Introduction: T cell-based immunotherapies (TCI) such as chimeric antigen receptor T cells (CAR T) and T cell engagers (TCEs) have revolutionized the treatment of relapsed/refractory (R/R) multiple myeloma (MM). Loss or downregulation of tumor antigen expression are key mechanisms of treatment failure, yet strategies to modulate their cell surface expression remain largely unexplored. Our recent work1 uncovers BCMA, a key target in MM, as a short-lived, K48-polyubiquitylated protein at the plasma membrane undergoing p97-dependent degradation via the ubiquitin-proteasome system. Proteasome inhibition (PI) with Carfilzomib (CFZ) markedly upregulated BCMA expression, enhancing the CAR T efficacy in vitro and in vivo. Treatment of patients (pts) with CFZ post CAR T relapse under the compassionate use „CarCAR“ program, enhanced BCMA expression levels in all pts, with clinical responses observed only in those with residual CAR T cells, indicating restored CAR T cell function.

Aim: Building on the above-outlined evidence that PIs such as CFZ can upregulate BCMA expression and restore/enhance CAR T efficacy, this project aims to systematically investigate PI pre-treatment with CFZ as a surrogate for subsequent CAR T response in the real-world setting.

Methods: This retrospective observational study included pts with R/R MM treated with BCMA-directed CAR T at our German academic center between 2022 and 2025. The study evaluated pre-treatment with CFZ prior to CAR T infusion, focusing on timing and interval between CFZ administration and CAR T therapy. Outcomes assessed included post CAR T overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and laboratory parameters such as CAR T peak expansion. Pts without prior CFZ treatment were excluded from the analysis.

Results: Among the n=75 TCI treated pts (CAR T and TCE) included in the analysis, we identified n=34 pts who received anti-BMCA CAR T therapy (comprising n=31 with MM, n=1 with POEMS, and n=2 with plasma cell leukemia) following prior CFZ treatment, with evaluable data sets. Median age was 66 years (range 37-79) with a female to male ratio of 1.13:1. For CFZ-based treatment, the median line of therapy was 3 (range: 1–6), whereas CAR T therapy was administered at a median of 4th line, ranging from 2 to 11. We here focused on in-depth analysis of optimal time intervals between CFZ administration prior to CAR T therapy. We observed that a shorter interval of 0–5 months between CFZ pre-treatment and subsequent CAR T infusion was associated with significantly higher overall response rates (ORR) at both day 30 and month 3 post-CAR T (p=0.01 and p=0.006, respectively), compared to intervals of 6 months and longer (up to a maximum of 48 months). A product-specific analysis limited to pts who received Ciltacabtagene autoleucel yielded similar results, reinforcing these findings. The median PFS was 15.6 months in the 0–5 month CFZ pre-CAR T interval group, compared to 9 months in the group with intervals of 6 months or longer (p=0.58). OS was not reached for either cohort. At 12 months, the estimated survival rate was 90.9% for the 0–5 month interval group compared to 68.9% for the group with intervals of 6 months or longer. At 15 months, survival rates were 79.5% versus 57.4%, respectively. CRS rates (83.3% vs. 100%, p=0.09) and ICANS incidence (11.1% vs. 0%, p=0.17) were comparable between groups. The median peak CAR T expansion occurred on day 14 vs. day 12.5 (n.s., p=0.40). A multivariable logistic regression analysis, adjusting for factors such as age, CAR T product and therapy line, remission status prior to infusion, EMD and other high risk disease factors, is currently underway and will be presented at the meeting. An expansion to multiple German and US academic centers is in progress as part of a comprehensive multicenter real-world data analysis initiative.

Conclusion: Shorter intervals, including bridging strategies that involve BCMA upregulation through proteasome inhibition with carfilzomib, may improve response rates and survival outcomes in patients receiving subsequent BCMA-directed CAR T therapy, without elevating toxicity. This strategy aiming to enhance deep eradication of MM cells may prove beneficial towards potential cure of certain MM subgroups.

  • Rieger L,…, Hecker JS*, Bassermann F*. Boosting CAR T Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens. Blood 2025 Jul 10. DOI: doi.org/10.1182/blood.2024027616

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2025
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