Background Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM), with multiple BCMA-targeting CAR T-cell therapies demonstrating high response rates. However, long-term durability and safety remain areas of active investigation. FHVH33-CD8BBZ is a fully human, heavy-chain-only BCMA CAR designed to have high levels of anti-myeloma activity and low levels of immunogenicity. We previously reported early clinical results from a late-line, first-in-human phase 1 trial (conducted 2018 to 2021, Mikkilineni et al., Molecular Therapy 2024) (NCT03602612) demonstrating deep responses with a favorable safety profile. We now present long-term outcomes.

Methods Twenty-five patients at the National Cancer Institute (NCI) with RRMM received a single infusion of FHVH33-CD8BBZ following standard fludarabine/cyclophosphamide lymphodepletion across 5 dose levels (DL), with DL 4 (6 x 10⁶ CAR+ T cells/kg) chosen for an expansion cohort. The CAR incorporates a heavy-chain-only human antibody binder fused to a CD8 hinge/transmembrane and 4-1BB/CD3ζ signaling domains. Disease status was monitored per IMWG criteria. Outcomes assessed include overall response (ORR), time to progressive disease (PD), duration of response (DOR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD), CAR persistence, and long-term safety. Data cutoff for this analysis was July 2025.

Results Patients had a median of 6 lines of prior therapy (range 3-10); 36% (9/25) had high-risk cytogenetics by updated IMWG criteria, and 32% (8/25) had extramedullary disease (EMD) at baseline. In the entire cohort, ORR was 92% (n=23), with a stringent complete response (sCR) rate of 56% (n=14) and a median time to best response of 2.8 months. Ongoing anti-myeloma responses continued at last follow-up in 24% of patients (6/25; including 1 at DL3 [5+ years (yr)], 3 at DL4 [4.0+, 5.0+, 5.0+ yr], and 2 at DL5 [5.0+ yr]). Overall median DOR in DL1-5 is 21.4 months. Nine patients (36%) have experienced/continue to experience DOR >3 years. In the highest dose levels (DL4-5), ORR was 92% (12/13), sCR 84.6% (11/13) and median DOR is 43.4 months (3.6 years) , all ongoing responders had achieved sCR and were MRD-negative. At any DL, no patient with EMD achieved sCR or a durable response. High-risk cytogenetics did not consistently predict outcome; notably, patients with high-risk abnormalities (t(4;14), or 1q) remain in response.

Kaplan-Meier analysis showed median PFS for the DL1-5 was 18 (IQR: 7.5, 50) months.. Focusing on highest DLs (DL 4-5), the median PFS was 43.4 months (3.6 years) (95% CI: 1.0, NR) in DL4–5 versus 18 months (1.5 years) (95% CI: 0.63, 6.0) in DL 1-5 (not statistically significant, log-rank test). Median OS was not reached for the highest two DLs (DL 4–5) or DL 1-5.

In a pre-infusion baseline covariate Cox model, no significant predictors of PFS were identified. No statistically significant associations were found between long-term responders (>3 years DOR or ongoing response) and peak CAR+ T cell level, day of peak CAR+ T cell level, or last day of CAR+ T cell detection.

There were no new safety signals. Notably, no patient experienced delayed neurological toxicities, IEC-colitis, or required treatment for refractory diarrhea. Three patients developed secondary malignancies, all skin cancers (melanoma, squamous cell carcinoma), with no pattern suggestive of CAR-related etiology.

Conclusions These results compare favorably to recently reported long-term outcomes with other BCMA-directed CAR T-cell products, particularly in terms of sustained sCR and manageable long-term toxicity. Favorable safety and durability profiles support development of this platform in earlier lines of myeloma therapy and in autoimmune disorders.

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2025
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