Abecma (idecabtagene vicleucel)

ORR was 75.4% (95% CI, 63.1-85.2) and CRR was 35.4% (95% CI, 23.9-48.2). The manufacturing success of ide-cel is reliable and consistently high, and when OOS ide-cel products emerged, they demonstrated consistent clinical efficacy and safety.

P2/3, N=312, Recruiting, Celgene | N=214 --> 312

P2, N=32, Recruiting, Massachusetts General Hospital | Trial primary completion date: Dec 2025 --> Aug 2026

P3, N=79, Active, not recruiting, Celgene | N=618 --> 79 | Trial completion date: Aug 2025 --> Nov 2029

P2, N=312, Completed, Celgene | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Jan 2026 | Trial primary completion date: Oct 2025 --> Jan 2026

MSK AEs represent a common, under-recognized toxicity affecting nearly one-third of BCMA CAR-T recipients, often causing severe and prolonged disability. The identification of predictive baseline PMN-MDSC reduction and persistent inflammatory cytokine elevation provides insights into pathophysiology and suggests potential for risk stratification and targeted therapeutic intervention. These findings warrant prospective validation and development of standardized assessment and management protocols.

P1/2, N=15, Recruiting, Universitaetsklinikum Erlangen AR

P2, N=32, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027

In this issue of Cancer Cell, Rade et al. report a longitudinal single-cell atlas of multiple myeloma patients receiving BCMA-directed chimeric antigen receptor (CAR) T cell therapy (ide-cel or cilta-cel) and identifiy features linked to long-term responses, including CD4+ T cell-driven cytotoxicity, memory-biased T cell states, reduced exhaustion, and microenvironment effects.

We then summarize the clinical development and distinguishing features of currently approved BCMA-targeted modalities-CAR T-cell therapies (ide-cel, cilta-cel), bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab), and the antibody-drug conjugate (belantamab mafodotin)-highlighting their efficacy, toxicity profiles, and practical positioning in relapsed/refractory MM. Finally, we review emerging resistance mechanisms, including γ-secretase-driven sBCMA elevation, ligand-rich APRIL/BAFF niches, and therapy-induced TNFRSF17 lesions, ranging from biallelic deletions to epitope-altering missense mutations and in-frame deletions within the BCMA extracellular domain. These insights inform rational strategies such as γ-secretase inhibition, dual-target CAR T-cells and bispecific T-cell engagers.

Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021-December 2024), 27 (13.6%) developed CirAEs. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P  1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.

Ide-cel and Cilta-cel are CAR-T cells directed against BCMA, having received FDA approval for RRMM based on the Phase 2 KarMMa and CARTITUDE trials, respectively...Additional anti-BCMA targeted medicines, including LCAR-B38M, completely humanized CAR-T (FHVH-T), P-BCMA-ALLO-1, ALLO-715, and anti-BCMA CAR-NK, provide promising treatment options. Moreover, the anti-CD19 Fast-CAR, designed to shorten production time, and PHE885, which possesses in-vivo proliferation capability, are regarded as very efficacious...The development of academic CAR-Ts such as ARI0002h, HBI0101, eque-cel, zevor-cel, anito-cel, and Sleeping Beauty (utilizing a non-viral vector) have importance due to their accessibility and cost-effectiveness...To overcome these issues, strategies are being implemented, including combination therapy, the incorporation of gamma-secretase inhibitors etc. In conclusion, CAR-T treatments have evolved into an effective therapy modality being anticipated to be utilized in earlier phases in the future. Gene editing (CRISPR) method contributes to the future perspective.