Ask AI
Back Back
From Brain to Vein: Navigating the Road to CAR T-Cell Therapy
Activity Information

Activity

Progress
1
Course Completed
Activity Information

Released: June 29, 2026

Joshua Richter
Joshua Richter, MD

From Brain to Vein: Managing the Road to CAR T-Cell Therapy

[00:00:04] Joshua Richter, MD: Welcome to Hematology Unscripted, brought to you by Decera Clinical Insights. I'm your host, Dr. Joshua Richter from Mount Sinai. Today, we're kicking off our series on multiple myeloma, and our main focus today is gonna be discussing bridging therapy when it comes to CAR T-cell administration.

So, really, we need to talk stem to stern about what bridging therapy is, what the definition actually is, why we need it, what the implications are, and really the nuts and bolts of how we use it in clinical practice. So, let's start off with a couple definitions. We used to talk about CAR T in the realm of vein-to-vein time, the time between when we collect the T cells and when we reinfuse them. But, in reality, we have a new verbiage that we call the brain-to-vein time, the time between when you think you need to give a patient a CAR T and when they actually receive it. And the time between when you first think about it and when you actually collect their cells is called the holding therapy. The time between the collection of the T cells and the reinfusion is the bridging. So, let's talk about what happens, starting with holding and leading into bridging. What are our goals? Our goals are a couple of things. When it comes to holding therapy, we want to be able to control the disease because, if the patient has a packed marrow, we're not gonna be successful at collecting T cells. In addition, we wanna make sure that we don't harm T-cell functionality because, ultimately, if we give aggressive polychemotherapy like D-PACE or high-dose cyclophosphamide, we're not gonna be able to collect healthy T cells. So, really, that first step for holding leading into bridging is providing appropriate therapy to control disease but preserving the T-cell fitness.

There's a number of ways we can do this. Let's think about the most common one. In the United States, many of our induction patients are receiving quadruplets like Dara-RVd and ultimately spending some time either on lenalidomide or CD38, like dara plus lenalidomide. Usually, we actually consider even giving CD38-based therapy in second line. So, oftentimes, we're thinking of going to a CAR T-cell therapy in third line in the United States. So, how do we approach a patient who's progressing on a CD38-based therapy and an immunomodulatory agent, and we need to both control disease and preserve T-cell fitness? There are a number of ways to do this. I'm gonna share one of the more common ways that I do it, which is using selinexor-based therapy, either selinexor and bortezomib or selinexor and carfilzomib. The reason for selinexor is that not only does selinexor not inhibit T-cell fitness, but there's actually a recent ASH abstract that showed that selinexor upregulates BCMA expression on plasma cells. So, it's kind of like setting things up to knock them down.

So, oftentimes, I'll give XVd or XKd for a cycle or two. Once the disease is controlled, we'll be able to collect cells, and then I'll continue the selinexor-based treatment during the bridging process, between apheresis and lymphodepletion, so that the patient continues to have disease control and we're able to get the patient to the CAR T-cell infusion most appropriately. We recognize that the status of your disease at the time of CAR T-cell infusion is very important in regard not only to efficacy but toxicity, such that patients with bulky disease tend to relapse earlier and tend to have more serious adverse events, such as delayed neurotoxicity, MNTs, and even the dreaded and rare Parkinson disease. One of the reasons that we utilize selinexor-based therapy for many of these patients is that there's actually been evidence that it can act quite effectively in extramedullary disease, a feature that we know, if present at the time of CAR T-cell infusion, negatively impacts outcomes. So, often, I give XKd for patients in this scenario.

