P946: tocilizumab pre-treatment significantly reduces the incidence of cytokine release syndrome in patients with relapsed/refractory multiple myeloma (rrmm) who receive cevostamab

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Interleukin (IL)-6 receptor blockade with the monoclonal antibody tocilizumab (TCZ) is an established strategy for the management of cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cells and bispecific antibodies. TCZ pre-treatment could prevent or limit the emergence and/or severity of CRS. Aims: To assess whether a single dose of TCZ given prior to the initiation of cevostamab, a FcRH5xCD3 bispecific antibody, reduces the incidence of CRS in patients (pts) with RRMM. Methods: A dedicated TCZ pre-treatment arm was included in the ongoing GO39775 Phase I study (NCT03275103) of cevostamab. Pts with RRMM for which no established therapy was available, appropriate, or tolerable were enrolled. A single 8mg/kg intravenous (IV) dose of TCZ was given 2 hours before the initiation of IV cevostamab at the 3.6mg step-dose level on Day (D) 1 of Cycle (C) 1; cevostamab was continued at the 90mg target-dose level on C1D8 and D1 of each subsequent 21-day cycle. Data from the corresponding 3.6/90mg non-TCZ group were used as a retrospective comparator. Corticosteroid, antihistamine, and acetaminophen pre-medication was given to all pts prior to cevostamab. ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019) were used to report CRS. All pts provided written informed consent. Results: At cut-off (August 22, 2022), 75 pts had enrolled (TCZ group: 31 pts; non-TCZ: 44; median age: 63 years in both groups). Median prior lines of therapy was 4 in the TCZ group and 6 in the non-TCZ (range: 2–11 in both groups). Most pts were triple-class refractory (TCZ group: 80.6%; non-TCZ: 86.4%) and many were penta-drug refractory (TCZ group: 45.2%; non-TCZ: 72.7%). Median follow-up was 8.5 months in the TCZ group (range: 1.1–16.8) and 12.8 months in the non-TCZ (range: 0.2–36.3). The overall rate of CRS was significantly lower in the TCZ group than in the non-TCZ (38.7% vs 90.9%, respectively; p<0.001; Figure). Grade (Gr) 3 CRS occurred in 2 pts (one in each group). No Gr 4–5 CRS occurred. In C2+, no CRS events were observed in the TCZ group vs 5 events in the non-TCZ group. Overall rates of non-CRS adverse events were generally comparable, with the exception of neutropenia (TCZ: 71.0%; Gr 3–4: 67.7%; non-TCZ: 38.6%, all Gr 3–4). Notably, neutropenia was reversible, manageable with growth factor where indicated, and did not lead to discontinuation. No negative impact on the anti-myeloma activity of cevostamab was observed in the TCZ group. Overall response rates were 54.8% (95% CI: 35.7–74.0) and 37.2% (95% CI: 21.6–52.8) in the TCZ and non-TCZ groups, respectively. Very good partial response or better rates were 32.3% and 25.6%, respectively. At cut-off, median duration of response was 11.3 months (range: 1–12) in the TCZ group and 10.9 months (range: 1–34) in the non-TCZ group. Peak IL-6 levels after the 3.6mg step dose were significantly higher in the TCZ group (median: 2311pg/mL) than in the non-TCZ group (median: 245pg/mL), likely due to TCZ-mediated reduction in IL-6 clearance. However, the peak level of C-reactive protein, a downstream marker of inflammation, was significantly lower in the TCZ group (median: 4mg/L) relative to the non-TCZ group (median: 123mg/L), suggesting near complete suppression of the IL-6-mediated signalling pathway. Summary/Conclusion: TCZ pre-treatment significantly reduces the incidence of CRS in pts with RRMM who receive cevostamab. Importantly, TCZ pre-treatment has no negative impact on the anti-myeloma activity of cevostamab.Keywords: Cytokine release syndrome, Antibody, Bispecific, Multiple myeloma