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    Myeloma Genomics and Microenvironment and immune profiling

    (OA-32) Idecabtagene Vicleucel (ide-cel) and Endogenous Immune Profiles Linked to Progression-Free Survival in Relapsed/Refractory Multiple Myeloma (RRMM) Patients

    Thursday, September 18, 2025
    16:40 - 16:50 East Coast USA Time
    Location: Room 718

      Abstract Presenter(s)

    • Bruno Paiva, PhD

      Director Flow Cytometry Core
      Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
      Pamplona, Navarra, Spain

    Introduction: Resistance to anti-BCMA CAR T therapy remains a significant challenge. Improved understanding of how T-cell fitness prior to aphaeresis determines efficacy, and if CAR-T and endogenous T-cell phenotypes associate with progression-free survival (PFS), is needed to aid in patient selection and development of future therapies with greater activity.

    Methods: We characterized immune dynamics and investigate its prognostic value in 120 RRMM patients treated with ide-cel in the KarMMa trial. Multidimensional and computational flow cytometry was performed in 266 bone marrow aspirates collected before and at months 1, 3, 6 and 12 after ide-cel infusion. 116 endogenous T-cell and 43 CAR T clusters were systematically quantified in a pileup analysis.

    Results:

    There were no differences observed in T-cell phenotypes at screening according to the number of years between diagnosis and treatment, ISS, tumor burden, number of prior lines of therapy, and prior stem cell transplantation. That notwithstanding, there were 41 T-cell clusters significantly associated with PFS. The clusters linked to higher risk of progression and/or death (HR ≥ 3.0) were defined by GrzmB expression in CD8+ and CD4+/CD8+ T cells, as well as by antigen-dependent differentiation markers such as CD27, CD95, CD45RA and CCR7. Patients having lower percentages of cytolytic and effector CD8 T cells showed longer PFS.

                Of the 76 patients profiled at month 1 after infusion, 55 had detectable CAR-T cells and in 16/55 the percentage was >1%. These patients showed significantly longer PFS when compared to those with < 1% CAR-T cells (medians of 15 vs 8 months, p=.015). A CD4/CD8 CAR-T cell ratio >0.09 also identified patients with longer PFS (medians of 11 vs 7 months, p=.007). In addition, the CD8+PD1+TIM3+, CD4+CD8+ GranzB+ and CD8+GranzB+HLADR+ CAR T clusters showed the strongest association with risk of progression and/or death (HR ranging from 2.4 to 6.4). Patients having higher percentages of cytolytic and potentially exhausted CAR T clusters showed inferior PFS.

                There is limited understanding of how the phenotype of endogenous T cells is modified after CAR-T infusion and potential tumor-antigen stimulation with tumor lysis. Notably, 47 of the 116 endogenous T-cell clusters were prognostic at the latest assessment performed after CAR-T infusion. Higher percentages of CD4+ stem central memory T cells (HR: 0.3, p=.007) and lower percentages of ICOS+ Tregs (HR: 5.25, p=.006) showed the strongest association with longer PFS.

    Conclusions: This is one of the largest studies of dynamic immune profiling in RRMM patients treated with anti-BCMA CAR T cells. We uncovered that T-cell phenotypes prior to aphaeresis are associated with PFS. Furthermore, CAR-T phenotypes after infusion may be as prognostic as its percentage. We also showed how CAR T cells modulate endogenous T-cell tumor surveillance. Altogether, this study supports immune profiling for improved understanding of response and resistance to CAR T cells in RRMM.