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Lowering Talquetamab Dosing Intensity to Improve Tolerability With Ajai Chari, MD

At the recent American Society of Hematology (ASH) Annual Meeting, Ajai Chari, MD, Director of the Myeloma Program at the University of California, San Francisco, sat down with Oncology Data Advisor to discuss his abstract and presentation regarding updated results from the MonumenTAL-1 study and what to look forward to from the ever-evolving treatment landscape of multiple myeloma.  

Oncology Data Advisor: Thank you so much for being here today with us, Dr. Chari. Would you like to begin with introducing yourself and your research interests?

Ajai Chari, MD: Thanks for having me. My name is Ajai Chari. I'm a Professor of Clinical Medicine and the Director of the Myeloma Program at the University of California in San Francisco.

Oncology Data Advisor: Incredible and thank you again for your time today. To begin, would you like to give us a little overview of the MonumenTAL-1 study?

Dr. Chari: The MonumenTAL-1 study is actually the study that led to the first GPRC5D therapy in myeloma. It's a bispecific antibody, and in the MonumenTAL-1 study, for which data has been presented previously, we found that at the recommended phase 2 dose, the response rate was over 70%. Progression-free survival (PFS) for the 0.8 mg/kg dose, which was given every two weeks, is 14 months, which is quite impressive, I think, for an off-the-shelf product. We also presented data at the International Myeloma Society (IMS) in Greece for one of the first drugs I've seen where the progression-free survival for high-risk and standard-risk are actually superimposable. And we also didn't see a lot of infectious deaths or complications, even though this drug was given in the era of COVID.

So, those are all the favorable efficacy findings, and importantly, the median time to response is about one month, and the median time to best response is three months. And those latter two points are important, because there are some unique side effects with this agent that are what I would characterize as on-target off-tumor, and those include dysgeusia or loss of taste, which can occur in as much as 70%, and also rashes, peeling of the hands and feet, diffuse maculopapular rashes, and finally nail changes. And I would say of those, the taste is the most challenging to deal with.

In this particular study that's being presented at ASH, the question was, "Since we know that this is a very active drug with rapid onset of response, can we back off on the dose?" And I should preface that we know we got the dose right initially, because in this monotherapy, single-agent with a median of five to six lines of therapy, many of whom were triple-class–exposed and had even received a prior bispecific, you need this activity, and the maximal activity came at this dose. But we also know that at this dose, you've got more side effects, because these unique side effects that we mentioned, I wasn't seeing. When I was a phase 1 dose-escalating participant as an investigator, we didn't see these side effects at the low doses. So, the main question being asked in this study is how do we optimize the dosing and schedule to get those benefits but not have these side effects?

Oncology Data Advisor: You kind of started to talk about it, but I wanted to ask, what was it that sparked the genesis thought of wanting to reduce the dosage of talquetamab?

Dr. Chari: The study's actually broken into two parts, what we're presenting. One is kind of a retrospective cohort, and what we did is we looked at about 50 patients who had gotten talquetamab at either one of the two doses: 0.4 mg/kg weekly, 0.8 mg/kg every two weeks, or either of those doses in what we call prior T-cell redirection cohort. So, in that combined data set of 50 patients, we found that there was no apparent decrease in efficacy with the reduction. In particular, progression-free survival seems to be maintained.

But there are a lot of flaws in doing that kind of retrospective analysis. One of my favorite statements is people who do better, do better. So, of course, you're going to reduce doses in patients who are responding, and they're going to do okay, but we wanted to confirm this in a prospective fashion, and I think that's the second part of the study. We looked at 19 patients in whom partial response or better was attained, and then we reduced the dose in one of two ways. You can reduce dose intensity by either reducing the dose, so they went from 0.8 to 0.4 every two weeks, or by the schedule, so instead of doing 0.8 every two weeks, it was 0.8 monthly.

Those 19 patients who had one or the other kind of dose reduction, we looked at those outcomes, and we found, again, surprisingly, no differences in efficacy. So, response, PFS, and duration of response compared favorably with the overall cohort, and we found that the side effects—those four side effects that we discussed—trended towards getting better with the dose reduction, and that was nice to see.

One of the other interesting things we found in part of this analysis was something that I've never seen in a myeloma study before, which was in patients who had these side effects that are on-target off-tumor, particularly this loss of taste and the palmar-plantar peeling. There was a 20% higher likelihood of those patients having a response, which I know our solid tumor colleagues see, because we have drugs that cause rashes that correlate with efficacy, but we don't have any drugs like this in myeloma where adverse events (AEs) correlate with efficacy. So, it was a unique finding, and when you put this all together, I think it's exciting that while we need to do more work, this is a good first way of dealing with these side effects.

Oncology Data Advisor: Definitely. This is such an interesting and exciting study. Did these findings that you're learning about spark any interest to study the effects of dose reduction in other bispecifics besides talquetamab?

Dr. Chari: Yes. I want to mention that actually you reminded me of something else in this study that we looked at, which I think fits with what you were raising. We looked at what the impact of dose reduction, dose intensity reduction, would be on the T-cell fitness. What we found was reducing the dosing intensity didn't change the T-cell number. There's a trend in the prospective cohort to less T-cell exhaustion by, for example, a co-expression of PD-1 and TIGIT or LAG-3, which makes sense, because if you repetitively hammer T-cells with a bispecific, they get tired—like teenagers who party too hard. And so maybe this dose attenuation makes a difference, and I think other bispecifics are also starting to realize that.

