Dual-Targeting CAR T Achieves sCR in 100% of Older Patients With NDMM

A B-cell maturation antigen (BCMA)/CD19 dual-targeting chimeric antigen receptor (CAR) T cell therapy produced stringent complete responses in all patients enrolled in a small phase 1 trial (NCT05840107) of older adults with newly diagnosed multiple myeloma (NDMM), including those classified as frail, according to findings published in Blood Advances.¹

The study evaluated AZD0120 (formerly GC012F), an autologous CAR T cell product manufactured on the FasTCAR next-day manufacturing platform as frontline consolidation therapy in transplant-ineligible patients aged 70 and older. All 8 treated patients achieved stringent complete response (sCR), and all achieved minimal residual disease (MRD) negativity by Euroflow at a sensitivity of 10^-6 within 1 month of infusion. MRD negativity was sustained at 100% in all evaluable patients at month 6 (n = 7) and month 12 (n = 2), with no disease progression or death at a median follow-up of 9.8 months post-infusion.

Background and Rationale

Multiple myeloma disproportionately affects older adults, with a median age at diagnosis of 69 years. Despite advances in treatment including BCMA-directed CAR T-cell therapies that have shown extremely high response rates in relapsed or refractory disease, older patients have been routinely excluded from clinical trials and are rarely considered candidates for cellular therapy in the frontline setting. Comorbidities, reduced functional status, and frailty increase the complexity of treating this population and can limit both eligibility and tolerance of intensive regimens.

Prior real-world data on anti-BCMA CAR T cell therapy in older patients with relapsed or refractory disease have shown response rates broadly comparable to younger patients,² though toxicity rates, particularly for cytokine release syndrome (CRS), have remained high in some cohorts. Investigating CAR T cell therapy earlier in the disease course, before patients accumulate greater disease burden and functional decline, represents a potentially important shift in treatment strategy.

Study Design and Patient Population

The single-arm, phase 1 trial was conducted at Shanghai Changzheng Hospital between May 2023 and April 2024.¹ Nine patients were enrolled; 1 withdrew due to disease progression before infusion. The remaining 8 received AZD0120 following 2 cycles of VRd (bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone) induction therapy. Patients were assigned to 1 of 2 dose levels: 1.5 × 10⁵ CAR+ T cells/kg (DL1; n = 3) or 3.0 × 10⁵ CAR+ T cells/kg (DL2; n = 5) using a 3+3 dose-escalation design.

Patients will be followed for progression-free survival, MRD, and duration of response for up to 2 years after infusion.

Baseline characteristics reflected a clinically heterogeneous cohort. The median age was 72 years (range, 70-78); 63% were male. Half the patients had IgA subtype disease, 38% had any high-risk cytogenetics, and 50% were staged as R2-ISS stage III. Four patients (50%) were classified as frail per the Intergroupe Francophone du Myelome (IFM) Simplified Frailty Score, and 25% had an ECOG performance status of 2 at baseline.

Safety

The safety profile was characterized primarily by hematologic toxicities, consistent with previously reported CAR T cell studies. Grade 3 or higher treatment-emergent adverse events included neutropenia (75%), leukopenia (50%), and lymphopenia (25%). All grade 3 or 4 hematologic adverse events resolved to grade 2 or lower within 30 days of infusion, notably faster than recovery observed in a previously reported AZD0120 cohort of patients with relapsed or refractory disease.

CRS occurred in 4 patients (50%), all grade 1, with a median time to onset of 9 days and median duration of 3 days. Three cases resolved without pharmacologic intervention; 1 required a single dose of tocilizumab (Actemra). No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed, and no treatment-related deaths or secondary malignancies were reported.

Among frail patients, who accounted for 75% of CRS cases, 2 individuals with baseline ECOG performance status of 2 improved to ECOG status 1 following infusion, including 1 who demonstrated improvement on the IFM Simplified Frailty Score. Infection occurred in 4 patients (50%), with 2 cases of grade 2 and 2 at grade 3; all resolved with standard management.

Efficacy

The investigators compared the sCR and MRD negativity rates of 100% at 1 month favorably with MRD negativity rates reported for anti-CD38-based quadruplet frontline regimens in transplant-ineligible patients.

CAR T cell expansion was confirmed in all 8 patients by flow cytometry, with a median duration of detectable circulating CAR T cells of 28 days. By quantitative PCR, median peak copy number (C_max) was 96,005.5 copies/μg genomic DNA, reached at a median of 10 days post-infusion. Pharmacokinetic parameters did not differ significantly between dose levels, and neither C_max nor area under the curve correlated with CRS occurrence.

Conclusions and Limitations

Although the results of the rapidly produced CAR T-cell therapy are favorable, the small patient population and short median follow-up limit the ability to draw conclusions about long-term outcomes. Additionally, the patients did not receive anti-CD38 monoclonal antibodies as part of induction therapy, which would be standard of care in transplant-ineligible patients.

The authors describe this as the first CAR T cell study focused specifically on older patients with NDMM, and call for age alone not to be used as a criterion to exclude patients from future trials or real-world access to anti-BCMA therapies. “Given these promising data, chronological age should not be used as a criterion to exclude patients from future clinical trials, nor from receiving anti-BCMA CAR T cell therapy in a real-world setting,” they stated.

REFERENCES

1. Liu J, Fan X, Peng L, et al. BCMA/CD19 dual-targeting CAR T cell therapy in older patients with newly diagnosed multiple myeloma: a phase I study. Blood Advances. Published April 2, 2026. doi:10.1182/bloodadvances.2025019036

2. Akhtar OS, Sheeba BA, Azad F, et al. Safety and efficacy of anti-BCMA CAR-T cell therapy in older adults with multiple myeloma: A systematic review and meta-analysis. J Geriatr Oncol. 2024;15(2):101628. doi:10.1016/j.jgo.2023.101628