How do you choose which CAR-T cell product to use?

How do you choose which CAR-T cell to use? I think this is a question we get a lot. I think the fundamental question is if a patient needs CAR-T, they should take it. They should get whatever is available. There are real issues right now with availability of slots, manufacturing, availability, things like that. So if they need a CAR-T, they should get whichever one is available.

I think if there is a choice, a lot of people would choose cilta-cel, or CARVYKTI is the commercial name for it, given the very long progression-free survival that we've seen on that trial. I think it's hard to compare different trials. The patient populations are different. The way they were used is a little bit different. So we can't say for sure that cilta-cel is better than ide-cel, but given the data we have, it would be reasonable to choose that.

I think the last consideration to make is whether or not there are other factors. Patients often have other co-morbidities, so other diseases like diabetes, high blood pressure, heart disease, kidney disease, and that can sometimes also play a role in which product to choose. We've had a fair bit of experience treating patients, for instance, who are in hemodialysis from kidney disease using ide-cel. In that scenario, it may be that one or the other product might be a little bit less toxic or less dangerous with particular comorbid conditions.

It's certainly great that we're living in a time where we have two FDA-approved CAR-T products for patients with relapsed refractory multiple myeloma. We even have a BCMA-targeting bispecific that was recently approved. So it's nice to have these options. But I do get asked all the time in the clinic from patients which CAR-T product to choose.

What about CAR-T versus bispecific? You know how to choose. It's not an easy decision. I think it's a very complicated discussion that should be had between the patient and his or her myeloma doctor, because neither of the two CAR-T products have been compared head-to-head in what we call a randomized control clinical trial — the most rigorous way to say which CAR-T product would be better. Certainly CAR-T versus bispecifics have not been compared.

The treatment logistics often involve, depending on where the patient lives, travel to a specialized center to get the treatment. It's not an off-the-shelf drug that you can decide, “Hey, if I qualify, can I just get this in the next few days or within a week?” This often takes months of planning and additional management while CAR-T is being made. So there's a lot of details to go through for the patient to decide if that is something that is feasible for them to do. Are there resources to help them get through the treatment? What are the side effects?

These side effects are often very different from the type of drug-based treatment they've had before, even stem cell transplant if they've had one before. So they need to understand the different side effect profile. It’s a very personalized decision.

For the doctor, talking with the patient involves considering if the patient has other health conditions that might make them a little bit higher risk for CAR-T or not, and what treatments the patient had before or most recently. There’s no one fixed answer for all patients. It’s very much an individualized decision.

I would say until very recently, despite having those two products FDA-approved, manufacturing access has been extremely limited when it came into availability in practice. That makes it more challenging. Our centers wanted to have this option for patients, but they don't have enough manufacturing slots for all patients who potentially could get the treatment. So there were long waiting lists, which also factors into selection consideration. Some patients can't wait that long for CAR-T.

Now we are seeing some of these manufacturing access challenges slowly improving. We’re seeing a little bit more slot access. So literally, last month versus today, the situation could be very different. That factors into my conversation with the patient — could I get a manufacturing slot and for which CAR-T product is it literally in the coming week, or are we talking about the coming months? Those must be factored in with the patient’s current myeloma status, how quickly the myeloma is progressing, and the current treatment to come together with a plan that is feasible for the patient and clinically most likely to work.

There have not been any head-to-head comparisons on ide-cel or ABECMA and CARVYKTI, but what we have seen is what’s available from clinical trials. Ide-cel targets the myeloma cells at one BCMA area, and CARVYKTI targets two BCMA areas. The response rate for ABECMA is about 73%, and for CARVYKTI about 98%. How do we choose? We choose based on disease burden, toxicity, and how the patient is doing prior to CAR-T.

Commonly at Moffitt, though there are no hard rules, if somebody is older, like above 75, and may have illnesses or comorbidities — for example, renal dysfunction, kidney problems, or they may be on dialysis, or wheelchair bound due to a myeloma lesion — we may consider ide-cel or ABECMA.