I want to take a minute to mention, because I feel like sometimes people criticize the way these studies are done, and they're like, "Oh, well. People are being overdosed," or "This dose was not right." We have to remember how clinical trials are done. Clinical trials are first done in patients who've exhausted all options. So, if you're penta–drug-refractory or exposed myeloma patient, you need that 70% response rate. You don't have the luxury of waiting for 20%, 30%, and then trying to get it. So, we always in myeloma want to start hard and pull back once we've achieved the goal, as opposed to starting wimpy and trying to catch up. That has never been borne out.

So, this philosophy of starting hard and aggressive to capture the disease and backing off has been studied with other bispecifics as well. Another thing that's been studied by some bispecifics is to stop the drug altogether to give patients a break. While it's very reasonable to ask what the right dosing schedule is, I think we have to distinguish, and this is what we're learning, is the initial dosing schedule to capture the disease in this heavily treated population may not be the long-term dosing schedule, but that's why we need studies like this to figure that out.

So, it's not that we should throw out the baby with the bathwater, let's keep the baby in the bath, but heat up the water. That's what I think these kinds of studies are doing, and I think it's really gratifying to be able to give these patients an amazing response without compromising it. And I would say one final thing is I've had the privilege of treating almost 100 patients with this drug, and in my 100-patient experience, I've only had one patient come off for non-progression, which I think speaks for itself. I don't have a magic sauce that I'm giving these patients. They're seeing their responses with myeloma, and I'm working with them and saying, "Listen, I know you're having taste loss. Let's back off on the drug. We'll skip a dose, reduce the dose." That's how we've been able to keep so many patients on so that they can get the maximal benefit.

Oncology Data Advisor: Definitely. This is so fascinating, Dr. Chari. Thank you so much.

Dr. Chari: And you are now drinking the "Myeloma Kool-Aid," because everything myeloma is interesting and fascinating.

Oncology Data Advisor: It really is, it really is, and especially in such a rapidly evolving field. One question I was also curious about is how did the dose reduction affect the quality of life of the patients? What did you witness?

Dr. Chari: Yes, it's a great question. I'm still waiting to get that patient-reported outcomes (PRO) data, and as soon as I have it, I'll share it, but I don't have it right now. But I think it's a super important question, because it doesn't matter what we say, it's what the patients experience, especially for these unique side effects. And I would say that's one other point. Part of the challenge with working with these unique side effects, like dysgeusia, is it's not a side effect we've been dealing with in myeloma or even in oncology in general very much. Even our head and neck colleagues, they have a lot of dry mouth and different toxicities, but we really haven't found a way of really describing this well. So future work on this space is to first get better tools, right?

Dysgeusia right now, by the National Cancer Institute (NCI) criteria, is grade 1 or 2. Well, that doesn't capture the full patient experience. That's like saying everything else in Common Terminology Criteria (CTC) should be one and two—no, it's one to five. So, we need better tools to assess the severity. We need to get granularity, because taste actually has different components: bitter, salt, sweet, sour. We're not doing granular tests on that. If we're going to really make a dent, we need to characterize the problem first, and then we need to understand the pathophysiology. Why does this happen? And then start targeting it with the right supportive care. But I think in the meantime, because that's a lengthy process, let's at least figure out the right dose for a patient if they've had a good response.

Oncology Data Advisor: What were some limitations that you experienced in this study that you would like to address in the future?

Dr. Chari: I think, obviously, these are small numbers; the retrospective cohort had 50 patients, the prospective had 19, but I think the data are so compelling, the drug is so active, and we know that as a class, bispecifics are very different than all the other drugs we've had in myeloma. Historically, if you had drug X and you had a response, if you held it for a week, two weeks, or a month, your myeloma's coming right back. That's not what we're seeing here. We're seeing a big delta between PFS and duration of response (DOR), which means that these remissions are quite durable, and we have the luxury of pulling back.

So, all the future studies with talquetamab are actually doing the 0.8 mg/kg every two weeks, and they're building in this planned dose de-escalation at around three months when the response is captured. I think as we try to understand the granularity and supportive care mechanisms, this will go a long way towards keeping patients comfortable and enjoying their quality of life.

Oncology Data Advisor: Definitely. Final question I was going to ask you was what are you and your team's next steps, but I think you answered that. So, is there anything else you would like to add on that you think would be important?

Dr. Chari: I think the one final point I would make is that in my experience, a lot of these side effects do improve when patients come off therapy, and I think that's another important message to convey to patients, like, "Look, when you're consenting patients for this drug, here are the side effects, but the responses are rapid. I'm going to work with you to find the right dosage schedule for your long-term." And I think that initial consenting part goes a long way in how patients approach their disease and treatment. So, I think that would be a good thing to share with patients.

Oncology Data Advisor: This has been a really fantastic discussion, Dr. Chari. Thank you so much for your time and your passion on this topic.

Dr. Chari: Thank you so much for having me.

About Dr. Chari

Ajai Chari, MD, is a Professor of Clinical Medicine and the Director of the Myeloma Program at the University of California, San Francisco. Dr. Chari's clinical interests and research encompass plasma cell disorders, such as multiple myeloma, AL amyloidosis, POEMS syndrome, plasmacytoma, and monoclonal gammopathies of uncertain significance (MGUS). He is remains active in clinical trials and has authored or coauthored a plethora of publications on these topics.

For More Information

Chari A, Oriol A, Krishnan A, et al (2023). Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: Results from the phase 1/2 MonumenTAL-1 study. Presented at: American Society of Hematology Annual Meeting 2023. Abstract 1010. Available at:

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 

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