REGN5458: A Trial for Relapsed/Refractory Multiple Myeloma a BCMAxCD3 Bispecific Antibody Naresh Bumma MD

REGN5458: A Trial for Relapsed/Refractory Multiple Myeloma a BCMAxCD3 Bispecific Antibody Naresh Bumma MD

By Naresh Bumma, MD – Ohio State University – The James

The current stage for multiple myeloma treatment has changed very drastically in the last few years, with drugs such as anti-CD38 antibodies (bispecific antibodies), IMiDs, and chromosome inhibitors being used earlier and earlier. And that has led to a need for novel therapies that use novel, newer agents to treat multiple myeloma. B-cell maturation agent, or BCMA, has come up as one of these targets on the plasma cell that has been utilized to treat multiple myeloma using different approaches, and bio T-cell languages are one of them. Linvolseltamab (REGN5458) is a new compound, which is a CD3 BCMA bio T-Cell Engager, that is being studied in treatment. Full relapse refractor multiple myeloma.

What is the standard of care in this disease state, and why choose to pursue the REGN5458 (Livoseltamab) trial?  

So for multiple myeloma in 2022 there’s a lot of debates still ongoing,  but I feel like our standard care still remains induction with either a triplet or quadruplet drug regimen followed by, Stem cell transplant in patients who are able to get that. And then add a relapse followed by maintenance therapy and add relapse to do predominantly a triplet if tolerable with drugs that have different mechanisms of action or novel mechanisms of action. I think what is happening now with studies bringing drugs that were in the relapse setting closer to the upfront setting, we’re now ending up in this era where patients get exposed to very active drugs such as image, PIs, chromosome inhibitors very early on. And then when they do progress they sort of gap in knowledge there as to what to do. I think the importance of this study is that it’s bringing a newer drug with a novel drug mechanism to this. And I feel like this study clearly shows that because almost 99% of the patients were triple exposed, so exposed to an image, a PI and a anti-CD38 antibody 87% of those patients were penta-exposed and 37 penta-refractory. So this is a patient population that we’re gonna see very soon when we start using all the drugs early on that you now have they’ve seen all these drugs. What else do we do? And I think this is where this study is important because it brings this novel agent that you can now look at for your patient.

Can you please tell us about the REGN5458 (Livoseltamab) trial design and why it was set up this way?  

So the trial design was, it was a phase one 2 design and we’re in 252 patients. Patients were had to have at least three prior lines of therapy with active disease and had to be exposed to an IMiD, a PI and a CD30 antibody. The phase 1 portion had 9 dose levels at dose escalation with a maximum dose level of 800. Interestingly, we did not reach maximum tolerated dose in this study. But the decision was made to move on to the phase 2 portion with 200 milligrams of the recommended doses for efficacy and to mitigate safety. The interesting part was that the first 2 doses were given as a step-up dosing to mitigate the risk of CRS and this was done inpatient, but then the latter doses were old than outpatient. When we look at the patients that were enrolled in this study, this was a very heavily predated population and with a median of 5 prior lines of therapy. Like I mentioned earlier, almost all of them were triple exposed. More than 80% repent exposed, 37% repent, refractory is also very important to know that this is a patient population with a heavy disease burden. So at enrollment, a bone marrow biopsy was done and 37% of patient had more than 50% plasma cells in their bone marrow. Also, the serum B similar level was 0.43 milligram. And then when we look at the safety data with this so the most common hematological adverse event was anemia, and the most common non hematological adverse event was cytokine syndrome with CRS. CRS is something that we’re seeing more and more with T-cell engaging therapies such as CAR T-cells or BCMA T-cell bio-specifics. The incidence of cytokine release syndrome in this specific trial was 44% and the majority of this was grade 1, only 9% had grade 3, there was no grade 4 CRS In this event. Only 18% of patients had Tocilizumab being used in them. This was very predictable, the median onset of CRS was 11 hours after the first dose and it lasted for a median of 15 hours. So very manageable, and most patients with discharge within the week of admission. Looking at neurotoxicity or ICANS, this was seen only in 5.6% of patients and only 1.2 was grade 3 or higher. Infections were seen in 59% of patients but only grade 2 to or higher in 29% and opportunistic infections were seen in 4% of patients, but only 3% grade 3 to or higher. Now looking at efficacy, so in the 200 milligram cohorts, which is the focus of the data that we’re presenting, the overall responses was 64%, which is impressive given, a heavily pretreated population with so many prior lines of therapy.

