CAR-T Dosing Matters: Real-World Data on Effectiveness and Outcomes | Ran Reshef, MD

Hello.

My name is Ron Reshef.

I'm the director of the cell therapy program at Columbia University Irving Medical Center in New York.

We are here in Orlando at ASH 2025.

This is Sunday today, and we are looking at a lot of presentations, many of which are revolving around myeloma and treatment with CAR-T cell therapy.

I presented specifically an oral presentation talking about CARVYKTI, or the way we call it, cilta-cel, which is the original name under which it was developed.

And it has become a revolutionary treatment for patients with myeloma.

And it has truly transformed the treatment paradigm for patients with this disease.

As we know today, a single infusion of this type of CAR-T — and there are some other types of CAR-T that are available in myeloma — can truly place patients in complete remission, even if they have failed multiple prior lines of therapy.

And CARVYKTI specifically is now even approved for patients who only had one prior line of therapy.

So fairly early patients can have the benefit of using this type of CAR-T.

One open question that we had in the field was about the dose of CARVYKTI that we administer to patients.

It's a little bit unusual in the medical field to have a drug approved with a dosing range rather than a specific dose.

So CARVYKTI was approved with a target dose of 0.75 million cells per kilogram body weight of the patient.

However, the FDA allowed a certain range, and that range was tested in clinical trials of between half a million and a million cells per kilogram.

What that means is that a patient who receives half a million cells and a patient who receives the full million cells are considered to have received the same treatment.

And that did not make a lot of sense to us.

And we certainly wanted to look into that information a little bit more closely, as the clinical trials did not really look into that.

This is where real-world data is really important.

And we conducted this type of analysis using the U.S. Myeloma Immunotherapy Consortium, which is a group of 15 large U.S. academic centers that collect data on myeloma patients undergoing treatment with CAR-T cell and other types of immunotherapy.

What we found was that indeed patients were receiving a broad range of cell doses, and in fact most patients receive a dose that is lower than the 0.75 target dose and might even be lower than the 0.5 minimum dose.

Those products are usually given under experimental protocol since they're not considered commercial products by the FDA, but about 5% of the patients in our dataset received those low-dose products.

And what we found, first of all, is that there was no real difference in side effect profile.

So receiving a higher dose or a lower dose did not really alter the safety of the product, which answers an important question because it has been suggested that perhaps if we lowered the dose of CARVYKTI, we might get a better therapeutic window — meaning we're going to get the same efficacy with better safety.

But this does not seem to be a safety advantage to giving a lower dose.

The only place where we saw a slight advantage was that delayed neurotoxicity was in fact a bit lower numerically in patients receiving very low doses.

However, there wasn't a clear what we call dose-response trajectory, so we can't say for sure that this is a finding that can be reproduced and validated by other cohorts.

What we did find is that there was a slight difference in efficacy.

Our analysis at least suggested that a higher dose was associated with a much more durable response, and the low dose was less favorable in terms of the durability of the responses.

And while our results, I would emphasize, were not statistically significant, despite the size of the cohort, which was 751 patients, which is quite sizable, it does propose that we need to look at the dosing very, very carefully, and perhaps in future trials.

These trials should really be designed either to target the more narrow dose range or, at the minimum, to look at the dose as a pre-specified analysis.

So at the end of the day, patients will know what the dose they're getting is and what is the impact of receiving a higher dose or a lower dose.

We don't have a good answer to that because it does seem like the out-of-spec products — the ones that don't meet all criteria — are not necessarily due to dose.

Some of them are due to dose, but some other criteria that the FDA has set are sometimes not met.

And we have far less data about those as well.

Criteria such as viability, vector copy number, and other parameters that play a role in that decision.

Occasionally patients don't have an option.

They may not have the time to wait for a second collection, and they may even choose to go to another product — not CARVYKTI — which we sometimes do in case of manufacturing failures.

But based on retrospective data alone, I don't think we can yet recommend to patients what to do with that information.

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