Low dose tocilizumab for mitigation of cytokine release syndrome with bispecific antibodies in relapsed/refractory multiple myeloma

Abstract Introduction/background: Cytokine release syndrome (CRS) is one of the most common adverse effects of bispecific antibodies (BsAbs) during the step-up dosing (SUD) phase of treatment. The addition of tocilizumab (Toci) at 8 mg/kg to pre-medication regimen (dexamethasone, acetaminophen and diphenhydramine) proved to be an effective mitigation strategy where CRS rates declined significantly from 72-80% to 14-30%. These findings prompted the National Cancer Comprehensive Network (NCCN) to recommend Toci as a pre-medication for CRS prophylaxis in the recent multiple myeloma guidelines. Based on published evidence regarding cytokine storm prevention with 4 mg/kg of Toci among patients with COVID-19 infections, we are reporting our center's experience using low-dose Toci (Toci-lo) for preventing CRS during the BsAbs SUD phase of treatment. Methods: Patients with relapsed/refractory multiple myeloma (RRMM) who were hospitalized for initiating BsAbs and received prophylactic Toci-lo administered prior to the first SUD per institutional guidelines were included (cohort 1). For comparison, a historic cohort of patients that did not receive Toci prophylaxis during the SUD phase was selected (cohort 2) using the institutional plasma cell disorders database after matching for the following: disease characteristics (high risk cytogenetic features, presence of extramedullary disease, elevated LDH), type of BsAbs, prior exposure to T-cell redirection therapies (TCRT) and absolute lymphocyte count. CRS was graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. The Fisher's exact/Chi-square test was used to compare CRS rates between the two cohorts. Univariate/multivariate logistic regression analysis was performed to estimate the CRS risk with Toci prophylaxis. All statistical analyses were performed using IBM SPSS statistics (version 26). Results: 64 patients were included in the analysis (33 in cohort 1 and 31 in cohort 2); baseline characteristics were comparable between the two cohorts except for the number of prior lines of therapy (cohort 1: 5, range: 2-11 and cohort 2: 7, range: 3-12; p=0.01); 18% (n=6) and 19% (n=6) were exposed to TCRTs (chimeric antigen receptor- T cells, CAR T-cells: 2, BsAbs: 2 and both: 2) in cohorts 1 and 2, respectively; high risk cytogenetics [17p del, TP53, gain/amp 1q, t(4;14), t(14;16) and t(14;20)] were present in 52% (n=17) of the patients in cohort 1 and 29% (n=9) in cohort 2 (p=0.08). Extramedullary disease was found in 36% (n=12) of patients in cohort 1 compared to 23% (n=7) in cohort 2 (p=0.28). Teclistamab was administered to 58% of the patients in both cohorts 1 (n=19) and 2 (n=18). Talquetamab was administered to 32% (n=11) and 29% (n=9) of patients in cohorts 1 and 2, respectively. The remaining patients in both cohorts received elranatamab (cohort 1: 10% and cohort 2: 13%). The CRS rate was significantly lower in cohort 1 (n=7; 21%, 95% CI:10.7-37.8%) compared to cohort 2 (n=17; 55%, 95% CI: 38.0-70.8%; p=0.009). Based on univariate and multivariate analyses (adjusted for prior lines of therapy), prophylactic use of Toci-low was associated with a significant reduction in the incidence of CRS during the SUD phase with an odds ratio of 0.2 (95% CI: 0.06-0.65; p=0.01). All CRS events were treated with Toci 8 mg/kg. Most of the CRS events occurred following SUD1 (57% in cohort 1 and 58% in cohort 2). The rate of grade 2 CRS was 0% in cohort 1 compared to 17% in cohort 2 (n=3; p=0.50). Recurrent CRS events were noted only in a single patient from cohort 1 and 26.0% (n=6) in cohort 2 (p=0.64). The rate of neurotoxicity/immune effector cell-associated neurotoxicity syndrome (ICANS) was 6% in cohort 1 (n=3) and cohort 2 (n=2). One patient in each cohort developed grade 2 neurotoxicity/ICANS which resolved more than 48 hours following management per institutional guidelines. Cost-effectiveness analysis of Toci-lo will be shared at the ASH meeting. Conclusion: Based on our findings, a single prophylactic Toci-lo proved to be an effective approach which can be utilized as an option to reduce CRS incidence during the SUD phase of BsAbs treatment.