Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC‐1 study of patients with relapsed/refractory multiple myeloma

Abstract

Background Teclistamab, a B‐cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC‐1 study. Cytokine release syndrome (CRS), a known manifestation of T‐cell redirection, was observed in 119 of 165 patients (72.1%). Methods Patients received once‐weekly teclistamab 1.5 mg/kg subcutaneously after two step‐up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. Results Most cases of CRS occurred during the step‐up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. Conclusions Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T‐cell–engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. Plain language summary Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC‐1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step‐up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step‐up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

CD8 effector T cells enhance teclistamab response in BCMA-exposed and -naïve multiple myeloma

“…Teclistamab dosing was as described in the MajesTEC-1 study, 8 and cytokine release syndrome (CRS) was diagnosed and managed in accordance with MSKCC institutional guidelines (SI methods A1), which are derived from standard recommendations. 16 The primary goal was to determine whether prior anti-BCMA therapy was associated with inferior outcomes with teclistamab. The study was approved by the MSKCC Institutional Review Board (IRB 18-143 and 14-276) and conducted in accordance with the Declaration of Helsinki and the Belmont report.…”

Teclistamab: Mechanism of action, clinical, and translational science

“…Most patients received supportive treatment for the management of CRS (110 of 119). Tocilizumab was administered to 36.4% of patients and did not affect the efficacy of teclistamab but decreased the risk of CRS recurrence compared to when tocilizumab was not used 14 . All CRS events fully resolved without treatment discontinuation.…”

“…Associations between CRS occurrence and baseline characteristics and demographics were also explored 14 . Baseline frequencies of some CD3+ and CD4+ T‐cell subpopulations expressing TIM‐3 and PD‐1 were associated with occurrence of CRS.…”

Teclistamab for Multiple Myeloma: Clinical Insights and Practical Considerations for a First-in-Class Bispecific Antibody

“…Though a number of additional immunosuppressive agents may be considered for refractory cases (Table 2), these interventions are rarely required with bispecific antibodies and thus experience with agents like anakinra and etanercept are primarily in CAR Ts. [48][49][50][51] Tocilizumab is highly efficacious for terminating CRS as well as for preventing recurrences and is typically the first agent used for teclistamab-related CRS. Side effects of tocilizumab include neutropenia (60%), headache (17%), diarrhea (8%), and a potential for increased rates of serious infections.…”

“…54 Furthermore, unlike tocilizumab, steroids did not reduce the rate of CRS recurrence in MajesTEC-1, with 77.8% of patients treated with steroids alone experiencing subsequent CRS events. 48 Prophylaxis against CRS is not standard practice at the time of writing. However, premedication with tocilizumab is being actively studied with a recent study of tocilizumab pretreatment prior to the FcRHxCD3 bispecific, cevostamab, reducing CRS incidence from 90.9% to 35.7% without impacting efficacy.…”