrence of significant toxicity (defined as experiencing ≥2 adverse events [AEs] graded 3-5 or serious adverse event).
Results
Forty-one pts, with a median age of 70, were enrolled across 14 medical centers in Israel between June 2018-August 2019. Durable and deep responses were achieved with an ORR of 90% (37/41): near CR-stringent CR 22% / very good partial response 42% / PR 27%. AEs graded 3-5 included mostly infections (43%).
Pts were relatively well-preserved in terms of functional and cognitive status at screening point and maintained stable during treatment (C4). No significant differences were observed between these 2 time points, except for a moderate increase in frailty and depression indices at the fourth cycle.
Achieving a deep hematological response (≥VGPR) was not associated with significant improvements in functional (ADL, IADL, HG, 4MW), cognitive, or frailty indices.
Across all functional tests, pts with pathological scores experienced considerably more toxicity during treatment compared to those with normal range function and compared to the overall study population. A total functional score, per patient, was defined as pathological if more than 2/5 functional tests [ADL, IADL, 4MW, HG, frailty score] showed pathological results, this occurred in 35% of pts (10/28 with available functional score). Significant toxicity occurred in 100% vs 55% among pts with pathological vs normal total functional score (p=0.02), and in 77% vs 58% of frail vs non-frail pts (p NS).
When compared to QoL indices, which are subjective and reflect patient self-reporting, there was a significant discrepancy between pts responses to questionnaires and the formal objective test results, in favor of the former.
Conclusions
Contrary to expectations, hematologic responses were not associated with enhancements in functional and cognitive indices, while pts reports indicated beneficial effects, highlighting importance of assessing both objective and subjective parameters. Possibly longer follow-up is needed to capture functional improvements in elderly FHR pts receiving a quadruple second line. Toxicity rate was associated with pathological functional (particularly HG, ADL, IADL) and depression (PHQ-2) scores; This can inform the development of a predictive model that complements the existing frailty score for predicting treatment-related toxicity and QoL improvements.