Initial Results from the Frailty-Stratified, Randomised Controlled Bayesian Adaptive Trial of Bortezomib Versus Lenalidomide in Transplant Ineligible Myeloma (TI-NDMM) - the FRAIL-M Study (AMaRC 19-01; ALLG MM22)
Authors: Lim Sueh-Li , Reynolds John , Pemberton Lucy , Wright Tricia , Lee Sophie Hyesuk , Mollee Peter , Shetty Anita C , Weston Helen , Byard Nina , Le Khoa , McQuilten Zoe K , Quach Hang , Spencer Andrew 
Published: December 2024

Introduction
Real-world survival for TI NDMM patients is significantly inferior compared to transplant eligible (TE)-NDMM patients, with data from the Australian and New Zealand Myeloma and Related Diseases Registry demonstrating median overall survival of 48 vs 68 months respectively (p &lt;0.001; HR=2.3), with age &gt;70 years the strongest predictor (OR 3.15; p &lt;0.001) for early mortality (death≤12 months of diagnosis). While lenalidomide (R), bortezomib (V) and dexamethasone (d) are available there have been no direct comparisons of VRd vs Rd vs Vd, to rationalise treatment selection and there remains no established standard of care for truly TI NDMM patients, who comprise 60% of all NDMM diagnoses. Moreover, frailty adversely impacts the likelihood of completing an intended course of therapy and tension exists between ensuring treatment tolerability with attainment of timely disease control. This trial aims to identify effective and deliverable backbone induction regimens for the rational exploration of integration of newer immunotherapeutics into the treatment algorithm for TI NDMM.
Methods
FRAIL-M (ACTRN12619001199101) is a novel, frailty-stratified, adaptive, Phase I/II trial that assigns participants to one of three strata (fit, intermediate-fit and frail) prior to 1:1 randomisation between 2 arms comparing bortezomib-based (arm A) and lenalidomide-based regimens (arm B) in TI NDMM. Frailty assessment utilises the validated IMWG Frailty Score and 3 geriatric assessment tools: the Katz Activity of Daily Living, the Lawton Instrument Activity of Daily Living and the Charlson Comorbidity index. The regimen assessed in each stratum aims to balance treatment deliverability with efficacy and contains a standardised dose reduction strategy in the event of toxicity. The primary objective is to establish, after 4 cycles (EOC4), the overall response rate (ORR) and safety as indicated by occurrence of deliverability-limiting toxicity (DeLT) in each stratum, defined as any trial treatment-related drug toxicity that mandates a dose modification (reduction or cessation) of R, V, or d within the first 4 treatment cycles. Dose levels within an arm and stratum are monitored via a Bayesian Optimal Phase 2 (BOP2) design. Interim analyses occur after 10, 20, 35 and 50 evaluable patients, after which, the regimen is deemed unacceptable if there is evidence that the probability of response is ≤ 50% or the probability of DeLT &gt; 35%. In the event of inefficacy, standardised dose escalation (+1 dose level) is permitted for all future patients assigned to the intermediate or frail strata. In the event of unacceptable toxicity, dose reduction (-1 dose level) is similarly permitted in all strata. The secondary objective is a preliminary comparison of V and R-based regimens in each stratum.
The trial was set-up with provision for 300 pts and initial caps of 50 pts in each of the 6 treatment arms. Accrual opened 02DEC2019, and by 12JUL2024 171 pts had been stratified and randomized - 29, 51 and 91 pts in the fit, intermediate and frail strata, respectively. We report interim results for the frail stratum (arms 3A, 3B).
Results
The frail strata currently comprises 91 evaluable patients, 56% males, median age 81 years (range, 63-90). In 3A, patients received V 1.0mg/m2 and d 12mg on D1, 8 and 15 of each 28-day cycle for a total of 12 cycles. The first interim analysis, performed after 10 patients had received 4 complete cycles, demonstrated an interim observed toxicity rate of 0% (no DeLTs) and an interim response rate of only 20%, below the minimum efficacy threshold of 50%. Therefore, 3A underwent dose escalation to VRd, now including R 15mg on day 1-21 of each 28-day cycle. The first 2 scheduled analyses at this higher dose have cleared the thresholds for both efficacy and toxicity. In 3B patients received R 10mg D1-21 and d 12mg D1, 8, 15 of each 28-day cycle and the first 3 scheduled analyses have indicated acceptable efficacy and toxicity so randomization to both arms continues. For the first 38 evaluable patients in arm 3B, ORR at EOC4 is 66% and DeLT rate is 21%.
Conclusion
The FRAIL-M trial combines stratification and randomization between 2 customised treatment arms within each stratum and use of BOP2 design to jointly monitor toxicity and efficacy in TI NDMM. Efficacy and deliverability look promising in 3B (Rd), with 3A now integrating R (VRd) following successful dose escalation. An updated analysis will be presented at the conference.