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The novel second-generation BCMA-directed CAR T-cell construct MDC-CAR-BCMA001 demonstrated activity and a favorable safety profile with no incidence of neurotoxicity in the compassionate use setting for heavily pretreated patients with relapsed/refractory multiple myeloma and systemic light chain (AL) amyloidosis who displayed preexisting organ insufficiencies, according to findings presented at the 51st Annual EBMT Meeting.
At a median follow-up of 13 months, 5 of the 6 patients treated with MDC-CAR-BCMA001 achieved an overall response, 4 of which were complete responses (CRs) and 1 of which was a very good partial response (VGPR). Additionally, all CRs translated in minimal residual disease negativity. The 12-month overall survival and event-free survival rates were 83% and 50%, respectively. Notably, 4 patients achieved sustained remission without a need for subsequent therapy.
Deep, rapid responses were also observed with the CAR T-cell therapy. The median decrease in free light chains was 98.4%, the median time to first response was 14 days, and the median time to best response was 41 days. Furthermore, rapid hematologic responses translated into organ responses, with 1 patient experiencing a cardiac VGPR, another achieving a renal VGPR, and a third experiencing an improvement in polyneuropathy.
“MDC-CAR-BCMA001 shows high efficacy in an extremely difficult-to-treat [patient] population and a favorable safety profile in vulnerable patients…in the compassionate use setting,” Kiavasch Mohammad Nejad Farid, MD, of Heidelberg University Hospital in Germany, stated during a presentation of the data.
Rationale and Study Overview
BCMA is considered a viable target for immunotherapy development in multiple myeloma and AL amyloidosis. Prognosis remains poor for patients with relapsed/refractory AL amyloidosis following progression on first-line daratumumab (Darzalex)-based therapy, and therapeutic outcomes worsen with each subsequent line of therapy in relapsed/refractory multiple myeloma. Although BCMA-targeting therapies have gained market access, no commercial product is currently available for AL amyloidosis, and BCMA-directed CAR T-cell therapy is not always feasible for certain patients, including those with BCMA-pretreated relapsed/refractory multiple myeloma.
To address this unmet need, investigators initiated compassionate use of the in-house, manufactured, second-generation BCMA-directed MDC-CAR-BCMA001 in patients with relapsed/refractory later-line multiple myeloma and AL amyloidosis. This construct incorporates a CD28 costimulatory domain and high avidity, making it particularly suited for targeting plasma cells with low antigen expression.
The study enrolled and treated 6 consecutive patients at the University Hospital Heidelberg between December 2022 and March 2024, including 3 patients with AL amyloidosis, 2 with multiple myeloma, and 1 patient who displayed concurrent multiple myeloma and AL. Patients underwent lymphodepletion with fludarabine/cyclophosphamide or bendamustine, followed by a fixed dose of 800 x 106 BCMA-directed CAR T cells. Leukapheresis, manufacturing, and the administration of CAR T-cells were all performed in house.
The median age among all patients was 65 years (range, 60-69) and the median number of prior lines of therapy was 7 (range, 5-12). All 6 patients were triple-class refractory, 5 patients previously received high-dose melphalan plus autologous stem cell transplantation (ASCT), and 2 previously received BCMA-targeted therapy. Moreover, the majority of patients had disease progression at the time of CAR T-cell infusion and displayed high-risk cytogenetics (5 each). Severe AL amyloidosis-associated organ dysfunction was observed, including Mayo Stage IV cardiac AL, stage III renal AL, and autonomic neuropathy. Accordingly, the authors emphasized that this is an extremely difficult-to-treat cohort with no other effective treatment options available.
Safety, Pharmacokinetics, and Next Steps for Investigation
Regarding pharmacokinetics, the CAR T-cell construct demonstrated robust, uniform expansion. The peak peripheral CAR T-cell expansion was a median of 10 days.
Regarding safety, the incidence of high cytokine release syndrome (CRS) was low, with only 1 patient experiencing a grade 3 or higher event. Grade 1 and 2 CRS events were observed in 50% and 33% of patients, respectively. The median time to onset of CRS was 1 day (range, < 1 to 3) and the median duration of CRS was 4 days (range, 2-6). Tocilizumab was used for 67% of patients, and 33% received corticosteroids. No patients experienced any immune effector cell-associated neurotoxicity syndrome (ICANS) and other late neurotoxicities.
Early immune effector cell-associated hematotoxicity (ICAHT) occurred in 83% of patients, 60% of which were grade 1; 20% were grade 2 and treated with granulocyte colony-stimulating factor (G-CSF); and 20% of which were grade 4 and treated with G-CSF and ASCT backup. Grade 1 late ICAHT was observed in 17% of patients and resolved spontaneously.
The median hypogammaglobulinemia level was 3.55 g/L (IQR, 2.39-4.69). Infections occurring after day 28 were reported for 67% of patients, 75% of which were grade 2 and 25% were grade 3. There were no grade 4/5 infections.
Study authors noted several special considerations for mitigating higher-grade CRS among patients with AL amyloidosis and organ insufficiencies, including early implementation of treatment with anti–interleukin 6 (IL6), earlier cytokine-directed treatment other than anti-IL6 agents for higher-grade or prolonged CRS, and more restrictive use of corticosteroids.
These findings support the ongoing phase 1 CARLOTTA001 trial (NCT05836896) evaluating the CAR T-cell construct in relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma.
Further clarification of the agent’s feasibility and activity in AL amyloidosis will hopefully be obtained from the phase 1 CLEAR AL trial, which is soon to be initiated, study authors concluded.
Disclosures: Farid reported receiving travel grants from Pierre Fabre and Kite/Gilead.
Reference
Farid K, Hegenbart U, Schönland S, et al. Successful treatment of patients with heavily pretreated systemic light chain al amyloidosis and multiple myeloma with the novel MDC-CAR-BCMA001. Presented at: EBMT 51st Annual Meeting; March 30-April 2, 2025. Florence, Italy. Abstract OS14-06.