Highlight
– Dual-nanobody variable heavy chain (VHH)-based BCMA CAR T-cell therapy (S103) achieves a 96.3% overall response rate at 1 month in relapsed/refractory (R/R) plasma cell myeloma.
– Responses deepen by 3 months, reaching 100% ORR and 81.5% CR plus VGPR.
– The therapy demonstrates efficacy in high-risk patients, including those with extramedullary disease, TP53 mutations, plasma cell leukemia, and anaplastic plasma cell myeloma.
– The safety profile is manageable with encouraging survival outcomes (1-year OS 61.1%, PFS 57.2%).
Study Background and Disease Burden
Multiple myeloma (MM), a malignant plasma cell disorder, remains incurable for many patients despite advances in therapy. Particularly challenging is relapsed/refractory (R/R) disease, where therapeutic options diminish and prognosis worsens. Over the past decade, immunotherapies targeting B-cell maturation antigen (BCMA), an antigen preferentially expressed on malignant plasma cells, have emerged as a promising strategy. Chimeric antigen receptor (CAR) T-cell therapies directed against BCMA have demonstrated impressive anti-myeloma activity, leading to durable responses. However, heterogeneity in CAR constructs, especially in the antigen recognition domain, influences efficacy and safety outcomes. Conventional CARs typically use single-chain variable fragments (scFvs) derived from antibodies, which may have limitations in stability and affinity. Nanobodies—single-domain antigen-binding fragments derived from heavy chain-only antibodies—offer a smaller, more stable alternative with superior affinity and specificity, potentially enhancing CAR T-cell function. This study evaluates S103, a BCMA CAR T-cell construct incorporating dual-nanobody variable heavy chain domains (VHHs), aiming to improve therapeutic outcomes in R/R plasma cell myeloma, including high-risk subsets.
Study Design
This phase I/II open-label clinical trial enrolled 27 patients with R/R plasma cell myeloma, registered as NCT04447573. The cohort included 4 patients with plasma cell leukemia and 1 patient with anaplastic plasma cell myeloma. Notably, 11 patients presented with multiple extramedullary lesions and another 11 harbored high-risk genetic abnormalities, including 4 with TP53 mutations. Patients received infusion of autologous CAR T-cells engineered to express the S103 CAR, constructed with dual-nanobody VHH domains targeting BCMA. Key efficacy endpoints included overall response rate (ORR), complete response (CR), very good partial response (VGPR), progression-free survival (PFS), overall survival (OS), and duration of remission. Safety assessments focused on adverse events associated with CAR T-cell therapy, including cytokine release syndrome (CRS) and neurotoxicity.
Key Findings
One month post-CAR T-cell infusion, the ORR was an impressive 96.3% (26/27 patients), with a combined CR + VGPR rate of 59.2% (16/27). By the 3-month evaluation, ORR rose to 100%, and CR + VGPR deepened to 81.5% (22/27). This improvement over time suggests ongoing CAR T-cell activity and disease clearance beyond the early response phase.
In vitro function verification of S103 BCMA CAR T cells.
The median duration of remission was 11 months, ranging from 2 to 36 months, evidencing meaningful durability. At one year, OS was 61.1% and PFS was 57.2%, indicating substantial clinical benefit in a heavily pretreated population with high-risk disease features.
OS and PFS of the 27 patients with R/R MM treated with S103 BCMA CART.
The long-term follow-up data for the 27 patients with R/R MM treated with S103 BCMA CAR T-cell therapy.
Importantly, efficacy extended to patients with adverse prognostic factors, including those with extramedullary disease, TP53 mutations, plasma cell leukemia, and anaplastic variants. These subgroups historically experience poor outcomes and remain underserved by current therapies.
Safety of the S103 CAR T-cell therapy was manageable. While cytokine release syndrome (CRS) and neurotoxicity, common toxicities associated with CAR T-cell agents, occurred, they were within expected severity ranges and responded to standard interventions. No unexpected safety signals were reported.
Expert Commentary
The incorporation of dual-nanobody VHHs targeting BCMA represents a novel advancement in CAR T-cell design, offering potential improvements in antigen binding affinity and CAR stability compared to traditional scFv-based constructs. These features may underlie the high response rates and sustained remissions observed.
The inclusion of challenging patient subsets, notably those with extramedullary disease and TP53 mutations, strengthens the relevance of these findings for real-world clinical practice where such high-risk profiles are increasingly recognized as unmet needs.
However, the relatively small sample size and single-arm design warrant cautious interpretation. Longer follow-up is necessary to confirm durability of response and long-term safety. Comparative studies against established BCMA CAR constructs will be critical to delineate the specific benefits conferred by the nanobody approach.
Conclusion
BCMA-targeted CAR T-cell therapy utilizing dual-nanobody VHHs, as exemplified by the S103 product, demonstrates a robust clinical response and a manageable safety profile in heavily pretreated R/R plasma cell myeloma. This approach shows potential to address high-risk patient subgroups with unmet clinical needs. Ongoing evaluation in larger cohorts and controlled trials will clarify its role within the evolving therapeutic landscape of plasma cell malignancies. These results underscore the promise of nanobody-based CAR designs to enhance immunotherapeutic efficacy in hematologic cancers.
References
Zhang XG, Wang L, Yang J, Hu XN, Wang H, Zhang LN, Zhou X, Liu Y, Wang Q, Lu PH. Efficacy and safety of BCMA nanobody CAR T-cell therapy in relapsed or refractory plasma cell myeloma. Blood Adv. 2025 Sep 23;9(18):4543-4552. doi: 10.1182/bloodadvances.2025016322 IF: 7.1 Q1 . PMID: 40569697 IF: 7.1 Q1 .