Also, if somebody has a neurologic history, like seizures, epilepsy, or some kind of traumatic injury, we try to be very careful. We generally prefer ABECMA rather than cilta-cel or CARVYKTI for those patients because there is an increased risk of developing what we call delayed neurologic toxicity in the form of neurocognitive disorders like Parkinson’s disease, for example. So we try to be a bit more selective.

Generally, younger, fitter patients potentially get CARVYKTI, while older, less fit patients may get ABECMA just for tolerability reasons. Again, there’s no one-size-fits-all, but these are some general guidelines.

With that said, we have a consortium of 15, growing to almost 18 centers, including major centers like Moffitt, M.D. Anderson, Stanford, City of Hope, Dana-Farber, Mayo Clinic, where we’re looking at patients treated with commercial products for ide-cel. We’ve submitted some data for cilta-cel or CARVYKTI that we hope to present at ASCO for ide-cel or ABECMA.

I can tell you our patients in the real-world setting receiving commercial products did just as well as clinical trial patients. The response rate looked really good, and toxicity was similar to clinical trials. Most of those patients would have been trial ineligible — like 75% had low blood counts, prior BCMA agents, or renal insufficiency.

Regardless, ABECMA seemed to do just as well in patients who would have been trial ineligible.

Regarding CARVYKTI, we just looked at data that is currently embargoed, but it should have some very interesting and hopefully helpful information coming soon at ASCO.

So we have a number of different CAR-T products. We have ABECMA or ide-cel, and CARVYKTI or cilta-cel. These are two standard of care products, but many other CAR-T products are in clinical development in various trial phases.

So the question of which CAR-T to go to right now is really about availability. If you have an opportunity to go on a clinical trial, we always promote clinical trials. They allow us to explore different CAR-T constructs, targets, and types.

Outside of clinical trials, for standard of care, it’s really what’s available. The availability of ide-cel and cilta-cel is really limited, mostly at academic centers. Not every academic center can get these products for their patients. So there are allocations of these drugs.

Often, it comes down to what is available. Ide-cel does not seem to perform as well as cilta-cel, but both are very effective in patients with heavily pretreated disease. Both are very good products. If you’re eligible for CAR-T, either is a good choice.

The decision about CAR-T is very complex. First, I love the breakdown of: can I get on a clinical trial related to CAR-T, or is there a standard of care CAR-T available now? The bandwidth for CAR-Ts is very low across the nation.

Many times, a standard of care CAR-T is not available. If there is a clinical trial spot available and you are eligible, and it looks feasible, I think you should sign up. Most CAR-T clinical trials are fairly straightforward right now — looking for a particular type of patient with simple eligibility and few bells and whistles to begin treatment.

If clinical trials aren’t an option, and you’re thinking about standard of care CAR-Ts, there are two products: ABECMA and CARVYKTI. Of those two, if you could choose, most people would choose CARVYKTI because the majority of patients treated so far have had longer disease control after CARVYKTI than after ABECMA.

Yes, CARVYKTI may have more neurologic side effects, or so-called neurotoxicity, but these patients have had multiple relapses. Their myeloma is difficult to control, and their life span is influenced by how well their myeloma is controlled. So a longer period of myeloma control makes CARVYKTI more appealing based on current data.

Should a patient wait for a CARVYKTI spot or go with ABECMA if there is a spot available? For most relapsed refractory patients who have had at least three prior lines of therapy, options usually are not pretty.

You’re dealing with Blenrep, which has significant eye side effects; Selinexor, with significant gastrointestinal and constitutional side effects like nausea, vomiting, fatigue; and then CAR-Ts.

Blenrep could be great because it mainly causes thrombocytopenia if you don’t have the eye side effects. Selinexor works well for a small proportion of patients who have a great response and few side effects, but that’s the minority.

CAR-T basically shines here with an excellent response rate and is a one-time therapy. So if you’re at the relapsed refractory myeloma stage and these are your choices, and you have ABECMA but no other CAR-T or bispecific, I would absolutely take it.