P-017: Impact of Genetic Ancestry on Outcomes and Toxicity of Ide-cel in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: CAR-T therapy has revolutionized RRMM treatment, but racial and ethnic disparities persist. We examined the influence of genetic ancestry, which has been linked to various myeloma cytogenetic and clinical features, on CAR-T efficacy and safety.

Methods: This retrospective single-center study included RRMM patients who underwent apheresis for idecabtagene vicleucel between 11/2018 and 02/2023 in clinical trials (KarMMa-2, KarMMa-3) or as standard of care (SOC). Data on demographics, disease features, treatment, and follow-up were extracted from medical records. Efficacy outcomes were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Safety outcomes were incidence and grade of CRS/ICANS, hematological toxicity, and infection. Number of medications and a revised HCT-CI score were used as measures of comorbidities. Genetic ancestry was estimated using ADMIXTURE from germline DNA genotyping. Patients were categorized by ancestral origin: African (AFR ≥75% or < 75%), European (EUR ≥50% or < 50%), and admixed (ADM ≥30% or < 30%). Comparisons used chi-squared tests and ANOVA. Associations with genetic ancestry were tested using logistic regression.

Results: Our analysis included 49 patients (10 trial, 39 SOC), 26 of whom self-identified as White, 13 as Black, and 10 as Hispanic/Latino. Median age was 60.1y (51.5-66.6). Those with AFR ≥75% had a higher rate of organ involvement (i.e. visceral extramedullary disease including myeloma renal disease; 67% vs 29%, P=0.03) and high bone marrow (BM) plasma cell burden with ≥50% involvement (56% vs 13%, P< 0.01) than AFR < 75%. Patients with EUR ≥50% had lower rates of organ involvement (24% vs 56%, P=0.03) and high BM plasmacytosis (10% vs 37%, P=0.02) than EUR < 50%. ECOG scores significantly differed at CAR-T referral, with AFR ≥75% associated with ECOG score ≥2 (67% vs 25%, P=0.02). ADM ≥30% was associated with higher BMI (35.6 vs 27.8 kg/m2; P=0.04). AFR ancestry was linked to a higher number of medications and more exclusions from clinical trials due to organ dysfunction, but baseline eGFR did not differ. High AFR ancestry was associated with risk of infectious complications (OR 7.82; 95% CI: 1.33-45.91; P=0.02) and grade 3+ neutropenia (OR 7.74; 95% CI: 1.18-50.77; P=0.03). Patients with higher AFR ancestry tended to have higher levels of inflammatory markers (ferritin and CRP). Ancestry was not associated with HCT-CI score or with ORR, PFS, OS, or rates of CRS/ICANS.

Conclusions: Our study highlights significant disparities in patient characteristics and treatment toxicity based on genetic ancestry. Patients with high AFR ancestry had more severe disease at baseline, higher ECOG scores, and greater rates of posttreatment severe neutropenia and infectious complications. Those with higher EUR ancestry had fewer baseline complications and severe adverse events. Our findings underscore the need to consider genetic ancestry in planning and prognosis for CAR-T therapy. Multivariate analysis is ongoing.