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Development of an Endothelial Activation and Stress Index (EASIX)-based predictive model for cytokine release syndrome and neurotoxicity after B-cell maturation antigen directed chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma

Bone Marrow Transplantation volume 60, pages 1079–1081 (2025)Cite this article

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The Endothelial Activation and Stress Index (EASIX) score [lactate dehydrogenase (LDH) (U/L) x creatinine (Cr) (mg/dL)/platelet count (109/L)] is a marker of endothelial dysfunction and was initially developed to predict overall survival (OS) after allogeneic hematopoietic cell transplantation [1]. Since CRS and ICANS are also driven through vascular endothelial activation, modifications of the EASIX score (EASIX with ferritin: EASIX-F; EASIX with ferritin and C-reactive protein (CRP): EASIX-FC; modified EASIX: mEASIX; and simplified EASIX: sEASIX) have been used to predict CRS and ICANS following CD19-directed chimeric antigen receptor T-cell therapy (CAR T) [2,3,4]. However, there are limited data on the utility of these scores in patients with relapsed/refractory multiple myeloma (RRMM) receiving BCMA (B-cell maturation antigen)-directed CAR T [5]. In this study, we sought to develop an EASIX-like model to predict CRS and ICANS after BCMA-directed CAR T, specifically for RRMM.

We retrospectively reviewed consecutive patients with RRMM at three US academic centers who received standard-of-care (SOC)/commercial BCMA-directed CAR T between May 1, 2021, and January 31, 2024. The data cutoff date was July 31, 2024, for safety and efficacy analyses. All patients received SOC CAR T after 4 or more prior lines of therapy and in the inpatient setting. None of the patients were treated with prophylactic tocilizumab or steroids to prevent CRS or ICANS. High-risk cytogenetics were defined as the presence of deletion (del) (17p), t(4;14), t(14;16), t(14;20), and/or gain or amp(1q) on FISH testing. We defined progression free survival (PFS) from date of CAR T infusion to disease progression or death, and OS from date of CAR T infusion to death due to any cause. Since we did not observe any deaths before the onset of CRS or ICANS during the first 14 days post CAR T infusion, we compared the incidence of CRS/ ICANS in different groups using Kaplan Meier estimates. We first assessed the utility of EASIX scores in predicting CRS and ICANS in the first 14 days after CAR T infusion. We then assessed the significance of these scores in addition to RRMM characteristics in predicting risk of CRS and ICANS using Cox models. All variables with a p value of <0.1 on univariate analysis were included in the multivariable model. We employed step wise backward elimination to arrive at the final predictive model.

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Fig. 1: Utility of EASIX based scores in predicting CRS and ICANS after BCMA-directed CAR T.

Data availability

De-identified data and analysis code used are available upon request to the corresponding authors.

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Author notes

  1. These authors contributed equally: Utkarsh Goel, Danai Dima.

  2. These authors jointly supervised this work: Leyla Shune, Jack Khouri.

Authors and Affiliations

  1. Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA

    Utkarsh Goel

  2. University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Danai Dima

  3. Department of Hematology/Medical Oncology, The Medical University of South Carolina, Charleston, SC, USA

    James A. Davis

  4. Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood, MO, USA

    Aliya Rashid, William Wesson, Evguenia Bhurtel & Leyla Shune

  5. Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    Louis Williams, Sandra Mazzoni, Fauzia Ullah, Joslyn Rudoni, Mikhaila Rice, Craig S. Sauter, Faiz Anwer, Shahzad Raza & Jack Khouri

  6. Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Yun Kyoung Ryu Tiger

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Contributions

UG, DD, and JK conceptualized the idea, designed the study, analyzed the data, and wrote the initial manuscript. UG, DD, JAD, AR, WW, LW, SM, EB, JR, MR, YKRT, CSS, FA, SR, LS, and JK provided study materials and collected data. JAD, AR, WW, LW, SM, EB, JR, MR, YKRT, CSS, FA, SR, and LS edited the manuscript. All authors approved the final manuscript version for submission.

Corresponding author

Correspondence to Utkarsh Goel.

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Competing interests

FA: Research Funding and Consultancy for BMS, Janssen, Allogene Therapeutics. JK: Consulting or advisory role for GPCR, Janssen, Prothena, Legend Biotech. Research funding for Prothena, Ascentage, Janssen, Karyopharm, GPCR. SR: Advisory board for Kite Pharma, Pfizer and Prothena biosciences. LW: Consulting for BMS, Janssen, Abbvie. CSS: Consultancy for Kite/a Gilead Company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, Ono Pharmaceuticals, MorphoSys, CSL Behring, Syncopation Life Sciences, CRISPR Therapeutics and GSK; Research Funding for Juno Therapeutics, Celgene/BMS, Bristol-Myers Squibb, Precision Biosciences, Actinium Pharmaceuticals, Sanofi-Genzyme and NKARTA. The remaining authors declare no competing interests.

Ethics approval and consent to participate

This study was IRB approved and was conducted under the Declaration of Helsinki. A waiver of informed consent was approved based on the retrospective nature of the study.

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Goel, U., Dima, D., Davis, J.A. et al. Development of an Endothelial Activation and Stress Index (EASIX)-based predictive model for cytokine release syndrome and neurotoxicity after B-cell maturation antigen directed chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma. Bone Marrow Transplant 60, 1079–1081 (2025). https://doi.org/10.1038/s41409-025-02612-3

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