Results of Bispecific Antibody Combination in Advanced Myeloma | Yael Cohen, MD | ASCO 2023

So, hi everyone. My name is Yael Cohen and I'm a hematologist from Israel. I work in the Tel Aviv-Sarosky Medical Center and I run the myeloma unit. And I'd like to update you on the exciting data I presented just a few minutes ago in ASCO. This is the redirect one clinical trial. It's a phase one B trial, so this means it's early development. And this is actually the first time the two drugs from the class of bispecific antibodies have been combined together to treat any hematologic malignancies. So the trial involved two drugs. One is teclistomab and this is a drug already approved in the United States for treatment of triple class exposed myeloma. So teclistomab is a bispecific antibody, which means it's an antibody with two arms. One knows to capture a T cell, which is an immune cell, and the other can identify a myeloma cell. And it does so by a specific marker on the myeloma cells called BCMA. So it's like a CD3 BCMA bispecific antibody. And then the other drug that was used in this trial is called talcuetomab. So this is a drug still in development, late stages of development. It also catches a T cell with a CD3, but the myeloma is targeted with a different marker called GPRC5D. So in this trial, the unique feature was that actually both of these two novel bispecific antibodies were combined together to treat patients with advanced myeloma. So the patients who enrolled in this study were relapsed or refractory or intolerant to their last line of treatment, and they had to have been exposed to drugs from the classes of proteasome inhibitors, such as bortezomib and imid, such as, for example, lenalidomide and anti-CD38 antibodies, such as daratumab. So the patients enrolled into the study, 93 of them, got various doses because this was what's called a dose escalation study since its early development. This means that we're trying to figure out which is the right dose of each drug and which is the schedule that will be most efficacious and, of course, safe for the patients. And we ended up with a certain dose of talcuetomab at 3 milligrams per kilogram given every two weeks in talcuetomab at 0.8 milligrams. So this is the recommended phase two regimen. And this was investigated in this cohort of 93 patients. And the safety of a combination of these two antibodies was really very encouraging. There were no new additive toxicities found by combining these two antibodies together. There were some decreases in blood counts, but the rates were really low. The infection rate, which we know is always an issue with myeloma treatments, was the same as that of tachyclostomab given as a monotherapy. Cytokine release syndromes, which is like the inflammatory response that the patients can get when the immune system is driven to fight the myeloma. So these were also of low grade. It means that they are easily manageable. They occurred only in the beginning of the treatment and resolved with simple treatment measures. The efficacy data from this study is really very encouraging. So these are very hard to treat patients because they are so refractory. But the overall response rate was 86 percent for the entire cohort. And those patients who got the selected dose, what we call the recommended phase two regimen, they had a response rate as high as 96 percent. So as probably many of you know, 96 percent response, you can't really get much better than that. And we only were able to see these levels of responses before with CAR-T therapy, with T cells that underwent engineering. So here we have an off the shelf drug combination that can yield the same kind of responses. And the unique feature of this study was that the population was enriched with patients who have what's called extra medullary disease. And extra medullary myeloma means that we have a tumor that lost its need or dependency in the bone marrow environment. And actually you get a lump of tumor in soft tissue. This can be under the skin or in the liver or any other place that is not related to the bone. And turns out that the treatment of patients with extra medullary myeloma is really very, very challenging. And in known treatments we have available today, they yield low response rates and the responses are really short living. Even CAR-T, which yields a slightly better response rate, still allows for really limited durability of response. And here in the redirect one study, combining these two novel by specifics yielded very high response rates, even in these very hard to treat myelomas. So the response rate at the selected regimen was as high as 85%. And the other important message is that these responses were really durable, so they lasted for over a year. So to conclude, the first study combining two by specifics, by specifics on their own are quite novel and promising drugs in myeloma. And here for the first time, two of them together really yielded excellent high efficacy without an excess of toxicity. Were able to manage even very hard to treat patients with extra medullary disease. So we're looking forward for further studies to further look at the opportunity of this treatment to extend the treatment for myeloma patients. So there's so much new data becoming available in myeloma. A few years ago it was limited to the ASHE meeting taking place in December, but now there's being more and more data also presented here at ASCO. And I just came out of a very interesting session. It was discussing various advanced regimens for maintenance treatment for myeloma combinations that might give a better solution for patients with high risk disease. There was also a presentation of a new by specific antibodies, several antibodies targeted at BCMA, a couple of new studies on CAR-T therapy. So things are continuing to move forward and fast for myeloma for the benefit of patients. These are really very exciting times.