Assessment of normal plasma cell biomarkers after arlocabtagene autoleucel (arlo-cel) treatment in patients with ≥3L relapsed refractory multiple myeloma (MM).

7530 Background: B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) are validated targets in MM. GPRC5D is expressed most strongly on MM cells with minimal expression on normal plasma cells (nPC), while BCMA is highly expressed on MM cells and nPCs. Anti-BCMA chimeric antigen receptor T cell therapy (CAR T) and T cell engagers (TCE), but not anti-GPRC5D TCE, are associated with B cell aplasia and worsened hypogammaglobulinemia. Uninvolved free light chain (uiFLC) and immunoglobulin G (IgG) were used as biomarkers of nPCs following treatment with arlo-cel, a GPRC5D-targeting CAR T therapy with promising efficacy and 19% grade 3/4 infection rate (Bal, et al. ASH 2024 Abstract 922), and treatment with a BCMA CAR T therapy. Methods: Clinical endpoints included treatment-emergent adverse events for patients treated with arlo-cel (NCT04674813; n = 84) and idecabtagene vicleucel (ide-cel, NCT03361748; n = 137). Biomarker analysis included complete responders (CR) treated with arlo-cel (n = 42) and ide-cel (n = 38). For uiFLC, Kaplan-Meier curves of time to clearance below the limit of detection (LOD; 1.3 mg/L for κ and 1.7 mg/L for λ) and time to first return above the LOD were used to calculate median time to event and compared using log-rank test. Logistic regression models adjusted for pre-treatment levels were used to test for differences in biomarker levels at specific time points. Hypogammaglobulinemia was defined as IgG levels < 500 mg/dL. Fisher’s exact test was used to compare infection rates. All analyses were restricted to the first 6 months after infusion. P-values less than 0.1 were considered statistically significant. Results: Arlo-cel cleared uiFLC below the LOD in 67% of CR compared to 100% of ide-cel CR (p < 0.0001). When cleared, time to uiFLC clearance was the same (median = 29 days; p = 0.82), but time to return above the LOD was significantly faster for arlo-cel (median = 101 days) than for ide-cel (median = 264 days; p = 0.001), indicating faster nPC recovery for arlo-cel. Post-infusion uiFLC concentrations were lower in ide-cel CR at 2 (p = 0.09), 4 (p = 0.05), 5 (p = 0.02), and 6 months (p = 0.09) compared to arlo-cel. Despite more post-infusion intravenous immunoglobulin usage for ide-cel vs arlo-cel CR (89% vs 26%), IgG levels were lower for ide-cel CR at 2 (p = 0.09) and 3 months (p = 0.01). Among treated patients, the proportion with hypogammaglobulinemia at 3 months (p = 0.05) and the 6-month infection rate (p = 0.03) were lower for arlo-cel. Conclusions: Arlo-cel patients had higher levels of uiFLC from months 2–6, demonstrating greater anti-tumor specificity and preservation of humoral immunity. As a result, arlo-cel has the potential to achieve lower rates of hypogammaglobulinemia and infections compared to BCMA-targeting therapies, with fewer interventions. Clinical trial information: NCT04674813 .