Arlo-Cel - GPRC5D CAR-T: High Response Rates in Heavily Pretreated Myeloma | Susan Bal, MD

Hi, I'm Susan Bal from the University of Alabama at Birmingham.

I'm delighted to share some results and some upcoming research that's ongoing about arlocabtagene autoleucel or arlo-cel.

So alrocabtagene autoleucel is an autologous Car-T cell that's targeting GPRC5D.

GPRC5D is a rational and promising therapeutic target for multiple myeloma because of its expression on the myeloma plasma cells with limited expression outside, mostly affecting the skin, nails, and the oral cavity.

And so those are predominantly where the side effect profile comes from.

It's already shown to be a very promising target.

We already have talquetamab or Talvey, which is an FDA approved medication, which also goes off the same target.

So arlo-cel is a Car-T cell that's going after GPRC5D.

Overall, in different meetings so far, we've shared results from the phase one study, which shows that in very heavily pretreated patients, those with three or more prior lines of therapy, we've already seen very impressive response rates, over 87%, with a complete response rate that's upward of 50%.

Median progression free survival looks about 18 months.

And the median overall survival is not yet reached, with a one year survival of 90%.

Which is very encouraging, particularly because almost half of the patients had received prior BCMA therapy.

So this is sort of a new frontier for myeloma treatments currently.

Right now there are several ongoing studies that are liberating arlo-cel in patients with relapsed refractory multiple myeloma.

One of them is the phase two, quintessential study that is looking at patients with three or more prior lines of therapy, in quadruple class exposures to multiple myeloma.

We have the quintessential two, which is a phase three study of arlo-cel versus standard of care in patients with early relapse, so those who have had 1 to 3 prior lines of therapy.

Then we also have the phase one study that we're presenting at ASH 2025.

It's a trial in progress, so we do not have the results yet, but it is an ongoing study that's looking at arlo-cel followed by maintenance with mezigdomide.

Mezigdomide is a novel CELMoD agent that has immunomodulatory properties, and the premise is that it can help potentiate the effects of arlo-cel and hopefully result in a longer duration of response, longer progression free survival, and hopefully improve patient outcomes.

So we're excited about this study.

It's currently enrolling as a phase one study.

Of course, we're looking at safety of this combination.

As you know, in Car-T cells after treatment we look at low blood counts, etc.

These immunomodulatory agents can also cause low blood count.

So we're looking at safety as the predominant area of interest and the primary objective and endpoint of the study.

We're also looking to establish the phase two dose that's going to move forward and be studied in a larger number of patients.

And then, of course, we're always interested in learning about other toxicity profiles such as cytokine release syndrome, ICANS, and more importantly, non-ICANS neurotoxicity that could be seen with this agent.

And then look at response and how response is modulated by addition of this therapy.

So in terms of what are some of the similarities and differences between arlocabtagene autoleucel or arlo-cel and talquetamab, there are, of course, some on-target off-tumor toxicities that are common across the GPRC5D targeting treatment.

These include effects such as taste loss or dysgeusia, a change in taste or weight loss.

We also have nail disorders, rashes, and skin toxicity.

Now these are seen at significantly higher rates.

Patients will receive talquetamab very likely because it's an ongoing therapy, whereas a one-time treatment Car-T cell, by definition, is given once and then the effects subside.

So we are seeing a lot less of these toxicities.

Less than a quarter to a third of our patients have had any, and most of these are not very severe.

They seem to improve without any intervention over a period of time.

So they're transient and self-resolving.

And in the vast majority of cases, they are not as intense.

We don't see as many grade three or higher events.

So it appears that the on-target off-tumor toxicity profile of arlo-cel is a bit better.

However, we have seen a signal of non-ICANS neurotoxicity, which is a syndrome of unsteadiness, balance disorders, ataxia, and dysarthria or trouble speaking that can be seen in a small number of patients, about 10% in the phase one program.

This is something that we're trying to understand better.

This has also been reported, but talquetamab shows lower frequency.

Balancing these on-target off-tumor toxicities is going to be key, and understanding which is right for which patient.

We have not seen any parkinsonism, cranial nerve palsy, or Guillain-Barré.

These are the different delayed neurotoxicities we've seen with BCMA-targeting Car-Ts.

We haven't seen any of those here, but we have seen this other non-ICANS neurotoxicity that needs better understanding.

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