CART-ddBCMA Demonstrates Promising Safety, Yields Durable Responses in Relapsed/Refractory MM

Matthew Frigault, MD, Assistant Professor, Massachusetts General Hospital Cancer Center, discusses findings from a phase 1 study evaluating the safety of a novel BCMA-targeting CAR T construct (CART-ddBCMA) that leverages a completely synthetic antigen binding domain for patients with relapsed/refractory multiple myeloma (MM).

Transcript:

Hi, my name is Dr. Matthew Frigault. I am a cell therapy and bone marrow transplant physician at Massachusetts General Hospital Cancer Center. I'm an assistant professor and also the clinical director of our cell therapy program. I'm here to talk about our ddBCMA trial.

Oncology Learning Network (OLN): What existing data led you and your co-investigators to conduct this research?

Dr Frigault: This was a first in human study. It was a phase 1 dose escalation, meaning that we really didn't have any clinical data to go by. This was a first in human, first dose, first patient kind of situation.

We add some preclinical data where we were looking at this new CAR T-cell that uses a novel binder that's different from a single chain variable fragment, or a camelid, which other products are currently using. But the theory being that we thought it would potentially be less energetic, meaning it would have better distance in the body, potentially more stable in the T-cells. And so this was a first human study.

The goal here was to assess primarily, safety, but to our luck we were happy to see that we had about a hundred percent response rate. So, in addition to the safety outcomes, we're also able to assess for efficacy in patients now going on for well beyond a year.

OLN: Could you briefly describe your study and its findings?

Dr Frigault: This is a phase 1 first human study of CAR T ddBCMA. What CAR T ddBCMA is it's a CAR T-cell ark, chimeric antigen receptors modified T-cell that uses a novel binding domain that is synthetically derived, computationally biology bioengineering, to be less immunogenic, to elicit less of an immune response and potentially be more stable in the cell surface of a T-cell.

Rather than taking pieces of antibodies or other pieces where we're designing this protein ourself and engineering it into the T-cells.

This was a study in relapse refractory (R/R) and multiple myeloma (MM). And so patients had to have prior IMiD exposure, prior PI and prior CD38 targeted therapy, have had at least 300 or more lines of therapy, and be triple-refractory.

This was done in 2 dose levels. Dose level 1, just a hundred million CAR T-cells and dose level 2, which was 300 million CAR T-cells. After the dose escalation component, when we had initially had treated the majority of patients that we decided to actually use dose level 1, as we were seeing really good long term results with a hundred million CAR T-cells.

Today we treated about 24 patients, if not more, but this was as of ASH. We have about 19 patients that are evaluable for efficacy, and 22 patients who are evaluable for safety. We're continuing to enroll in the expansion cohort at a hundred million cells as we get ready for the PEDAL study.

The exciting thing here is that despite having a really highly refractory group of people. So, these are folks who had about over 40% of them had more than half of their bone marrow involved with myeloma, around 40% of patients had extramedullary disease, so disease outside the bone marrow and other organs. Ninety percent had what we call high risk cytogenetics. So bad features at time of diagnosis. Eighty-three percent were a triple-refractory and 71% were penta-refractory. A very fundamentally refractory group of people.

Despite that, what we were able to see is a 100% overall response rate (ORR). Every single patient treated that of the 22 who are evaluable, had a response. As we see over time, and as I've seen in other studies, those responses, although they're a partial response (PR) or a very good partial response (VGPR) or complete response (CR), they continue to deepen over time.

By around 5 months or after around 70% of patients have been what we can call a stringent CR, meaning no evidence of disease in the bone marrow based on imaging or other kind of biomarker chemical tests. In fact, the majority of patients were actually MRD negative by NextGen sequencing.

These are very, very deep responses. We now have patients who are well beyond what the median follow this study was around 283 days, but we had patients going out to around 640 days from time of infusion and an ongoing response. Very, very exciting.

OLN: Were any of the outcomes particularly surprising?

Dr Frigault: Anytime you see good respond traits in a phase 1 trial, it's exciting, right? It's something you don't know what to expect and that's the part of the excitement phase 1, also part of the hope in phase 1, right?

I wouldn't say it's surprising because I'm a big believer in CAR T-cells. I think there's other drugs that are currently in development. So cilta-cel, which is a J&J product that's hopefully going to be approved in the next month or two, has similar response rates, has very durable responses.

The fact that we're seeing things comparable to what we would consider best in class, we've seen the numbers before, but this is now what I would consider comparable product. So, very happy to see that. We knew it was possible. We hope to continue to see that. But like I said, it's at phase 1, so you never know what you're getting yourself into.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Frigault: When we think about R/R MM, especially penta-refractory patients, we're talking probably an overall survival (OS) in the orders of months.

These patients are typically, especially with penta-refractory, have rather poor outcomes compared to patients at first diagnosis or in these CAR T-cell trials. The fact that we have patients who are multiple relapsed, the fact that we have patients who had failed other BCMA targeted therapies. And so this is targeting BCMA, but patients have failed BCMA ADCs on the study, and they also had great responses and had durable responses.

Clinically I think it's a whole new class of therapies for MM. We're seeing success in lymphoma and leukemia. We have ide-cel which is currently approved for BCMA positive or MM, which is also targeting BCMA. And so, this is hopefully going to be another really good option in the gauntlet of clinical therapies for patients.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr Frigault: We're continued to accrue in the expansion cohort. After we did our dose escalation, we're expanding through additional efficacy and safety data in our patients, but we're also working to design the pivotal phase 2 study, which will hopefully be used to warrant an approval of a new CAR T-cell multiple myeloma. These studies are definitely ongoing.

We're also starting to look into activating and treating patients in the second arm of this study, which starts to combine this novel binder that we've created as an infusion, which then can link up inside the body with a CAR T-cell, which may have some differences in expansion, persistence, and potentially be even safer. We're starting to go down that road as well, as we continue to develop phase 2 component.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

Dr Frigault: MM, as rare of a disease it is compared to say things like lung cancer, it is still thought to be an incurable disease in many patients.

I'm optimistic that therapies like these that can induce durable responses in highly refractory folks, that we're going to continue to give more and more access to patients who currently need it.

There are wait list for CAR T-cells for patients like this. And so, I hope with more and more improved products, we're going to get patients increased access and improve overall outcomes.

Source:

Frigault MJ, Bishop MR, Rosenblatt J, et al Phase 1 Study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv. Published online April 25, 2022. doi:10.1182/bloodadvances.2022007210