Carvykti (ciltacabtagene autoleucel)

Two patients who had relapsed after CAR T-cell treatment with idecabtagene vicleucel achieved partial and very good partial responses and were successfully transitioned to a second CAR T-cell therapy with ciltacabtagene autoleucel. SVd demonstrates meaningful activity in patients with penta-refractory MM and prior failure of BCMA/GPRC5D-targeted immunotherapies. The ORR of 61%, disease control in 78% of patients, and median PFS of 4.3 months support further evaluation of SVd in this highly refractory setting after failure of BCMA- and GPRC5D-directed approaches.

P4, N=75, Not yet recruiting, Universitair Ziekenhuis Gent

P1, N=40, Not yet recruiting, Washington University School of Medicine | Trial completion date: Jul 2028 --> Nov 2028 | Initiation date: Jan 2026 --> May 2026 | Trial primary completion date: Oct 2027 --> Feb 2028

P2, N=60, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jan 2028 --> Apr 2028

P1, N=16, Recruiting, Washington University School of Medicine | N=12 --> 16 | Trial completion date: Mar 2027 --> May 2028 | Trial primary completion date: Apr 2026 --> Jun 2027

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.

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.

P2, N=60, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2028 --> Apr 2029

P2, N=11, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Nov 2026 --> Aug 2027

Intra-procedure WBC concentration correlates with collection efficiency and provides a more meaningful real-time indicator of MNC harvest performance than pre-procedure counts alone. Incorporating intra-procedure monitoring into apheresis workflows may enhance yield predictability and streamline CAR-T manufacturing logistics.

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.