Talquetamab Tolerability and Dose Interruption Considered in R/R MM

Omar Nadeem, MD
Clinical Director, Myeloma Cellular Therapies Program
Dana-Farber Cancer Institute
Instructor in Medicine, Harvard Medical School
Boston, MA

DISCUSSION QUESTIONS

• Are you familiar with step-up dosing used for bispecific antibodies approved to treat relapsed/refractory multiple myeloma (R/R MM)?​
• How comfortable are you managing toxicities associated with GPRC5D-directed therapy?

Paul S. Unger, MD: What's the quality of life like for patients on [talquetamab (Talvey)] in terms of toxicity while on treatment, beyond the step-up dosing and cytokine release syndrome [CRS] or neurologic [toxicity]?

Omar Nadeem, MD: To give you a short answer, it's a mixed bag. How many of you have used selinexor [Xpovio]? That’s a pretty tough drug in some patients, especially if you give it at a high dose. The approval came at an 80-mg, twice-a-week dosing schedule, which was [difficult], and then we started giving it weekly with a lot of antiemetic support and all that.

Talquetamab [does not] require so much supportive care, but it has very unique toxicities, particularly the dysgeusia that leads to weight loss.¹ Sometimes you see some skin toxicities. Many of those patients have an incredible response to this agent, so we do have time to hold the therapy and do some of the supportive care…. Some patients don't have any of that. As they get further into this, we get a better sense as to what their experience has been. Dose modifications and dose holds are critical, especially for people who are in response, and then being more preventative about some of these known toxicities of this target is important to try to get people through it.

I've had some patients who had pretty significant dysgeusia who we had to hold therapy for and then give it to them at a very reduced schedule, and they're able to eventually tolerate it. I think the more experience we get with this, we are going to get better clarity. So far in my experience, at least, it doesn't seem to be disease burden–related.

Peter Georges, MD: Because this is an antibody, I would think if you held the dose, you don't expect things to improve quickly.

Nadeem: [It can take] a couple of weeks, sometimes even longer. Because this binds the target and continues to deliver the T cell response to those areas, which then leads to the inflammation and persistent symptoms, it can linger for patients who have had severe toxicity, and then sometimes you have to revisit the step-up dosing in those patients that you ended up holding for.

Georges: The other question is, do the adverse events [AEs] correlate with response?

Nadeem: In my experience so far, yes, patients who have had the most profound AEs have been in a complete response, many times with undetectable light chains.

Eric Bravin, MD: Are you rigid about that cutoff for re-hospitalizing them and giving the induction doses? Do you have any flexibility there if you're a few days over and you think they're going to get in trouble with toxicity if you re-treat them after 33 days instead of 29 days?

Nadeem: I don't personally think so. In other settings, particularly in some of the clinical trials that I've been a part of for a while now, some people have been getting it even every 3 months for various reasons, and we have not repeated step-up dosing. We can't endorse that because we don't have the data yet to support it, but I have done delays that are a week or beyond the standard schedule that [have not been an issue].

Sometimes I would redo the premedications for those patients. The premedications are for the step-up dosing and the first full dose for a lot of these bispecific antibodies, and it does include steroid medicines. You can think about doing that if you wanted to make sure they don't get recurrent CRS, but many times, especially if they're in a response, it doesn't trigger the same T cell expansion as it did at the onset. That’s what this is all about. Some of that hinges on their response. Patients who have experienced progression because we've held so long are the ones I worry more about, because they're most likely going to then have that expansion again, if it’s going to work, and then those you have to be mindful of. But prophylactic tocilizumab [Actemra] and dexamethasone are being studied, and the use of that, if it makes it to the clinical practice, will eliminate a lot of this issue.

_Reference:

_{1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591}