Novel CART-ddBCMA Leads to 100% Response Rate in First-in-Human Myeloma Trial


In a first-in-human study of patients with relapsed or refractory multiple myeloma, the autologous CAR T-cell therapy CART-bbBCMA led to at least a partial response in all treated patients.

Deep and durable responses were noted in a phase 1 trial (NCT04155749) of the autologous CAR T-cell product CART-ddBCMA to treat patients with relapsed or refractory multiple myeloma, including those with poor prognostic factors, according to data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

At the 2 dose levels studied, 100 million (dose level 1) and 300 million (dose level 2) CAR-positive T cells, the maximum-tolerated has not yet been reached. Of the 12 patients who were included in the analysis, all 12 responded to treatment; this included 6 complete responses (CRs)/stringent CRs, 3 very good partial responses (VGPRs), and 3 partial responses. Eleven of the 12 responses were ongoing at the time of data cutoff, and responses continue to deepen.

“We had an impressive 100% ORR with responses seen beyond 1 year with ongoing minimal residual disease (MRD) negativity. All but 3 patients were able to achieve a VGPR or better, and responses continued to deepen over time,” lead study author Matthew J. Frigault, MD, clinical director of the Cellular Immunotherapy Program at Massachusetts General Hospital, said in a poster presentation on the data. “We saw robust CART-ddBCMA expansion, and we had persistence of the CART-ddBCMA that was ongoing at around 4 months in 1 patient. We also saw that the patients were MRD negative. All evaluable patients were MRD negative at 1 month, except for patient 4 who has also retreated and did eventually have progressive disease.”

CART-ddBCMA is an autologous CAR T-cell product that utilizes a novel computationally designed synthetic protein-binding domain that is not derived from antibodies or single chains and is engineered to reduce immunogenicity and increase stability on the cell surface.

The first-in-human, phase 1 trial continues to enroll patients with relapsed and refractory multiple myeloma. To be eligible for enrollment, patients needed to have previously received an immunomodulatory drug, proteasome inhibitor, and CD38-targeted therapy. Patients needed to have previously received at least 3 therapies or be triple refractory.

After patients underwent screening and were enrolled to the trial, T cells were collected from participants via apheresis, and then the cells were processed. For lymphodepletion, patients were given 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on day -5, -4, and -3. On day 0, participants were infused with CART-ddBCMA.

At the time of data cutoff, which was April 14, 2021, a total of 16 patients had enrolled to the trial. Of the 16 patients, 13 received treatment with CART-ddBCMA. To date, 1 patient is not yet evaluable, and 2 patients are pending treatment. One patient discontinued the trial prior to cell infusion because of an adverse effect (AE) unrelated to the product. There was a 100% manufacturing rate, with a median CAR expression of 74.5% (range, 61%-87%).

Six patients received the CAR T-cell product at a dose level 1, and another 6 received it at dose level 2. The median ages in the 2 groups were 73 years (range, 66-75) and 60 years (range, 53-65), respectively. More than half of patients had bone marrow plasma cell involvement of over 50% and more than half had extramedullary disease at time of treatment. The majority of patients had high-risk cytogenetics.

For dose levels 1 and 2, the median number of prior lines of therapy was 5 (range, 5-7) and 4 (range, 3-16), respectively. More than half of patients had undergone prior autologous stem cell transplant, and all but 2 patients were penta-refractory. Patients with IgG, IgA, light chain, and extramedullary disease only were represented on the trial, Frigault noted.

Additional data demonstrated that patients who had previously received treatment with a BCMA-targeted antibody-drug conjugate (ADC) also experienced “impressive” responses, according to Frigault.

One patient in particular had bulky extramedullary disease, bone marrow disease of 50% at baseline with high-risk cytogenetics, penta-refractory disease, and previously received treatment with a BCMA-targeted ADC. By 1 month, the patient was PET-CT negative, bone marrow negative, and was MRD negative 10-4.

“[This patient] had a rapid decline in the M protein with complete normalization of the serum-free light chains,” Frigault added. “This patient now remains MRD negative and PET negative at 6 months.”

Regarding safety, only 1 serious AE was found to be related to CART-ddBCMA, which was prolonged hospitalization while the patient was recovering from immune effector cell-associated neurotoxicity syndrome (ICANs). No treatment-emergent grade 3 or 4 infections were reported with the product.

Some of the most frequent grade 3 or 4 hematologic AEs reported with the CAR T-cell product included neutropenia(n = 12), lymphocytopenia (n = 12), decreased hemoglobin (n = 9), and thrombocytopenia (n = 6). “[These effects are] standard in most CAR T-cell studies,” Frigault noted.

In dose level 1, cytokine release syndrome (CRS) was reported in all patients, but these effects were only grade 1 or 2 in severity. The median onset to this effect was 2.5 days (range, 0-4) and the median duration was 5 days (range, 2-7). To manage the effect, 4 patients received tocilizumab (Actemra), while 3 patients were given dexamethasone.

In dose level 2, 5 of 6 patients experienced grade 1 or 2 CRS, while 1 patient had grade 3 CRS. In this group, the median onset to the effect was less than 24 hours (range, 0-1), while the median duration was 3 days (range, 1-9). Five of these patients received tocilizumab, 2 had dexamethasone, and 1 received anakinra (Kineret).

One patient who received 100 million cells experienced grade 1 or 2 ICANs, while 1 patient who received 300 million cells had grade 3 ICANs. In the dose level 1 group, both the onset to neurotoxicity and the duration of the event was 2 days. In the dose level 2 group, the onset to neurotoxicity was 6 days, while the duration of the effect was 14 days.

“This is an ongoing phase 1 expansion now at 100 million CAR-positive cells, given the favorable safety profile and 100% response rate,” Frigault concluded. “Currently, we’re designing and planning the pivotal phase 2 study.”


Frigault MJ, O’Donnell E, Raje NS, et al. Phase 1 study of CART-ddBCMA, a CAR-T therapy utilizing a novel synthetic binding domain, for the treatment of subjects with relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(suppl 15):8015. doi:10.1200/JCO.2021.39.15_suppl.8015

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