CART-ddBCMA Elicits 100% ORR in Relapsed/Refractory Multiple Myeloma


The autologous CAR T-cell product CART-ddBCMA was found to elicit a 100% objective response rate in patients with relapsed/refractory multiple myeloma, with deep and durable responses noted in those with poor prognostic factors.

Matthew J. Frigault, MD, of Massachusetts General Hospital

Matthew J. Frigault, MD

The autologous CAR T-cell product CART-ddBCMA was found to elicit a 100% objective response rate (ORR) in patients with relapsed/refractory multiple myeloma, with deep and durable responses noted in those with poor prognostic factors, according to data from a phase 1 trial (NCT04155749) presented during the 2021 ASCO Annual Meeting.1

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.”


1. 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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