Krina K. Patel, MD, MSc, discusses the use of CAR T-cell therapy in multiple myeloma, potential target antigens beyond BCMA, the rich research landscape, and the role of quadruplets and radiation therapy.
The development of immune-based therapies, such as CAR T-cell therapy and bispecific T-cell engagers (BiTEs), have already shown impressive single-agent activity, explained Krina K. Patel, MD, MSc, who added that, in the future, the optimal use of these agents may be in combination with other immunomodulatory drugs, such as cereblon E3 ligase modulators (CELMoDs), to enhance their activity.
“In the future, I think we’re going to get rid of all chemotherapy; everything is going to be [centered around] immune therapy,” said Patel, an associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on multiple myeloma.
The virtual event covered exciting treatment developments in frontline and relapsed/refractory multiple myeloma, current and future applications for CAR T-cell therapy, and the integration of radiation in the treatment of patients with myeloma.
In the interview, Patel, who chaired the meeting, discussed the use of CAR T-cell therapy in multiple myeloma, potential target antigens beyond BCMA, the rich research landscape, and the role of quadruplets and radiation therapy.
Patel: Having this first standard of care has been so big for our patients. We have more demand than supply, but having gotten our first patients through, these are patients that couldn’t necessarily make it onto the clinical trials, because their kidney function was just a little bit too high, or their disease is non-secretory. Trials don’t allow for that, so to get those patients onto CAR T-cell therapy now has been fantastic because we’re improving access rather than limiting access.
There’s still a long way to go, but we’re really excited that there’s going to be a second CAR T-cell therapy down the road. We’re excited that it’s going to hopefully go through, and we’ll have even more options [in that case]. We have always had problems getting enough slots for our patients on trials. Unfortunately, our patients aren’t cured. But with the advent of CAR T-cell therapy, we have seen patients get these phenomenal responses, not only response rates in the 80% to 100% range—where most drugs in this range [have around a] 30% [response rate]—but a progression-free survival [PFS] of over 1 year with 1 dose of cells. The fact that you’re not on any therapy that whole time, and you’ve had myeloma for this long, and you pretty much had everything already, that’s a miracle.
Then, patients are responding to [treatments] again, even upon relapse, even though we can’t cure [the disease] yet. When [patients] relapse, they’re responding to [drugs] that they were already refractory to before, and that tells me that this is doing something to the myeloma clone or to the microenvironment. I get really excited, because that’s what we’ll learn [about] as we get more patients on [this treatment].
The fact that we have so many BCMA-directed therapies is a good thing. I don’t think you have to pick one or the other; it’s really going to be about sequencing for most patients. We need to learn about resistance mechanisms so that we don’t give someone BCMA-directed therapy if they don’t have BCMA expression anymore, but that happens in a smaller number of patients than the majority, especially after CAR T-cell therapy where that pressure isn’t constantly on BCMA.
Eventually it’s going to be: Can we get them on to more than one CAR T-cell therapy? Upon relapse [after one CAR T-cell therapy], can they go on another one? We have had some anecdotal cases in clinical trials where they’ve allowed that. This will give us more data to hopefully support all of these things.
The antigen part of it, too, is really what’s important. BCMA is great, but now, with these new antigens that are coming in, we’re going stick CAR T-cell therapy to them too and maybe combine them. It’s a game changer. I’m really excited to see head-to-head [data] with stem cell transplant [vs CAR T-cell therapy].
In lymphoma, we’re getting all of these data soon. Hopefully, by the 2021 ASH Annual Meeting, we will see all the data about transplant vs CAR T-cell therapy in first relapse. In myeloma, we tell our patients to go to transplant as consolidation. Hopefully, we’ll have those trials to see if maybe we finally beat high-dose melphalan 40 years or 50 years later.
Everyone always says, “Well, you can cure some lymphomas, you can cure some leukemias. Why can’t we really cure any myeloma?” Most people say, “Maybe we functionally cure 10% of our patients because their myeloma stays down for over 10 years.” Unfortunately, we all die from something, but their myeloma never came back. To me, that doesn’t mean cure.
I think the plasma cell is just way smarter than all these other cancer cells in general. There are a lot of different antigens. Why do we do combination therapy? Why isn’t it just 1 drug [that is needed]? For most patients, 1 drug works for a little bit, and then it gets resistant. The myeloma cell learns how to circumvent that pathway, and it becomes resistant to that [drug]. If you use multiple pathways, you end up with a better response, because it takes longer to become resistant to all the drugs that you’re using.
It is the same way with the antigen. If we figure out that partly, resistance mechanisms are antigen dimming or antigen loss, if you use different antigens, you can keep someone in response, just like you think about combination therapy.
The biggest antigens so far [include] CS1, and SLAMF7 is one that we have used for monoclonal antibodies already, but there are CAR T-cell therapies that are using this, both autologous and allogeneic. The issue is that there are some normal T cells and B cells that have CS1 on there. Sometimes if your CAR T-cell therapy is too strong, it might kill some of those off. It’s not perfect, but there’s a lot of value to CS1 because the majority of patients have CS1 expression.
