Bridging Therapy & Lymphodepletion: What to Expect on the CAR T Timeline

Lisa Hatfield: 

Dr. Patel, you have a unique perspective on how patients enter the CAR T pathway. Many patients hear the term bridging therapy but don’t fully understand bridging therapy. So what is bridging therapy, and where does it fit into the CAR T timeline? And can you also explain the difference between bridging therapy and lymphodepletion?

Dr. Krina K. Patel: 

Yeah, so great. I’m actually going to add a third term, too, called holding therapy into this to make it a little bit, hopefully, makes more sense. So, when somebody comes to me for CAR T therapy, you know, usually it’s because their numbers are going up, right? Their myeloma’s coming back, it could be slowly, it could be fast, but they’re eligible for CAR T next, and so we talk about it, and they want to move forward.

My next thing right then is, okay, I have to get insurance approval, so we submit, we have to do something called an ID panel, and we have to submit everything. And that could take 1 to 2 weeks, so thankfully it doesn’t take very long anymore, it doesn’t take months, but, it still can take 1 to 2 weeks. So if somebody is having disease that is progressing. I could have a patient that has a fracture from a bone lesion, or lots of lesions, or kidney issues that they’re having.

Well, I need to get them started on something else, so that I can knock that myeloma down so that they don’t have worse outcomes from the myeloma itself. So that’s called holding therapy. Basically, before I collect their T cells, I need to do something so that they don’t have a major crisis or, you know, bad outcome from the myeloma.

Then there are other people, that it’s just a biochemical progression, it’s not really causing organ involvement, I have time. I don’t need to do holding therapy, so we just wait until we get their apheresis slot, their approvals, they get their apheresis. And then I have to start treatment. So again, it takes for today, it takes about 4 to 6 weeks for most patients, some 8 weeks to get their CAR Ts back once we send them off. If we don’t do anything for that myeloma during that time, for most people, that myeloma is going to start growing and then start causing problems. So bridging therapy is the treatments that we give to kind of help knock the myeloma down, or at least keep it from growing if they don’t have very much myeloma, during that time, those CAR T cells are being made. So after we’ve collected, we start the bridging therapy, and then we go, you know, usually one to two cycles, and then we go onto the CAR T therapy once we have the cells ready.

And then the LDC chemo, the lymphodepletion, is basically two chemos called cyclophosphamide (Cytoxan) and fludarabine (Fludara). It’s the same for all the CAR Ts that are approved as of today. Similar dosing. It’s 3 days of it for both drugs. And this chemo is basically, it’s similar to the chemo we get with transplant, that high-dose melphalan (Alkeran), but not anywhere close in terms of how big a dose it is. It’s much lower dosing outpatient.

Most people are not having any kind of nausea, vomiting, or, you know, GI symptoms. But it’s enough treatment to knock the immune system down. So, if we didn’t give lymphodepletion chemo, if we gave the CAR Ts without it, most people, your immune system, your own T cells that are still in your body, would see the CAR part of the T cell, the CARs, and say, this is not me, this is a foreign thing, I need to kill it, so it kills it off.

And so what we need to do is turn off your T cells, the ones on your body still, just for a little bit. And then give those CAR Ts so when they go in, they have a chance to go kill the myeloma. And then usually a couple of weeks later, your own immune system’s coming back, and they’ll start taking out the CAR Ts after they’ve done what they need to do. 

So, the LDC chemo is a part of the CAR T, it’s not really affecting the myeloma so much, but again, just turning the volume of your own immune system down so that the CAR Ts have time to do what they need to do. And so, you know, that’s the same. The bridging therapy, kind of going back, those options we have lots of. So when patients go to CAR T earlier, there’s a lot of different therapies I can use to help knock that myeloma down, and what we know is that patients who have less myeloma going into the actual CAR T-cell therapy have a lot less toxicity, including some of the big toxicities we worry about, like neurotoxicity, or, you know, high-grade CRS cytokine release syndrome. It decreases by so much in terms of the actual toxicity occurring.

And then it also improves efficacy. We know that patients who have myeloma that’s decreasing on the way to CAR T are the ones that are more likely to have the many years of remission, or even getting to that 5-year mark that we’ve seen with cilta-cel (ciltacabtagene autoleucel [Carvykti]) now. So, that bridging therapy is really, really important, as is the LDC, and for some people, the holding therapy, too.

Lisa Hatfield: 

Okay, thank you. So, two follow-up questions to that. If somebody is going through bridging therapy and you are not seeing their myeloma numbers decreasing or the tumor burden’s not being reduced, is there a cutoff for that? Is there a certain number you want to see, and will you hold the CAR T? And how long can you store those CAR T cells? And on the flip side of that, have you ever had a patient that thinks, well, this bridging therapy’s working pretty good, do I actually need to get my T cells reinfused? Has anybody ever asked you that question?

Dr. Krina K. Patel: 

Yeah, those are great questions. So, yes, there are patients of mine where their bridging therapy didn’t work the first cycle, so we switched, we changed to something else to really knock it down, and I will say, if people have higher risk disease, high-risk cytogenetics, or extramedullary disease, or they had plasma cell leukemia in their blood, or just they had a lot of myeloma by the time they came, and we’re not knocking it down. Those are my patients I really want to knock this thing down for. So, you know, fourth line or later, we end up going to talquetamab (Talvey) a lot, because it can knock it down, and I’m not worried about the T cells anymore, because I’ve already collected them, and then it’s a different target, so I’m not worried that there’s not going to be the BCMA target for the CAR Ts to find, right? That the other therapy did something. So, it’s actually worked really well. We’ve had a few papers on that already out there, so a lot of people use it.

Yeah, I do take the bridging therapy thing very seriously, because again, you decrease the toxicity, and that’s huge for our CAR T cells. And you increase the efficacy. So again, if you get a one and done, and you get time off treatment, I want to make sure you get the longest time possible, right?

I’ve had a couple of patients that have responded really well to talquetamab, especially. And we’ve decided, you know, either to keep going with talquetamab or go to the CAR T. The CAR Ts are good for about, one of them is 9 months, cilta-cel, they say, is 9 months. Ide-cel (idecabtagene vicleucel [Abecma]), we were told, usually a year. So we do have the ability to hold them.

The few times I’ve held it, for a little bit longer than even one or two cycles, one of my patients that, you know, just had a lot of side effects to a lot of myeloma therapies, we did really low dose treatments for things he’s had in the past, but just combined it differently. Carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone (Decadron), but we did low dose. 

It worked, but because of side effects, we had to keep it at low dose. So we actually did six cycles of that before he went on to the CAR T, because again, when he came in his M protein was, like, 8, and we really wanted to reduce that burden of disease so that hopefully he wouldn’t have any of the major side effects with CAR T, and he got his CAR T, and he did really well relative to, I think, how he would have done if we had gone when his M protein was so high. So, it is individually, you know, based on how much disease somebody has, what side effects they’ve had to other therapies.

What options do we have available that, you know, have a good chance of working? But yes, you know, we sometimes do give more than one cycle, or even change that bridging to make sure we knock it down.

Lisa Hatfield: 

Okay, thank you. Do you have any [ACT]IVATION tips, particularly for questions that patients might ask their specialist when they’re going in for CAR T regarding bridging or lymphodepletion?

Dr. Krina K. Patel:

Yeah, so the goal of bridging is to really knock the myeloma down, and especially for high-volume disease, but even low volume. And it’s making sure that you improve efficacy, but, you know, don’t increase toxicity. Those are the main takeaways for bridging therapy.