Isatuximab with Pomalidomide and Dexamethasone Provides Comparable Efficacy Outcomes in Frail Routine Care Myeloma Patients in a UK-Wide Cohort

Background: The use of frailty assessments in the management of relapsed/refractory multiple myeloma (RRMM) patients is required, in order to individualise treatment decisions, which would aim to reduce the risk of under-treating fit patients or over-treating frail patients. In addition to IMWG, R-MCI and MRP myeloma prognostic frailty tools, a new simplified frailty score developed by Facon et al (2020) was predictive of outcomes in elderly newly diagnosed myeloma patients treated as part of the FIRST trial. However, there are no data to describe its utility in RRMM patients treated in the real-world. Method: We conducted a UK-wide retrospective real-world study of RRMM patients treated with isatuximab plus pomalidomide and dexamethasone (IsaPomDex). We report patient characteristics, and clinical outcomes according to frailty categories using the new frailty scoring system, including overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and adverse events (AE). Frailty scoring was based on 3 key components: age (≤75 years: 0, 76-80 years: 1, >80 years: 2), Charlson co-morbidity index (CCI) score (≤1:0, >1: 1) and ECOG performance status (PS) (0: 0, 1:1, ≥2:2). The sum of all 3 components would define patients as frail (if ≥2) or intermediate-fit (if <2). Results: In a total cohort of 106 patients evaluable for frailty, median follow-up (FU) was 12.1 months (IQR 10.1-18.6 months). Seventy-two patients (67.9%) were frail, whilst 34 patients (32.1%) had an intermediate-fit status (i.e. non-frail). Patients in the frail subgroup had a higher median age (frail: 71 vs. intermediate-fit: 57.5 years), a higher proportion of patients with PS score of ≥1 (frail: 95.9% vs. intermediate-fit: 29.4%), a higher co-morbidity burden expressed as a higher median CCI score (frail: 4 vs. intermediate-fit: 1), and poor renal function defined as GFR<60ml/min (frail: 51.4% vs. intermediate-fit: 26.5%). Median number of prior therapies was identical between subgroups (3 vs. 3). Patients in the frail subgroup received a numerically lower median number of IsaPomDex cycles during follow-up, but without a statistical significance (frail: 6 vs. intermediate-fit: 9.5, p=0.1664). There was no statistical difference in treatment discontinuation rates (frail: 51.4% vs. intermediate-fit: 50%, p=0.894). Discontinuation rate due to death was numerically higher in the frail subgroup but without statistical significance (frail:16.7% vs. intermedicate-fit:11.8%, p=0.234). ORR was comparable across frailty subgroups (frail: 65.3% vs. intermediate-fit: 67.7%, p=0.779). Median PFS was numerically higher in the non-frail group but without statistical difference (frail: 10.1 vs. intermediate-fit: 13.7 months, log-rank p=0.5259). There was no statistical difference in median DOR (frail: 10.1 vs. intermediate-fit: 10.2 months, p=0.685). There was a trend for a longer median OS in the non-frail group but without statistical difference (frail: 15 months, 95% CI 12-NE vs. intermediate-fit: not reached, 95% CI 16.7-NE, log-rank p=0.3571). Data on AEs is presented after a median number of IsaPomDex cycles (IQR) of 4 (2-8), and a median follow up (IQR) of 3.7 months (0.5-12.4). Incidence rate of any grade AEs was (frail:87.5% vs. non-frail: 88.4%, p=0.763). Incidence rate of any grade haematological AEs was (frail: 76.4% vs. non-frail: 67.6%, p=0.341). Incidence rate of ≥G3 infections was (frail: 22.2% vs. non-frail: 11.8%, p=0.199). Incidence rate of ≥G3 haematological AEs was (frail: 58.3% vs. non-frail 38.2%, p=0.053). Incidence rate of AE-related inpatient hospitalisations was (frail: 26.4% vs. non-frail: 14.7%, p=0.18). Our study is limited by its retrospective, non-randomised nature with the inherent possibility of unmeasured confounding factors, patient selection bias, the potential for medical chart misinterpretation, and under-reporting of toxicities. Conclusion: Despite the limitations of our study, we showed the high prevalence of frailty in RRMM patients in the real-world (67.9%), which is significantly higher than in the overall ICARIA-MM trial population (28%) (Schjesvold et al 2021). Our study also demonstrated comparable efficacy outcomes between frailty subgroups (ORR/PFS/DOR), but a trend for worse toxicity outcomes in frail compared to intermediate-fit patients.

Rampotas:BMS: Honoraria; Sanofi: Honoraria. Basu:Sanofi, Pfizer, BMS: Consultancy, Speakers Bureau; Sanofi: Honoraria, Other: advisory board. Ramasamy:Takeda, Bristol Myers Squibb, Janssen, Amgen, GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; Sanofi, Adaptive biotech, Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.