FCHR5 is another great potential target. There are some T-cell engagers that people are looking at [there]. GPRC5D is a great target that is really on hair follicles, but, otherwise, not too many other normal tissues have it. That’s been the hardest part, and I think is why lymphoma is ahead of us [with CAR T-cell therapy]. CD19 works so well for them, which was great. We tried it for myeloma thinking, “Maybe there’s a stem cell or early plasma cell that we could kill,” and [we saw] some mixed response there. It wasn’t a home run. When we found BCMA, a target that’s really on myeloma cells, the majority of patients have it, and it works; that really was the home run for myeloma.
Now, every antigen that we look at has to get to that level. There’s a high threshold that we have to reach, but all of these new targets that people are looking at do have a lot of promise. It’s just a matter of making sure you don’t increase the toxicity. People have even made CAR T-cell therapies for CD38 and CD138. However, that is on some normal tissues, like the lungs or red blood cells, so you have to make sure you can toggle it to where it’s not causing the toxicity but giving you the response.
As we get smarter, we’re going to be using all of these targets; it might not be perfect like BCMA, but we need to learn more, and eventually, we’ll be able to hopefully target all of those [antigens].
Elranatamab is one of the T-cell engagers. Here, you’re not actively taking the T-cell out, putting in a receptor in like a CAR T-cell therapy and then giving it back, but you’re harnessing a patient’s own endogenous T cells to come close to the myeloma and then kill that myeloma cell. The way I look at it is like handcuffs. The CD3 takes the T cell that’s already there, the BCMA takes the myeloma cell and puts it next to each other, and that CD3 kind of puts a little bit of fire under the T cells’ butt to get activated and to kill that myeloma cell.
Many studies have been done for CAR T-cell therapy and BiTEs for BCMA, but out of all of them, elranatamab is sort of in that top 3 in terms of the response rates and how quickly it has been dose escalated and is going for fast track approval from the FDA. We’ve seen some fantastic responses of 80% or higher in their highest dose levels, which is pretty phenomenal. Nothing in these patients who have been this relapsed/refractory has ever, before CAR T-cell therapy and now T-cell engagers, has ever gotten to that level. The data are a little bit early right now, but if you show that the PFS is 1 or 2 years or maybe longer than that of CAR T-cell therapy, maybe they’ll win out. [Regardless,] it’s still a great option for patients who have gotten CAR T-cell therapy and patients who can’t get CAR T-cell therapy. There are all kinds of reasons why T-cell engagers might be more advantageous for certain patients, or just using it in a different combination and sequence for CAR T-cell therapy vs T-cell engagers.
The biggest adverse effects [AEs] are still cytokine release syndrome and neurotoxicity. We still don’t see very much of that compared with other cancers, which is great. It’s been pretty manageable. As patients go farther and farther, it seems that they don’t get as much of that. We are looking for infections and counts for both T-cell engagers like elranatamab vs CAR T-cell therapy, which are a little bit different between the 2, but [they] have the same types of AEs that we usually see.
Everyone always compares them to immunomodulatory drugs [IMiDs], and I know they’re not the same thing, but because we have so much experience with [that class], it’s sort of like the next generation of oral medications that work really well against myeloma. We’re excited [about these agents].
When I give s patient CAR T-cell therapy and they relapse afterwards, and I can use IMiDs again and patients are responding when they were completely refractory to those IMiDs beforehand, I can’t even imagine what CELMoDs are going to do because they also increase interleukin [IL]-2 and other things that help your immune cells. It works directly to kill the myeloma, but the immune changes that it produces helps with all these other immune therapies. You’re talking about T cells and natural killer [NK] cells, and then you throw a CELMoD in there that helps activate some of those, and then if you put a bispecific with it, you’re just going to get even more activated cells.
It helps in the sense of combination therapy, and [may be used] as a maintenance [treatment] after one of these bigger therapies and once a patient achieves minimal residual disease [MRD] negativity vs a combination of immune therapy.
In the future, we’re going to get rid of all chemotherapy; everything’s going to be immune therapy. That combination is what’s really going to help. Even with monoclonal antibodies, for instance, we know that you use NK cells and T cells for ADC and antibody-dependent cellular cytotoxicity, but if you have something that helps activate those cells plus the actual monoclonal antibody, you’re going to get a much better response likely than without it. I see it being able to be combined with pretty much any immune therapy and enhance it.
The fact that I have 6 or 7 different choices for frontline therapy now is the biggest thing. I can tailor what I need to give my patient based on their circumstance [which is great]. When I was a fellow around 6 years ago, we mostly gave VRd [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] because that was the newest thing, and it made sense. Now, in just a short period of time, I have all kinds of options, with monoclonal antibodies, or still giving VRd, or KRd [carfilzomib (Kyprolis), lenalidomide, and dexamethasone].
