Safety, tolerability and early efficacy of mdc-CAR-BCMA001 – a high affinity BCMA targeting CAR T-cell therapy in patients with multiple myeloma and diffuse large B-cell lymphoma

Abstract Background: BCMA is a validated target for T-cell engagers and chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Initial response rates of BCMA directed therapies are high but relapse remains a significant problem. Some early reports also suggest low level BCMA-expression by diffuse large B-cell lymphoma (DLBCL). We aimed at evaluating MDC-CAR-BCMA001, an autologous high affinity BCMA-targeting CAR T-cell product, in MM failing on previous BCMA-targeted therapies and to assess its potency in BCMA-positive relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL). Methods: BCMA-expression was assessed by immunohistochemistry (IHC) and qPCR on patient-derived tissue samples in n=20 DLBCL, n=23 MM and n=19 normal tissue controls. MDC-CAR-BCMA001 is a second generation, fully humanized autologous CAR T-cell product containing a single-chain variable fragment derived from the antibody J22.9 FSY that binds to human BCMA with an affinity of 2.2 +/- 0.3 nM, a CD28-dervied co-stimulatory and a CD3ζ activation domain. It is tested in this ongoing investigator-initiated phase I dose-escalation trial in adult DLBCL and MM patients, who failed standard of care therapy including approved CD19-directed CAR-T and BCMA-targeted immunotherapy, respectively. Patients receive fludarabine (30 mg/m2/d) and cyclophosphamide (500 mg/m2/d) on days -5 to -3 followed by a single infusion of MDC-BCMA-CAR001 at 3 pre-defined dose levels (DL) ranging from 0.5 to 9.0 x106 CAR T-cells/kg. The primary aim of this trial is to assess safety and to identify a maximum-tolerated dose (MTD). In addition, CAR-T cell expansion is monitored by serial flow cytometric and qPCR evaluation of peripheral blood. This trial was registered with www.clinicaltrials.gov as NCT05836896 and funded by National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ). Results: BCMA expression was readily detectable by IHC in all assessed DLBCL samples. Expression levels by qPCR were considerably lower in DLBCL than in MM but, on average, 3-fold higher than in non-tumor controls, suggesting feasibility of targeting BCMA with a high affinity CAR T-cell product in DLBCL. As of July 1st, 2025, 12 patients have been consented for this phase I trial of whom 10 underwent leukapheresis and 6 received treatment with MDC-CAR-BCMA001. Patients were heavily pretreated with 9 prior lines in rrDLBCL and a median of 6 prior lines in rrMM. All but 1 MM patient had received prior BCMA-directed CAR T-cell therapy, the remaining patient had been treated with a BCMA bispecific T-cell engager. Overall MDC-CAR-BCMA001 was well tolerated, without any related non-hematologic adverse events greater than grade 1 or dose limiting toxicities. All dose levels have been cleared for safety by the time of this analysis and the MTD has formally not been reached thus far. Two patients developed a grade 1 cytokine release syndrome (CRS), but no patient experienced neurotoxicity events. In particular, movement and neurocognitive treatment-emergent adverse events did not emerge. There was no need for the administration of tocilizumab or steroids. Circulating CAR-T cell levels peaked at day 14 post infusion and remained detectable up to last time point currently available (150 days). Of note, CAR-T expansion was not only observed in rrMM but also in rrDLBCL patients, suggesting successful target engagement in both disease entities. At day 28 post infusion, overall response rate was 67% (including 1 CR and 1 sCR) in rrMM, while best response observed in rrDLBCL was stable disease. Data from additional patients treated at the highest dose level will be reported at the meeting. Conclusions Our results demonstrate safety and preliminary efficacy of MDC-CAR-BCMA001, a high-affinity fully humanized BCMA CAR T-cell product. We validate BCMA as a potential target in rrDLBCL and rrMM patients that are progressive on prior approved immunotherapies. We are further exploring the potential of MDC-CAR-BCMA001 to reinstall responsiveness when conventional anti-CD19 or anti-BCMA immunotherapies have failed.