Talquetamab Well Tolerated in Relapsed/Refractory MM

Jesus G. Berdeja, MD, Director of Myeloma Research, Sarah Cannon Research Institute, Nashville, Tennessee, shares updated results from a phase 1, first-in-human study of talquetamab, a bispecific IgG4 antibody that binds to GPRC5D and CD3, in relapsed/refractory multiple myeloma (MM), the data of which are being presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.


Hello. My name is Jesus Berdeja. I'm the Director of Multiple Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee, United States.

Myeloma is very much like most other diseases. There's been this explosion of immunotherapy, in particular these T‑cell redirecting therapies, which include the CAR‑T therapies and the bispecific antibodies. In myeloma, in particular, these have been mostly directed toward BCMA. That has resulted fairly impressively. Eventually, patients relapse. The question is, “What do we do next?”

Luckily, in myeloma, we have a little bit of riches in terms of directed targets. One of these targets is GPRC5D. GPRC5D is highly expressed in myeloma and has very little expression in any other tissue, which lends itself very nicely to these directed therapies, including this one in particular that we're presenting at ASCO.

I'll be presenting the updated results of the phase I first‑in‑human study of talquetamab, which is a GPRC5D CD3 bispecific antibody in relapsed refractory myeloma.

This is a so‑called MonumenTAL‑1 study. This is, again, a phase I dose‑escalation study in heavily pre‑treated patients with at least 6 prior lines of therapy. We started with IV dosing and then turned to sub‑Q dosing, because it actually looked better from a PK and pharmacodynamic standpoint.

In the sub‑Q dosing, we did the dose‑escalation and found that there was no MTD. What we did find was, based on safety and efficacy in pharmacokinetic and pharmacodynamic data, the 405 micrograms per kilogram subcutaneous‑Q weekly schedule was recommended as the phase II dosing.

This particular presentation is looking at those patients that have been treated at the RP2D, which is a total of 30 patients. What we basically saw was that this is a very active treatment. It is off the shelf, meaning that it is available to patients immediately. At this dose, we saw no significant toxicity that was unexpected.

The main toxicities that we worry about, or that we see with these T‑cell redirecting therapies, are cytokine release syndrome and neurotoxicity. In this case, 73 percent of patients had cytokine release syndrome. Of those, 60 percent had grade 1, which usually means a fever and nothing else. Only 10 percent had grade 2, and only one patient had grade 3 cytokine release syndrome.

Again, this has actually been in line with what other T‑cell redirecting therapies have reported, and probably lower even from the grade standpoint. In terms of neurotoxicity, that was very minimal, only seen in just a handful of patients, and again, all grade 1, usually in the setting of cytokine release syndrome.

In terms of the activity, we are very pleased to see that in these 30 patients at the RP2D, the overall response rate was 70 percent, with the majority of patients who are 60 percent having at least a very good partial response or better. Now, these patients have not been followed for very long, but, if we go back to the patients that have been in the study longer, especially in the IV doses, we have patients that have been in response for 22 months and ongoing. We're very hopeful that this will translate to prolonged response rates.

The most exciting thing about this is, again, this isn't going to be a new target. Unfortunately, in myeloma, we still don't have a cure. Despite all the new FDA approvals, most patients eventually go through all the therapies and relapse, and we constantly need new targets.

The nice thing about something like this that targets something different than BCMA, is that this could potentially be used after, or even instead of, a BCMA‑directed therapy, and without the fear that if you fail one BCMA therapy, that you can't use another, which at this time, we were not sure if we can do that or not. This offers a new target. It basically should become a nice addition to the armamentarium that oncologists will have to treat their patients.

A phase II expansion study has actually already been started called MonumenTAL‑2, that is looking at the RP2D dose that we're presenting here of 400 micrograms per kilogram.

Depending on the combination studies, and then moving this to earlier lines of therapy, is the likely next steps.

GPRC5D is going to be the next big target in myeloma, and you will start seeing other therapies directed at it including CAR‑T therapies and others, like we saw with BCMA.

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