If you decide to use selinexor as a core of your bridging therapy, there's a couple of dos and don'ts to optimize the toxicity profile, as we've learned a lot in our institution about how to minimize the side effects by being aggressive in a prophylactic standpoint. For the most part, selinexor should be administered once weekly at doses ranging from around 60 to 100 mg, depending upon the myelotoxicity of the partner. I tend to give these regimens on a 28-day cycle, with the selinexor 3 weeks on and 1 week off in the same fashion that we administer our IMiDs, like lenalidomide or pomalidomide. And I highly recommend primary prophylaxis with 3 medications to prevent nausea and GI symptomatology. Dexamethasone is the first one. You get that for free. Then, we tend to add a 5-HT3, like ondansetron. And the third drug, we typically recommend a regimen like aprepitant or fosaprepitant. There's another drug, rolapitant, also called Varubi, which has the fewest drug-drug interactions and can be administered on days 1 and 15 of your 28-day regimen. If you're unable to obtain the Varubi or rolapitant or aprepitant or fosaprepitant, low-dose olanzapine at 2.5 mg can be an excellent adjunct to help prevent the nausea that can be associated with selinexor. If you follow these regimens, we tend to have minimal toxicity, which is important in the time leading up to CAR T-cell infusion.

There are a few other scenarios that I wanna talk about for bridging, and this is after we've collected the T cells. For patients with very aggressive disease, we have 2 other options we can utilize. One is polychemotherapy, and although regimens like DCEP, V-DCEP, and VD-PACE can harm the T cells, we recognize that since their T cells have already been apheresed, the time between apheresis and T-cell infusion is kind of a free zone where it's okay if you actually harm those T cells. But that being said, D-PACE and polychemotherapy can be not just very effective therapy but typically fairly toxic treatment and often involves prolonged admissions to the hospital and risk of febrile neutropenia.

Alternatively, more recently, we've begun to look at the utilization of a non-BCMA-targeted bispecific antibody in the bridging setting, and that's using the GPRC5D-targeted CD3 bispecific talquetamab. Now, this is a highly effective regimen, with very high response rates, although it is associated with CRS and ICANS and the on-target, off-tumor toxicities of GPRC5D, such as dysgeusia, rashes, and weight loss. Even though this is a very effective therapy, we have noted patients that received talquetamab during bridging go into prolonged remissions following CAR T. However, they may still have some residual dysgeusia in the months following this.

Ultimately, the choice of therapy that you make for bridging really will depend on what drugs your patient has had before. What are they refractory to? What are they naive to? How fast is this disease growing? How bulky is it? And these factors all go in there because, ultimately, we don't wanna give therapy that's so aggressive during the bridging setting that the patient is not able to recover functionally in time to receive their CAR T-cell infusion. So, as with everything, the road here is really to pick the Goldilocks answer. We don't wanna give them too little so that the disease progresses, and they have high-burden disease at the time of CAR T-cell infusion, which minimizes efficacy and maximizes toxicity. We don't want the porridge too hot either by giving aggressive polychemotherapy or even high-dose therapy, such as melphalan, as, although this can control the disease, it may also result in additional toxicity, preventing the reinfusion of the CAR T.

I find that the Goldilocks road in the middle is using a selinexor-based regimen, as typically this is a therapy that the patient has not yet had, and we can combine this with proteasome inhibitors or IMiDs, and, with proper prophylaxis, it can be a highly efficacious and tolerable regimen that can be administered in the outpatient setting. Again, admission for things like DCEP or talquetamab may be warranted for the more aggressive type bridging therapy. But if you're also going to then admit the patient for 14 days for the CAR T, we wanna try to avoid admission prior, as patients tend not to like being in the hospital. So, ultimately, the goal should really be to control disease and minimize toxicity during this bridging time. And again, in the therapy that we call holding, prior to the T-cell collection, we wanna make sure that we don't harm the T cells. And this is a particular area where selinexor may be advantageous because not only does it improve T-cell fitness but, again, it does upregulate BCMA expression on the plasma cells.

So, like a game of, bowling, it sets them up to knock them down.

And with that, my name is Dr. Joshua Richter. Thank you so much for tuning in to Hematology Unscripted. Looking forward to seeing you at future events.

This transcript was generated by AI and edited for clarity.