Defining the Rates of Cytokine Release Syndrome Associated with Talquetamab Step-up Doses

Introduction/Background: Talquetamab (Talq) is a first-in-class bispecific T-cell engager antibody directed against G protein-coupled receptor class C group 5 member D (GPRC5D), approved to treat patients with relapsed/refractory multiple myeloma (RRMM) after at least 4 lines of therapy (including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody). In the MonumenTAL-1 study, an overall response rate was noted in 70% of patients with 23% achieving a complete response. Cytokine release syndrome (CRS) occurred during the step-up dosing phase at a rate of 77%; however, there was no breakdown of CRS rates by step-up dose (SUD). This study sought to characterize CRS rates after each Talq SUD in a real-world setting to discern whether patient hospitalization is required for the entire period of the step-up dosing schedule. Methods: In this retrospective single-center study, patients with RRMM who received Talq between September 2023 and July 2024 were identified via the institutional plasma cell disorder research database. Patients were included if they completed the step-up dosing phase for the weekly or biweekly dosing schedule. Chart review was performed to collect various patient and disease characteristics, including demographics, cytogenetic risk, prior lines of therapy (LOT), start dates of Talq SUDs, and CRS onset/grades. The Chi-square/Fisher exact test was used to compare CRS rates after each Talq SUD. Differences in time to onset of CRS between the SUDs were compared using the Kruskal Wallis test. Univariate and multivariate logistic regression analysis were performed to assess the impact of prior exposure to T-cell redirection therapy (TCRT) on CRS incidence. Statistical analyses were performed using IBM SPSS statistics (version 27). Results: 40 patients who completed the Talq step-up dosing phase were included in this analysis, including 17 who received the biweekly step-up dosing schedule. The median age was 66 years (range: 41-85 years), and 42% (n=17) were male. The median number of prior LOT was 7 (range: 4-16), and 69% (n=27) had prior TCRT. High risk cytogenetic features [t(4;14), t(14;16), t(14;20), TP53 mutations, del(17p) and 1q amplification] were present in 50% (n= 20) of patients. With an overall incidence of 75%, CRS occurred at a rate of 30% (n=12), 33% (n=13), 10% (n=4) and 6% (n=1) with SUD1, SUD2, SUD3 and first full dose (FFD, p=0.03), respectively. Pairwise comparisons revealed statistically significant differences in CRS rates between SUD1 and SUD3 (p=0.047), SUD2 and SUD3 (p=0.026), SUD1 and FFD (p=0.001) as well as SUD2 and FFD (p=0.001). Grade 2 CRS occurred in 5% of patients with SUD1, 15% with SUD2, 5% with SUD3 and 0% with FFD (p=0.40). Logistic regression analysis indicated no association between prior exposure to TCRT and CRS incidence (OR: 0.62, 95% CI: 0.13-2.60; p=0.61). The median time to onset of the first CRS event was 20 hours (range: 11-40 hours), 14 hours (8-48 hours), 28 hours (24-31 hours) and 31 hours after SUDs 1, 2, 3 and FFD (p=0.33), respectively. Conclusion: Our real-world data indicated that the Talq FFD was well tolerated, characterized by a significantly low incidence and severity of CRS events. Reducing the length of hospital stay with the Talq step-up dosing schedule, and administration of Talq FFD in outpatient settings could be considered in clinical practice.