Model-Based Exploration of the Impact of Prophylactic Tocilizumab on IL-6 Dynamics in Multiple Myeloma Patients Receiving Teclistamab Treatment
Authors: Zhou Jia , Vishwamitra Deeksha , Guo Yue , Verona Raluca , Perales-Puchalt Alfredo , Stephenson Tara , Hodin Caroline , Banerjee Arnob , Chastain Katherine , Haddish-Berhane Nahor , Wang Weirong 
Published: February 2025

Objectives: Teclistamab (tec), the first approved B-cell maturation antigen × CD3 bispecific antibody (BsAb) with weight-based dosing for the treatment of patients (pts) with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Within MajesTEC-1 study (NCT03145181/NCT04557098)1-3, the phase 1 exploratory prophylactic tocilizumab (toci) cohort previously demonstrated that a single dose of prophylactic toci (administered up to 4 hrs before the first step-up dose (SUD) of (tec)) reduced the overall incidence of cytokine release syndrome (CRS) to 26% after tec treatment3,4. As a competitive antagonist, toci inhibits the IL-6 pathway by competing with IL-6 for binding to the soluble IL-6 receptor (sIL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6 and thereby blocking IL-6 signaling. By blocking IL-6R, toci reduces IL-6R–mediated IL-6 clearance, leading to an increase in serum IL-6 levels5. A mechanism-based PK/PD model was used to evaluate the impact of toci prophylactic treatment on the sIL-6R/IL-6, and the duration of blockade of IL-6 signaling pathway in pts following tec treatment. Methods: The model was built by using reported toci PK parameters and sIL-6R target engagement. The time course of IL-6R RO for pts receiving prophylactic toci following tec treatment was estimated from the PK of toci and competitive binding kinetics. Among the pts with evaluable serum IL-6 levels, the highest peak IL-6 level in the pts without CRS (N&#3f9) from prophylactic toci cohort of MajesTEC-1 was selected as the worst-case scenario. The IL-6R RO in pts receiving prophylactic toci in the worst-case scenario was characterized by model simulations and were compared to the calculated IL-6R RO in the cohorts following tec treatment without prophylactic toci (N&#3f40). Results: Among the pts who received prophylactic toci, the median and highest peak serum IL-6 levels were 208.6 pg/mL and 1701.8 pg/mL in patients without CRS, respectively. The model simulation showed that a single dose of toci at 8 mg/kg IV given prophylactically could lower the IL-6R RO by IL-6. In a pt with 1700 pg/mL of serum IL-6 treated with toci, IL-6R RO was maintained below the level of RO achieved with 10 pg/mL of serum IL-6 in the absence of toci for approximately 10 days. An IL-6 level of 10 pg/mL was considered as a representative value in the pts without CRS following tec at the approved dosing regimen without prophylactic toci, as more than half (58%) of these patients showed peak serum IL-6 level below 10 pg/mL. The duration of IL-6R RO reduction covers the two SUDs and the first full treatment dose according to the tec approved dosing schedule. Conclusions: The modeling and simulation results showed that a single dose of toci given prophylactically at 8 mg/kg could block IL-6R RO for approximately 10 days following the 1st SUD of tec. The results further support this approach for lowering overall risk of CRS during the SUD schedule in RRMM pts treated with tec.Citations: 1. TECVAYLI (teclistamab). Summary of product characteristics. Leiden, Netherlands: Janssen Biologics BV; 2022. 2. TECVAYLI (teclistamab-cqyv). Prescribing information. Horsham, PA: Janssen Biotech, Inc; 2022. 3. Moreau P, et al. N Engl J Med 2022;387:495-505. 4. van de Donk NWCJ, et al. J Clin Oncol 2023;41(suppl 16):8033. 5. Uchiyama Y, et al. Int Immunopharmacol 2008;8:1595-601.The results in this abstract have been previously presented in part at the 65th American Society of Hematology (ASH) Annual Meeting; December 9–12, 2023; San Diego, CA, USA and published in the conference proceedings as abstract 4670