Introduction. Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell therapy (CAR-T) approved for patients with triple-class exposed relapsed/refractory multiple myeloma (TCE RRMM) (Munshi NC, et al. N Engl J Med 2021;384:705-716). Treatment-related toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are prevalent and common to all CAR T-cell therapies. We examined the association of serum cytokines and pre-CAR-T bone marrow composition with toxicity and early response among patients with TCE RRMM treated with ide-cel.

Methods. Patients treated with commercial ide-cel at H. Lee Moffitt Cancer Center between May 5 th, 2021 to May 18 th, 2023, and that consented to a biospecimen collection protocol, were included. Serum cytokine levels (GM-CSF, IL2, IL6, IL15, IFNγ, Angiopoietin 1&2 [ANG1, ANG2] and TNFα) were measured at apheresis, pre-lymphodepleting (LD) chemotherapy (day -6), infusion (D0) and at least weekly until day 28 using the Ella system (ProteinSimple). Inflammatory markers (C-reactive protein [CRP], ferritin, and albumin) at pre-LD were measured in the clinical laboratory. Marrow biopsy plasma cell burden (PCB) and marrow aspirate immune cell phenotyping of T cells, myeloid cells, and natural killer (NK) cells by flow cytometry were calculated prior to LD. High PCB was considered ≥50% CD138+ plasma cells. CRS and ICANS were graded per the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. Patient characteristics, cytokines, and other biomarkers were examined by any grade and ≥ grade 2 CRS and ICANS and day 90 (D90) response using Wilcoxon rank sum or chi-square tests.

Results. 86 patients were included, and 30 (35%) were analyzed by flow cytometry. Patient characteristics included a median age of 66 years (range, 43-83), 30% high PCB, 33% high-risk cytogenetics, and a median of 6 prior lines of therapy (range 4-13). Any grade CRS occurred in 80% of the patients, ≥ grade 2 CRS in 19%, any grade ICANS in 14%, and ≥ grade 2 ICANS in 10%. Tocilizumab was administered to 65%, 29% received steroids, and 2% received anakinra. At D90, 52/78 (67%) had achieved ≥ partial response (PR) and 26/78 (33%) had either stable disease (SD), progressive disease (PD) or had died. Three deaths occurred by D90 and were attributed to complications of myeloma progression.

Older patients (≥ 65 years) were more likely to develop any grade CRS (p=0.04) and ICANS (p=0.047), and those requiring bridging chemotherapy were more likely to develop ICANS (p=0.025). High PCB was not associated with CRS or ICANS, but was associated with T cell exhaustion and increased CD56 dim NK-cells (p<0.05, Figure A).

At apheresis, patients with higher TNFα levels were more likely to develop ICANS (p=0.004), but no other cytokines were associated with toxicity at this timepoint, although patients with CRS and ICANS had numerically higher IL-6. At LD, elevated ratio of ANG2/ANG1 (p=0.029), IL-15 (p=0.019), and high CRP/low albumin ratio (p=0.007) were observed for patients that developed ICANS. Higher peak cytokines, ferritin, and CRP were associated with any grade CRS (p<0.05), and higher peak IL6 was associated with grade ≥ 2 CRS (p=0.03). Patients that developed any grade ICANS had higher peak IL6, IL15, ANG2 /ANG1 ratio, ferritin, and CRP (p<0.05), and these associations persisted for IL15, ANG2/ANG1 ratio, ferritin, and CRP for grade ≥ 2 ICANS (p<0.05). Achievement of ≥PR at D90 was associated with higher peak levels of GM-CSF, IL2, IFNγ, and TNFα (p<0.05, Figure B).

Conclusion. In this analysis of real-world TCE RRMM patients treated with commercial ide-cel, inflammatory markers, pre-treatment marrow plasma cell burden, and immune cell subsets were associated with treatment-related toxicities and early responses. These findings provide insights into potential avenues for toxicity prevention and therapeutic optimization in high-risk patients. Additional studies in a larger patient cohort are warranted to understand the complex relationships between inflammation, immunity, toxicity, and efficacy among TCE RRMM patients treated with ide-cel.

Hansen:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; International Myeloma Society Young Investigator Award: Research Funding; Pentecost Family Myeloma Research Center: Research Funding; OncLive: Honoraria; Survivorship: Honoraria; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Peres:Pentecost Family Myeloma Research Center: Research Funding; National Institute of Health/National Cancer Institute: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding. Abraham Miranda:Moffitt Cancer Center: Current Employment. Huggar:Bristol Myers Squibb: Current Employment. Patwardhan:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Oswald:H. Lee Moffitt Cancer Center and Research Institute: Current Employment; Pentecost Family Myeloma Research Center: Research Funding; Dana-Farber Cancer Institute: Consultancy. Grajales-Cruz:Janssen: Membership on an entity's Board of Directors or advisory committees; Cellectar: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau. Blue:Janssen: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Kite Pharmaceuticals: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Liu:BioLineRx: Membership on an entity's Board of Directors or advisory committees. Nishihori:Moffitt Cancer Center: Other: Personal fees from Karyopharm and Novartis outside the submitted work; Medexus: Speakers Bureau. Shain:Takeda: Honoraria; Adaptive: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Karyopharm: Research Funding; AbbVie: Research Funding. Baz:Karyopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria; Regeneron: Research Funding; HIKMA Cancer Network: Honoraria; Curio Science: Honoraria; AHOMPR: Honoraria; ASH: Honoraria. Alsina:Bristol Myers Squibb: Consultancy, Research Funding; Janssen Oncology: Consultancy, Speakers Bureau; RevHealth LLC, Red Med LLC: Honoraria; Genzyme: Consultancy, Honoraria. Castaneda:Adaptive Biotechnologies: Speakers Bureau; Moffitt Cancer Center: Current Employment. Tiwana:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Botros:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Locke:BioPharma Communications CARE Education: Other: Institutional; Aptitude Health: Other: Travel Support; Caribou: Consultancy; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GammaDelta Therapeutics: Consultancy; Cowen: Consultancy; Daiichi Sankyo: Consultancy; EcoR1: Consultancy; CERo Therapeutics: Other: (Institutional); Calibr: Consultancy; Cellular Medicine Group: Consultancy; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Travel Support; Emerging Therapy Solutions: Consultancy, Other; Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinical Care Options Oncology: Other; Society for Immunotherapy of Cancer: Other; National Cancer Institute: Other; Imedex: Other; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group (GLG): Consultancy; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Freeman:Celgene: Consultancy, Honoraria; ONK Therapeutics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

Figure 1
Figure 1
View largeDownload slide
This content is only available as a PDF.
2023
Sign in via your Institution