Looking at the quality of the response, so VGPR or better was 45%. We did look at MRD (minimal residual disease) by flow cytometry, which is 10 to 5 minus 5, and out of those that were accessible it was 60%. Looking at the duration of response the longest duration we have as the logic that cut off. Was 28 months and longer in the 50 milligram cohort where we have longer follow-up we see that the patients who responded had a chance of maintaining their response of 60% at 18 months. In the 20 milligram cohort, it was 89% at 6 months. 

It would also have, interestingly, in the 50 milligram cohort, 8 patients that were able to increase the dosage to 200 hundred milligram to get a better response. And 6 out of 8 of those patients did respond, and 4 out of those patients had a VGPR or better. What we are having early and deep remissions, that are sustained with a response rate of 64% in the 200 milligram cohort. VIPR or better of 45%, MRD (minimal residual disease) is 60%. We are seeing a fairly manageable safety profile with zeros of 44%, infections are at 54%, but only 29 grade 3 or higher, on this study there were 14 deaths. 6 were from pneumonia, 4 were from Covid-19, unfortunately, and then 4 others were from other different causes. However, none of these were attributable to the drug itself. So overall we think that this is a, effective drug with a good response, very good response rate with a manageable safety profile that definitely I think is, has a place in the treatment of relapse refractory multiple myeloma.

What are the most common questions you get from your colleagues about the REGN5458 (Livoseltamab) study?  

The first most common question is efficacy of the drug which we talked about, at the 200 milligram, does 60% overall response rate, 45%, VGPR or better, 60% MRD (minimal residual disease). The second is this response durable. Which we again for the 200 milligram cohort, 89% at 6 months. The second question is obviously tolerability, right? We would like a drug that is also not only effective, but also palatable. And the biggest thing that people look. Who have not done too much of T-cell directing therapy are concerned about is cytokine release syndrome and how this compares with other T-cell redirecting therapy, which with Linvolseltamab (REGN5458) cytokine release syndrome of 44% but only 18% requiring Tocilizumab is very manageable. And it is also very predictable in its onset and its duration. I would say another common question is the administration of it which is the first 2 doses being given inpatient as a step-up dosing, after which it can be given weekly as an outpatient, and then after 16 weeks go down to every 2 week dosing. I would send that. The third one would be, any pre-medications that we require with this medication. And usually it is antihistamines with antagonists, acetaminophen and IV dexamethasone for the first dose as needed. So I would say those are the common ones that they ask me.

What are the key takeaways from this research and data on REGN5458?  

So I would say the first key update is that We’re now in an era where we are, patients are living longer and longer, but myeloma as, even though we are inching, we are getting closer to the cure, is still not curable. So we have to think about what are the steps or what are the treatment options we have in our back pocket when patients’ disease progression happens on what is now becoming standard of care. So your anti-CD38 antibody, your image, your PI, and how can we harness immunotherapy and T-cell redirecting therapy for these patients. I would say the other thing we also have to keep in mind, and which has been made very clear by the pandemic, is access to care. When we look at CAR T-cells and being able to access centers that do CAR T-cells, the bispecifics do bring a certain advantage of being able to be given off the shelf. And with an outpatient dosing, not being in the hospital that much, it is something that is attractive to that specific approach. However, we do have to be cautious with infections and learn how to manage that. And I would say it is a sort of, we’re getting in an era where we have an environment of riches, but that doesn’t mean we should sit on laurels and we should always look forward to what would be the next step to make this more of a marathon and keep our patients alive and in good shape and being able to enjoy their life and not be in the hospital as much as they otherwise would be.

What is REGN5458 (Livoseltamab)?

REGN5458, also known as Livoseltamab, is a monoclonal antibody that is being developed by Regeneron Pharmaceuticals for the treatment of various types of cancer. Livoseltamab (REGN5458) works by targeting and blocking a protein known as DLL3, which is found on the surface of certain cancer cells.

DLL3 is a promising target for cancer therapy because it is expressed at high levels in various types of cancer cells, including small cell lung cancer, neuroendocrine tumors, and other solid tumors. By blocking DLL3, Livoseltamab may help to slow or stop the growth and spread of these cancer cells.

