CAR-T cells co-targeting BCMA and CD19 in RRMM: Results from the UKMRA Phase 1 MCARTY trial in relapsed refractory multiple myeloma Free

Introduction: BCMA directed CAR-T cell therapy for multiple myeloma (MM) shows promise, but relapses continue to occur despite deep responses. Hypothesizing that increased persistence may prolong responses, we developed a CAR-T cell product double transduced to co-express a highly sensitive, Fab-based BCMA CAR (D8) and a CD19 CAR from obecabatagene autoleucel (also known as CAT19), which is known to drive long-term persistence.

Methods: The MCARTY trial (NCT04795882) is a single centre, Phase 1 dose escalation trial uniquely designed with two cohorts to iteratively evaluate D8 CAR-T cells (Cohort 1) and D8/CAT19 CAR-T cells (Cohort 2) in patients with relapsed/refractory MM at a dose of 50 or 150x10⁶ CARs. Inclusion criteria are: progression or stable disease to last treatment, 3 or more previous lines of therapy, exposure to proteasome inhibitors (PI), immunomodulatory drugs (IMID) and CD38 antibodies, ECOG 0/1. Selection was not based on prior BCMA exposure. Notably, dual transduction in Cohort 2 results in 3 populations of CAR-T cells (D8+CAT19-, D8-CAT19+, D8+CAT19+) which can be individually tracked in patients.

Results: As of 30^th June 2025, 15 patients have been treated, 6 patients with D8 CAR (n=3 at each dose level) and 9 patients with D8/CAT19 CAR-T cells (3 and 6 patients at the lower and higher dose levels respectively). Median age was 50 (range 33-66), previous lines of therapy 4 (range 3-8) and 5 patients (33.3%) had high risk cytogenetics.

Doses were well tolerated, CRS was seen in 14 (93%), all Grade 1-2, there was one case of Grade 1 ICANS and no other neurotoxicity. At a median follow up of 21 months, clinical responses ≥PR were seen in 14 patients (ORR 93%). Twelve achieved a CR/sCR (80%, 11/11 evaluable were MRD- to 10^-5 by clonoSEQ). Overall median PFS was 18 months (95% CI 5-N/A). Prolonged remissions (>24 months) have been observed in 3 patients from both cohorts so far.

Median PFS in Cohort 1(D8) and Cohort 2(D8/CAT/19) were 15 (95% CI 5-N/A) and 18 months (95% CI 2-N/A) respectively. The persistence of CARs was variable between patients and while D8 CAR expansion in the first month (28D AUC) was similar in both cohorts, D8 CARs were detectable up to 3 months (median 2) in Cohort 1 and 5 months (median 3) in Cohort 2.

We had hypothesized that the persistence of CAT19 would result in improved survival of D8+CAT19+ cells compared to D8+ cells. In contrast, we observed expansion of both dual and single targeting CARs but persistence of dual D8+CAT19+ CARs was consistently less than that of single transduced CARs. As a possible explanation, by single cell RNA sequencing, an apoptotic signature score (including genes FOS, FASLG, BCL2A1, TNF, calculated by UCell) was increased in D8+CAT19+ compared to single targeting CARs (p<0.01).

Further, overnight activation with plate bound CD19 and BCMA of the CAR product caused over-expression of genes mediating INF-a, INF-g, inflammatory responses and NFKB signalling pathways in all populations. However, activation of D8+CAT19- CARs appeared greater in Cohort 2 vs 1 (p<0.01). Together, this data indicates variability in single vs dual targeting CARs with D8+CAT19+ CARs having an increased susceptibility to apoptosis and a suggestion that D8+CAT19+ and D8-CAT19+ may support activation of D8+CAT19- CARs in patients receiving the dual transduced product.

Summary: Data from the first 15 patients in the Phase 1 MCARTY trial indicate safety and a high ORR in patients treated with CAR-T cells targeting BCMA alone or dual transduced to target BCMA and CD19. There is a suggestion that a dual targeting strategy can increase BCMA CAR activation and persistence but not through the expected mechanism of being ‘piggy-backed’ on the CD19 CAR-T cells. We have thus modified the manufacturing process to equalize the proportion of single and dual expressing CARs in the D8/CAT transduced product and are introducing a higher dose level to improve persistence and potentially outcomes. We have also initiated the Phase 1 ALARIC study (ISRCTN49320109) of D8 and D8/CAT19 in systemic AL amyloidosis.