Bispecific Antibodies, CAR T-Cell Therapy, and BCMA-Directed Therapy for the Treatment of Multiple Myeloma With Curative Intent

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Sundar Jagannath, MD, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, provides an update on how immunotherapy and cellular therapy are changing the treatment landscape in multiple myeloma. 

Transcript:

Hi, I'm Sundar Jagannath, professor of medicine at Mount Sinai School of Medicine in New York. I'm also the director of the Center of Excellence of Multiple Myeloma at Tisch Cancer Institute. Today I had the pleasure of talking about new drugs for the treatment of multiple myeloma with a curative intent.

Myeloma has been a challenge for a long time. Part of it was attributed to the genomic instability and the diversity of the myeloma clones in any given patient. Multiple clones, including drug-resistant clones, were already present at the time the patients were started on treatment and so the treatment was not quite effective in eradicating all the tumor cells. But recently we also realized that while there is no major difference between [monoclonal gammopathy of undetermined significance] MGUS and smoldering myeloma and multiple myeloma in the genetic composition, and yet smoldering myeloma and MGUS stayed stable for a long period of time. This is due to the control of the tumor cells by the microenvironment, especially the immune microenvironment. Now we want to harness the immunotherapy to find a cure for myeloma.

I reviewed the results of the drug that is already approved, belantamab, which is an anti-BCMA [B-cell maturation antigen] antibody drug conjugate (ADC). We showed that this drug was quite effective in inducing responses, with an overall response rate of 30% in relapsed/refractory myeloma patients. Some of these remissions were quite durable, but hampered by the side effects of ophthalmic toxicity, or eye toxicity. The patients usually have to be monitored by an ophthalmologist or by an optometrist for corneal toxicity. This is of some concern, but we also noted that this toxicity could be mitigated by using steroid eyedrops, which reduces the toxicity by 50%. And moreover, you can give it less frequently and in combination with immunomodulator drug to get the best results.

Then I talked about bispecific antibodies. We targeted the anti-BCMA bispecific antibodies. There are several of them. As a class, these drugs are all very effective with an overall response rate of 60 to 70%. But what is more remarkable is that these responses in the majority of the patients are deep responses, complete remissions and MRD-negative status. Because of the deep responses, the responses are also durable, so the durability runs about 18 months duration of response, and the progression-free survival (PFS) is 12 months. So, finally, in triple-class refractory myeloma patients, patients who have been exposed to immunomodulatory drug, proteasome inhibitor and anti-CD38 monoclonal antibody, these bispecifics are able to induce deep and durable responses. That is indeed remarkable.

Then I reviewed the 2 CAR T-cells that are approved and looked at what the future looks like. The 2 CAR T-cells both are directed against BCMA. They also induce deep and durable responses and complete remission. MRD negative status is achieved in many of the patients. One of the drugs, ciltacabtagene autoleucel (cilta-cel), had a response rate of 98%, and the responses were durable at 3 years plus, such that the progression-free survival was not reached. The median was not reached even at 28 months follow up. So, these bispecifics are also giving us deep and durable responses.

I also presented that patients who relapse after the bispecific antibody, they could be still re-treated with another bispecific antibody, except the target should be different. If they fail [with a] BCMA-directed bispecific antibody, then they could be treated with the GPRC5D-directed bispecific antibody called talquetamab, or FcRH5 directed bispecific antibody, cevostamab. These drugs are also inducing deep and durable responses, even in patients who had already failed one bispecific antibody. Likewise, if the patient failed talquetamab or cevostamab, these patients can go through even a BCMA-directed CAR T-cell therapy for a deep and durable response. 

What about patients who are failing CAR T-cell therapy? Even those patients, they could be rescued now with a bispecific antibody which is directed other than BCMA. Also, we realized that many of the patients who relapse after BCMA-directed therapy, they don't relapse just because the tumor cells no longer express BCMA. [In the] majority of relapses, they still express BCMA so you can still look at targeting BCMA.

In a nutshell, I was able to present that there have been tremendous advances in the bispecific antibody arena, as well as CAR T-cell cellular therapy. These are called immunotherapies.

One more area I introduced was the so-called cereblon E3 ligase modulating drugs (CELMoDs). These are selective ubiquitin ligase-modulating drugs. And in this there were 3 different drugs I highlighted. One is in phase 1 dose escalation, C4, which completely 100% blockage. And then the other 2 are from another company, BMS, which have gone a long way. And these are drugs which are also coming potentially into the clinic sooner and have shown that they also have excellent response [rates] against triple-class exposure refractory patients, with the response rate going up to 50% with these drugs. 

And moreover, I showed the basic science results or actually, clinical report results, of patients who had before going on therapy and on cycle 2, day 15, the bone marrow we can show the NK cells are activated, T-cells are activated. These are phenomenal drugs and I'm pretty sure they will be useful in combination with bispecific antibody, with CAR T.

Even with these existing drugs in clinical trial either approved or ready to be approved, I think cure should be feasible in the majority of myeloma patients who come to you as patients today. Thank you.

Source: 

Jagannath, S. How Immunotherapy and Cellular Therapy are Changing Our Approach. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.