Predictors and Characterization of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) in Patients with Multiple Myeloma Receiving Teclistamab
Authors: Pasvolsky Oren , Afrough Aimaz , Feng Lei , Dong Wenli , Richards Tiffany , Davis James A , Dima Danai , Grajales-Cruz Ariel , Vazquez-Martinez Mariola A , Sannareddy Aishwarya , Goel Utkarsh , Banerjee Rahul , Gaballa Mahmoud R. , Lieberman-Cribbin Alex , Rana Masooma S , Julian Kelley , Ferreri Christopher J , Shune Leyla O. , DeJarnette Shaun , Ouchveridze Evguenia , Susanibar-Adaniya Sandra , Portuguese Andrew J. , Forsberg Peter A. , Hosoya Hitomi , Mikkilineni Lekha , Kaur Gurbakhash , Rossi Adriana , Herr Megan M , Eberwein Erin , Lin Chenyu , Blue Brandon , Raza Shahzad , Lin Yi , McGuirk Joseph P. , Atrash Shebli , Sborov Douglas W , Voorhees Peter M. , Anwer Faiz , Hansen Doris K. , Patel Krina K. , Sidana Surbhi , Cowan Andrew J. , Anderson Larry D , Richard Shambavi , Garfall Alfred L. , Lee Hans C. , Khouri Jack 
Published: December 2024

Background: Teclistamab (Tec) received regulatory approval for the treatment of relapsed refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. The risk of CRS and ICANS with Tec is well established with a manufacturer's recommendation of inpatient observation for 48-hours for CRS/ICANS monitoring after the initial 3 step up doses. There are limited real-world data on the characteristics of and risk factors for CRS and ICANS with Tec. Such data could inform management of Tec patients (pts), including patient selection for inpatient or outpatient step-up dosing.
Methods: RRMM pts treated with standard-of-care Tec across 13 U.S. academic institutions were included in this analysis. The follow-up data cutoff was 30 April 2024. CRS and ICANS classification was based on the American Society for Transplantation and Cellular Therapy consensus grading criteria. Multivariable logistic regression models were fitted to estimate the effects of covariates on CRS and ICANS events, with a particular focus on grade ≥2 CRS, any-grade ICANS, and the combination of CRS grade ≥2 and/or any-grade ICANS.
Results: 385 pts were included in the analysis, with a median of 6 lines of prior therapy. Median age was 68 years (range 31-92), 88 patients (25% of pts with available data) had ECOG ≥2, and 301 pts (78%) would have been ineligible for MajesTEC-1. 48 (33%) of 145 evaluable pts with a baseline bone marrow (BM) prior to Tec had &gt;50% BM plasma cells, 139 pts (36%) had extramedullary disease (EMD) (either paraskeletal or true-EMD) and 5 pts (1%) had plasma cell leukemia prior to start of Tec. 224 pts (59%) received Tec with an accelerated step-up dosing regimen, defined as having at least one step-up dose interval of ≥ 2 days.
220 pts (57%) developed any-grade CRS [Grade 1: 46% (N=179), grade 2: 10% (N=37), grade 3: 0.8% (N=3), grade 4: 0.3% (N=1)]. Median time to CRS from start of Tec was 3 days (range, 0-15). Fifty-four pts (14%) developed any-grade ICANS [Grade 1: 7% (N=26), Grade 2: 5% (N=18), grade 3: 3% (N=10), grade 4: none]. There were no grade 5 CRS or ICANS events. Median time to onset of ICANS from start of Tec was 4 days (range, 0-25). There was one case of hemophagocytic lymphohistiocytosis in the entire cohort. 38% of pts received tocilizumab and 17% of pts received corticosteroids.
In univariate analysis (UVA), baseline platelet &lt;50, triple-class refractory, penta-refractory status, and EMD prior to start of Tec were associated with increased risk for CRS grade ≥2 (p-values &lt;0.1) and incorporated in MVA.
Baseline platelet &lt;50, age &gt;60, ECOG ≥2, Hgb &lt;8 g/dL, BM plasma cells &gt;50%, and ferritin or CRP in the upper quartile were associated with increased risk for any-grade ICANS in UVA (p-values &lt;0.1).
Baseline platelet &lt;50, ECOG ≥2, Hgb &lt;8 g/dL, BM plasma cells &gt;50%, ferritin or CRP in the upper quartile, and prior BCMA exposure were associated with increased risk of CRS grade ≥2 and/or any-grade ICANS in UVA (p-values &lt;0.1).
Accelerated step-up dosing, renal impairment (CrCl &lt; 30 mL/min) and baseline LDH in the upper quartile were not associated with an increased risk of either CRS or ICANS in UVA.
Baseline BM plasma cells &gt;50% was excluded from multivariable analysis (MVA) due to high number of missing data, since most pts (62%) did not undergo BM biopsy prior to start of Tec.
In MVA, risk factors for CRS grade ≥2 included baseline platelet &lt;50 at the start of Tec treatment (OR: 2.35, 95% CI 1.08-5.08; p=0.03) and penta-refractory disease (OR: 2.48, 95% CI 1.13-5.45; p=0.02). Risk factors for any-grade ICANS included platelet &lt;50 (OR: 4.18, 95% CI 1.88-9.28; p=0.0004), age &gt;60 (OR: 7.54, 95% CI 1.63-34.89; p=0.01) and CRP in the upper quartile (OR: 2.51, 95% CI 1.16-5.43; p=0.02). Risk factors for CRS grade ≥2 and/or any-grade ICANS included platelet &lt;50 (OR: 2.65, 95% CI 1.42-4.94; p=0.002) and ECOG ≥2 (OR: 2.07, 95% CI 1.19-3.61; p=0.01).
Conclusions: This real-world analysis of RRMM pts treated with Tec revealed comparable rates CRS and ICANS relative to the MajesTEC-1 study, and these were mostly limited to grade 1/2. MVA demonstrated a significantly higher risk of CRS grade ≥2 and/or any-grade ICANS in pts with baseline platelet &lt;50 and/or ECOG ≥2, the former may reflect BM disease burden. These results may help identify pts who are at higher risk for IEC related toxicities with Tec that would warrant inpatient monitoring during initial step-up dosing.
OP, AA, & LF: co-first authors. AG, HCL & JK: co-senior authors