Ankit Kansagra, MD, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center and assistant director of the Outpatient Stem Cell Transplant Program, discusses newly approved multiple myeloma (MM) agents and takes a look at the pipeline for interesting therapeutics that may come to market.
DocWire News: We’ve seen a couple of new therapies become FDA-approved in the past few months for multiple myeloma, including belantamab mafodotin and isatuximab. Can you talk about some of these new agents, including the data behind their approvals and your opinion on them?
Dr. Kansagra: We can start with belantamab mafodotin. Obviously, this is the first of its class in the BCMA-directed therapy. So this is an antibody drug conjugate, meaning that there is a drug called MMAF, which is attached to the antibody, which is against the BCMA on the cell surfaces, which is on the surface of all the plasma cells or, I would say the, the malignant plasma cells predominantly. Basically, what this drug does is the antibody attaches to the myeloma cell and the chemotoxin or the chemotherapy, which is attached to the antibody, gets into the myeloma cells and destroys that.
I think it was innovative for two main reasons. First, is it’s the first of its kind targeting BCMA in multiple myeloma. And the second thing, this is the first of a kind antibody drug conjugate in myeloma. We do have a few antibody drug conjugates in other hematological malignancies or cancer itself, but this was the first to see it. I think what’s the most impressive about this is its mechanism affection. The second very impressive thing about this was its response rate. We have seen patients on the DREAMM-1 and DREAMM-2 studies, which led to the approval of the medication, we already are seeing that the response rates patients are getting are really excellent. Even though the response rates were not amazing, maybe it was in the 30% range or so, we would have loved to see more for our patients, it persisted, the progression-free survival was excellent when we are looking at non-CAR T-cell therapy.
I hate to compare the BCMA antibody drug conjugates, or bispecifics, to CAR T-cell therapies. They are kind of comparing different modalities of treatment. So those are not direct comparisons, but when you look at therapies in that category, where you are four-, five-, and six-line out with your treatment, and you have a single-agent drug with no dexamethasone in the treatment armamentum, it probably is one of the best options you can think of. It has an every three-week infusion, which is how it can be delivered with minimal toxicities, other than its ocular challenges. Obviously, we have learned that’s the biggest challenge with it. It comes with the REMS program or the certification where the patients have to be monitored for their eye toxicities.
We have learned and, as we have had patients on clinical trials and then the expanded access programs and as all the country gets ready for its commercial use, we will start learning how this is going on, how much more ocular issues are going up, how is it going to be feasible for the patients—is it going to be feasible all around the country, is it feasible for a small community hospital, or it’s going to be hard to get an eye care provider. The company is understanding those challenges by listening to a lot of the physicians around the country, so I hope there are more resources available for our patients to have access to these therapies, because this is certainly an important therapy available to our patients.
Now, what is exciting about this is with any other antibody drug conjugate, or antibody-directed therapies, like we saw with daratumumab, this is obviously a potential of combination with other things. So belantamab is already looked at in combination with bortezomib or lenalidomide or pomalidomide, and multiple other things, including checkpoint inhibitors and other antibodies. There is a potential to improve on that response rate and probably trying to limit the toxicities with it. That’s the fine balance in any drug development we see and hope to see, that it’s coming along and further in the development lines, maybe when there’s already some studies being developed in the newly diagnosed setting where belantamab will be given to patients who are just newly diagnosed in combination with [bortezomib] and [lenalidomide]. I think there is a lot of excitement from these compounds, and hopefully we can get even better response rates.
Now, isatuximab is a CD38-directed antibody. This is a second of its generation antibody in multiple myeloma. We have daratumumab, which is the first CD38-directed antibody. Isatuximab comes in with a slightly different way of how it attaches to CD38 and its length of effectivity and subtle changes in the mechanism of it. There were some new answers in how the drug itself works. In regard to its earlier lines, we have seen it as they did one of the biggest phase III studies and combining it with pomalidomide and showed very impressive results rate, which we anticipated knowing some of the data behind that daratumumab and pomalidomide use more in the real world than in commercial utility. That was the first huge thing.
The second thing is, this drug has become available—it’s a shorter infusion time; cost-wise, it’s somewhat cheaper than daratumumab, if I understand correctly. Obviously, there are new answers to that, but overall, it might be a cheaper alternative or an option from just a cost bucket of it. There are certainly some added benefits to it. Now, it comes as a second antibody, so a lot of doctors have been using CD38 antibodies for a while now, close to four or five years. A lot of us have been used to [daratumumab] and now the subcutaneous form of [daratumumab]. That is certainly taking off the IV medications out of the list, and more and more people are focusing toward the subcutaneous versions of it. There are pros and cons of using [daratumumab].
The utility of re-dosing with the CD38 antibody or different CD38 antibody after they’ve relapsed with one, I think there might be some avenues to explore with the use of isatuximab. There are few more CD38 antibodies which are in development by different companies, which we had seen some phase I data from the last ASH meeting, if I’m not wrong. CD38 is still a good target in myeloma, and time will tell what excitement we can get with the newer drug delivery or newer modalities of attacking CD38.
DocWire News: Are there any other investigational agents not yet approved in the pipeline that you’re really interested in?
Dr. Kansagra: Yes. Tons of them are out there coming up. What we have already started seeing, as I mentioned, the CD38 from Takeda has one of the compounds, which is looking very interesting as a single-agent activity. Now, CELMoDs, which is CC-220 and CC-480, which are kind of the newer generations of immune-modulation drugs being out there or cereblon inhibitors coming from Celgene or BMS out there. I think they are looking really impressive in the early data as a single-agent activity that has already combination trials with CC-220 coming up in different phases and forms, that is looking very good.
I didn’t really touch on any of the bispecific therapies—there are about five different companies making BCMA-targeted bispecific therapies. But, along those lines, we have different targets on bispecifics, which are being developed. Not every one of those BCMA-targeted, or bispecifics, have some nuances—one is subcutaneous, one is IV; one has more cytokine release syndrome (CRS), one has less CRS. But these are very early in their development, so it’s very hard to say that the response rates are going to be the same at the end of the day or not.
The interesting part is going to be the newer targets. There is the GPR5CD, which is a bispecific, which is coming out of Janssen, which is going to be an interesting target. There is obviously interesting options and combination bispecific therapies, which are being developed. I think that is certainly excitement along those lines.