MonumenTAL-1: Talquetamab in Relapsed or Refractory Multiple Myeloma


Comprehensive discussion on the MonumenTAL-1 trial of talquetamab, a GPRC5D- and CD3-targeted agent, in the setting of relapsed/refractory multiple myeloma.


Luciano Costa, MD: Back to Dr Rossi to carry on our discussion.

Adriana Rossi, MD: That is so interesting. At this very encouraging space, I think we find that patients who would have been considered to have no options now have not only responses but encouraging and positive outcomes. Could you tell us a little bit about how you chose this specific therapy at that time?

Luciano Costa, MD: That’s a great point, Dr Rossi. I think this patient would have been deemed terminal and not amenable to any available therapy more than two years ago. He’s now doing well thanks to the innovations that were brought through clinical trials. As I’m sure you have experienced yourself, we have those patients in front of us. We go by what is available, what trials we have, what mechanism of action we have not explored yet, and what this patient is likely to tolerate. At that point, we had the slots for the GPRC5D bispecific antibody. It had shown some good efficacy in preliminary results at earlier doses. We pursued because there was not a target that had been explored at that time. I chose this case on purpose because, historically, we have developed CD38 monoclonal targeting agents, BCMA [B‑cell maturation antigen] targeting agents, and GPRC5D targeting agents. It gives what I think is the wrong idea that we have to follow that particular path, but when you have a patient with triple-class refractory myeloma, any of those novel approaches are better than trying to recycle other older agents. That was his opportunity at the time. He could have very well gone on a CAR T-cell trial at the time, but it just so happened that he’s a lot better lined up for the antibody. I’m glad, because he did benefit from that for quite some time.

Adriana Rossi, MD: Absolutely. We had one of our fellows present at ASH [American Society of Hematology] our cohort of patients who’d had bispecifics and were then salvaged with further T-cell redirecting, be it CAR T or bispecific therapies. Not only is this relapse refractory space full of questions like how do we choose and how do we sequence and how do we combine our standard therapies, but now we are spoiled for choice in the T-cell redirecting where, again, we have different modalities and different targets and no real guidance or experience to say how to sequence them. It’s up to living through collecting this data and keeping an eye on them. I will mention that the GPRC5D targeting was evaluated in the MonumenTAL-1 trial. That was the equivalent early study where they used the step-up dosing. As you said, we’ve learned that this is how we primarily can mitigate the toxicity, and we evaluated two different schedules, one at 405 micrograms per kilo given weekly on a 21-day cycle and an alternative of 800 micrograms per kilo dose every other week on a 28-day cycle. The results were remarkably encouraging and the weekly schedule had an overall response rate of 70%; the biweekly, 67%; and a greater than CR [complete response] was 13% on the weekly and 19% on the every other week. With a little bit more follow-up at 10 months, about over half of the patients remained on therapy, so these are durable, deep responses. Again, CRS [cytokine release syndrome] is quite limited at grade one and two, with only one case of grade three that, interestingly, happened to be on the weekly schedule. There were a lot of new toxicities. Do you have any thoughts on how these unique toxicities to talquetamab might help or hinder us, and where to place it in our treatment paradigm?

Luciano Costa, MD: That’s very interesting. I think if you look across all bispecifics, the pattern of toxicity has been somewhat monotonous. You have the CRS with the initial doses or step-up dosing. You have the overall risk of infection, the hypogammaglobulinemia, and the transient cytopenias. Our dose seems to be more mechanism related, not necessarily unique to the target. I think with the GPRC5D, it is a little bit different. As a side note, when you do essentially tissue and tumor profiling, you find the GPRC5D, which is a transmitting brain receptor with unknown ligand and unknown function. It’s found in myeloma cells, plasma cells, and it’s found in some cells on the cutaneous tissue and some lymphocytes adjacent to our taste buds. That causes what is unique toxicity. You can have a skin rash and you can have some screen disformation, particularly in hands and feet. You can have nail dystrophy and dysesthesia. That is important to know because, to counsel patients, we try a lot of treatments. We use moisturizer and sometimes even steroid creams. We are careful to not break the nails and things like that, but those effects don’t have a major risk themselves other than being uncomfortable to patients. The important thing is, the experience tells us that those symptoms tend to improve or even disappear over time. I usually tell patients, “Hang in there; you are responding. This is going to get better.” Patients are willing to handle that for a few weeks or a few months in the interest of having their disease under control, which, of course, is something that they really value.

Transcript edited for clarity.

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