How should you sequence CAR-T and BsAb therapies?

CAR-T cell therapy and bispecific antibodies are two of the most powerful weapons in the fight against myeloma. But when it comes to using them, one big question remains; which comes first? Should you start with CAR-T therapy and follow up with bispecific antibodies, or flip the order? And how does sequencing impact patient outcomes and durability of response?

In today's HealthTree University lesson, we're breaking down the science, the strategy, and the real world clinical decisions behind sequencing CAR-T and bispecific antibodies, and why getting the order right could make all the difference. How should you sequence CAR-T cell therapy and bispecific antibody therapy? We have, as we know, two FDA approved CAR-T products. We have idecabtagene vicleucel or ABECMA, ciltacaptagene autoleucel or CARVYKTI.

Both target the same protein on the myeloma cell called BCMA. These are approved as soon as second and third line of therapy. And then we have multiple bispecific antibodies, which are other type of immunotherapies that are readily available. We have two that are FDA approved that target also this protein, the same protein on the myeloma cell called BCMA.

The names of those are teclistmab and elranatamab. And then we have a third called talquetamab, that targets a uniquely different protein on the myeloma cell known as the GPRC5D word salad. Since the recording of this video, a third BCMA directed bispecific antibody called linvoseltamab has been FDA approved. So these products generally, I mean, as we said, myeloma is an incurable disease, our patients will need both of these treatments.

I think what creates makes it a little bit easier is currently at this time is that CAR-T's are approved earlier. So generally you're going to get a CAR-T and then bispecifics can be given after the CAR-T. So the sequencing of CAR-Ts snd bispecifics is becoming more and more important, because we know probably that the single best product that we have in myeloma has been cilta-cel, which had a response rate of 98% and a progression free survival of almost three years, 35 months.

And when you have a BCMA bispecific given before that, although it's a small data set, that progression free survival drops to five and a half months, and I think to go from three years to less than half a year is a big detriment, and we should try to avoid that at all, if at all possible. So I would say if somebody is thinking about a CAR-T in the future, which would typically be young patient without neurologic history, without any doesn't have to be young, but somebody who doesn't have a major neurologic history or medical problems.

Also, disease is not explosive, so that person could be getting CAR-T in the future should try to avoid the BCMA bispecific. But certainly there are many clinical trials ongoing looking at CAR-T in the front line, looking at bispecific combinations on the front line. So certainly it's a complicated question, but generally speaking, yes, we will sequentially give CAR-T and bispecifics, minding that ideally we'd like to antigen target switch or switch the protein on the myeloma cell that we target with each of these products.

And that will help minimize mechanisms of relapse or resistance and exhaustion, or preventing these T cells from getting tired. I think switching that target will be beneficial. The other question, of course, is can you use a non-BCMA bispecific like talquetamab which targets GPRC5D and the answer is possibly but we don't know. I would say we should be thoughtful about CAR-T in terms of what you do before you collect the T cells and what you do after.

So pre-apheresis, I would still maybe have if you could avoid it, avoid any bispecific. After the apheresis is done for collecting the T cells, then maybe I would be much more okay using the talquetamab. But I think the jury is out. And the reason I say all that is we know that with talquetamab, the response rate and PFS is quite good.

But then if you use a Bispecific prior to that, it drops to less than five month PFS from say 12 months, which means that switching targets is not enough. So that's why I think for now, if at all possible, avoid bispecific before CAR-T. Are there times where a bispecific antibody may be used first? So speaking a bit to the sequencing, if somebody has let's say rapidly progressing disease and they can't wait for the CAR-T manufacturing.

Right. Or if somebody lives, you know, far, far away, they don't have access to the academic center or depending on their comorbidities or risk for infection, risk for toxicities. I think, you know, those are all important considerations of when to use a CAR-T versus a bispecific first. But let's say if all things are equal, including access, the International Myeloma Working Group, and there are some new guidelines that were just published, led by my colleague Doctor Luciano Acosta does confirm that a CAR-T before a bispecific is the ideal approach and the way to go.

Can you respond to a CAR-T if you've been on the bispecific therapy, is there a wait period that you might think about between them? So sometimes, you know, a patient might have to get a bispecific first for multiple different reasons. And if you've been on a Bispecific, that doesn't mean that you can never get a CAR-T there generally is a washout and it depends what is the bispecific.

Right. So a lot of times we are using talquetamab as bridging the CAR-T-cell therapy. Because talquetamab targets a different area on the myeloma cell, the GPRC5D. So it's actually we're all friends. We want to use talquetamab because it helps with a great response. But let's say we're using a Bispecific that has the same targets, the same area on the myeloma cell as the CAR-T this BCMA.

Yes, you can use it, but generally what we see in the response might be a little bit lower. But if that washout is six months, 6 to 9 months, ideally we've seen those patients tend to be better. That is if, you know, if it's clinically feasible to have that long of a washout. But that doesn't mean that if you've had a bispecific, you can't have a CAR-T I still think you can.

Why does it need a washout period? How do bispecifics affect T cells? bispecific you know, T cells with bispecifics. There's some new studies coming out. You know some translational studies Francesco Mara led this from the Memorial Sloan-Kettering where they're showing that with bispecifics, you're getting more mutations to some of the genes rather than the CAR-T so certainly mutation is a mechanism of resistance that might cause the disease to come back.

But another, you know, like simple thing to consider is that with a bispecific, you're constantly targeting the T cells. And, you know, the T cells might just get tired. With a CAR-T cell it's kind of a one and done type of treatment. And then you're off treatment and you give these cells a break for a prolonged amount of time.

So I think these might be some consideration like resistance relapse mechanisms. And then just the exhaustion part and giving the T cells a break from treatment. So when it comes to sequencing CAR-T cell therapy and bispecific antibodies, the answer isn't one size fits all. It depends on the patient, the disease stage, prior treatments and emerging data. But one thing is clear how we sequence these therapies could mean the difference between response and relapse.

As the science continues to evolve, so must our strategies, and staying informed is key.

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