In terms of the patient, we look at a lot of things, but the 2 main things are standard- vs high-risk disease and frail or fit [status]. I don’t want to overtreat someone that’s going to end up with more toxicity, and I don’t want to undertreat someone that could take more to make sure that their myeloma stays down.
Quadruplets are fantastic. I’m a big proponent of making sure you use all your best therapies early because that really is where you get that myeloma down the longest, and that usually means better quality of life [QOL,] too. However, our goal is going to be getting everybody to an MRD-negative state. I don’t have a lot of data to support that yet. We definitely have data out there that patients who get to MRD negativity and stay there for at least 1 year are the ones who do the best anyway.
Do we need 4 drugs to get everybody to MRD negativity, or if 3 drugs are enough, are we going to then induce resistance, or more infections, or more toxicity? The quadruplets will probably get more patients into MRD negativity, but really, we need a biomarker, in the end that tells us the ones who are going to do well anyway, maybe I don’t have to give them 4 drugs.
The fact that we have this monoclonal antibody against CD38 with some of our most powerful supportive therapies with it, [such as] pomalidomide [Pomalyst], makes a lot of sense because it helps [with] some immune activation too with NK cells and T cells. Isatuximab plus pomalidomide and dexamethasone [Pd] had a much longer PFS, and it was a pretty dramatic improvement, which is great. We also saw more patients who got deeper responses [with the triplet]. It was 15% vs 3% for the triplet vs the doublet.
Carfilzomib plus isatuximab [and dexamethasone] is really where I am even more impressed since carfilzomib is not really considered an immune therapy; it’s a proteasome inhibitor. It’s a great drug, but to work with a more immune-based therapy [is impressive]. They had fantastic and deep response rates. Greater than CR [complete response] rate was 37% vs 27.6% for the triplet vs the doublet, and the MRD-negative status was 30% vs 13%. We know that the deeper response patients get, the more likely their PFS is going to be longer. The same thing is true with tolerability. Most of my patients do well with both of these triplets and tend to have better QOL when their myeloma is responding better.
The fact that we have so many new therapies in the past couple of years tells us how much more we’re learning about myeloma. In a patient population where cure is not possible for the majority of patients, we need ammunition to be able to fight it longer and longer. We know that the longer patients live, the more therapy they have access to.
With melflufen, you’re getting more drug to the myeloma cell, and decreasing toxicity, which is still important and probably will give you better responses. We don’t have a head-to-head trial of melphalan vs melflufen, but I would think that, because it is being targeted to the myeloma, you would see improvement. It is the same thing with belantamab mafodotin, with completely different mechanisms of action. There’s probably a lot more we can learn from in the next few years. Single-agent therapy is not ideal. Selinexor plus bortezomib is probably much better tolerated and has better PFS compared with selinexor by itself. We’ll probably see with the other drugs that combinations probably work better. I’m excited to have those data come out and hopefully get approval soon for all those drugs.
My go-to is immune therapies. Things like co-stimulatory molecules and other therapies that can really help CAR T-cell therapy work better are what I’m excited about. We’re working with Nektar on IL-15, which is exciting. Venetoclax [Venclexta] is a great drug for patients with translocation 11;14. Hopefully, some of those studies will finish soon. That [would] be our first approved drug for a specific, myeloma subtype, which will be exciting, and hopefully help us to develop more biomarkers for the rest of these types of treatments.
Radiation and surgery can be adjunctive therapies. If you have a cortical lesion that potentially puts that patient at risk for fracture of a long bone, for instance, or a bone that you use for normal functioning, it makes sense to do something quickly. Radiation can help improve or preserve QOL.
We have lots of patients who end up with bone disease, and if they have painful bone disease, sometimes radiation can work a lot faster. Our radiation team has been phenomenal at coming up with new dosing and decreasing the dose of radiation so that you don’t get cytopenias. If you radiate a lot of bone marrow, you’re going to end up with low counts, and then you can’t give the chemotherapies and immune therapies you want to. They have been working with us to come up with ways so that we get pain and potential fractures, etc., fixed quickly, without compromising long-term effects. That was the biggest takeaway from her talk: how you integrate radiation with systemic therapy.
The other big thing is that there are immune effects that radiation leads to. How do we capitalize on that? If patients have target lesions, can we give something like radiation to help improve at least the local immune system and the cytokines etc., so that when we give other therapies, they work better?
There has been at least 1 report from Memorial Sloan Kettering Cancer Center, which showed a patient who got CAR T-cell therapy and didn’t respond very well and was having cord compression, and when they got radiation, suddenly, their endogenous cells improved, increased, and their myeloma in other areas got better even though the radiation was just in the spine. That tells us that with the cytokine storm that can happen with CAR T-cell therapy, you’re improving endogenous cells too. Then, how do you harness that to help knock the myeloma down? We’re just at the beginning of that, too.