In preclinical studies, Livoseltamab (REGN5458) has shown promising results as a potential treatment for small cell lung cancer and neuroendocrine tumors. In a phase I clinical trial, Livoseltamab was well-tolerated and showed preliminary evidence of antitumor activity in patients with advanced small cell lung cancer.

Regeneron Pharmaceuticals is currently conducting a phase II clinical trial to further evaluate the safety and efficacy of Livoseltamab (REGN5458) in patients with small cell lung cancer and other DLL3-expressing solid tumors. The trial is expected to enroll approximately 160 patients and is designed to evaluate the efficacy of Livoseltamab as a monotherapy and in combination with other cancer treatments to help with progression-free survival (PFS).

Overall, Livoseltamab (REGN5458) represents a promising new approach to cancer therapy, and further clinical trials will help to determine its potential as a treatment for a variety of solid tumors.

10 Key takeaways about the REGN5458 (Livoseltamab) Clinical Trial

1. Linvolseltamab (REGN5458) is a bispecific antibody that targets BCMA (B-cell maturation antigen) and CD3, which is being studied as a potential treatment for relapsed/refractory multiple myeloma.

2. The LINKER-MM2 clinical trial is evaluating the safety and efficacy of linvolseltamab in combination with other cancer treatments, including dexamethasone and pomalidomide, in patients with relapsed/refractory multiple myeloma.

3. The study is being conducted across multiple centers in the United States and Europe, and will enroll approximately 160 participants.

4. The primary endpoint of the study is the overall response rate, which measures the proportion of participants who experience a partial or complete response to the treatment.

5. Secondary endpoints include progression-free survival (PFS), overall survival, duration of response, and safety.

6. The preliminary results from the study have shown that Linvolseltamab (REGN5458) in combination with dexamethasone and pomalidomide is well-tolerated and has demonstrated promising efficacy in patients with relapsed/refractory multiple myeloma.

7. The most common adverse events associated with the treatment include cytokine release syndrome, which is a known side effect of bispecific antibodies, as well as anemia and neutropenia.

8. The study is ongoing, and final results are expected in the coming years.

9. If successful, linvolseltamab could provide a new treatment option for patients with relapsed/refractory multiple myeloma who have exhausted other available therapies.

10. The development of bispecific antibodies like linvolseltamab represents a promising new approach to cancer treatment, and could potentially be used to target other types of cancer in the future.

Naresh Bumma, MD – About The Author, Credentials, and Affiliations

Naresh Bumma, MD,  is a highly accomplished medical professional, currently serving as an Assistant Professor of Clinical Radiation Oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Dr. Bumma received his medical degree from the University of Miami Miller School of Medicine and completed his residency training in Radiation Oncology at the University of Texas MD Anderson Cancer Center. He also completed a fellowship in Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy at the University of Texas Southwestern Medical Center.

As a radiation oncologist, Dr. Bumma specializes in the use of radiation therapy to treat cancer. He has a particular interest in the treatment of brain tumors, head and neck cancers, and lung cancers. He is also an expert in the use of advanced technologies, such as stereotactic radiosurgery and stereotactic body radiation therapy, to deliver highly precise doses of radiation to tumors.

In addition to his clinical work, Dr. Bumma is an active researcher and has authored numerous peer-reviewed articles and book chapters. His research interests include the development of new radiation therapy techniques, as well as the use of radiation in combination with other therapies, such as immunotherapy, to improve cancer outcomes.

Dr. Bumma is highly regarded by his colleagues and patients alike for his compassionate and patient-centered approach to care. He is dedicated to providing the highest quality of care to his patients and is committed to advancing the field of radiation oncology through his clinical and research work.

Regeneron Pharmaceuticals – About the Company

Regeneron Pharmaceuticals is a biotechnology company that develops and manufactures innovative drugs and treatments for various medical conditions. Founded in 1988, Regeneron is known for its work in developing targeted therapies for cancer, eye diseases, and inflammatory conditions. The company’s flagship drug is Eylea, a treatment for wet age-related macular degeneration, and its COVID-19 treatment, a monoclonal antibody cocktail called REGEN-COV, has received emergency use authorization from the FDA. Regeneron has also been recognized for its commitment to sustainable practices and has been named to Forbes’ list of America’s Best Employers.