Lower-Intensity Talquetamab Dose Shows Potential in Multiple Myeloma

Tara K. Gregory, MD

Codirector, Plasma Cell Dyscrasia Program

Colorado Blood Cancer Institute

Denver, CO

TOP TAKES FROM TARA K. GREGORY, MD

• Gregory says the MonumenTAL-1 study enrolled patients with high-risk features seen in the real world.
• Talquetamab showed high efficacy across the cohorts of the study.
• Unique toxicities of talquetamab include skin, oral, and nails.
• An analysis showed reduced dose intensity improved some toxicities and maintained efficacy on the trial.

Targeted Oncology: What was the significance of the MonumenTAL-1 trial (NCT03399799/NCT04634552) of talquetamab (Talvey) in the relapsed/refractory multiple myeloma population?

Tara K. Gregory, MD: Talquetamab was [investigated in] the MonumenTAL-1 study, and there was a phase 1 and phase 2 component. What I think is fantastic about the study is that first they're trying to figure out their dosing schema. Do you have a smaller dose every week, or do you go every other week?… They also had these patients profiled [based on whether] they had seen anti B-cell maturation antigen therapy before.

All of these patients were triple class [exposed]; there were high [rates of] penta-refractory disease, and a lot of high-risk cytogenetics.¹ I expect [patients with high-risk cytogenetics] to be approximately 30% in my trials. If I don't have at least 30% or more, I don't have an adequate myeloma study for a product. [For] extramedullary plasmacytomas, they [often exclude] these patients from studies. A lot of times, studies only want 10% of patients who have extramedullary disease. These [cohorts] have a 20% to 30% extramedullary disease rate—those are typically going to be your patients with more aggressive [disease]. They're further along down the line. Their plasma cell [is not behaving the way it] should behave anymore. Plasmas cells shouldn't know how to make lumps and tumors. By the time they learn how to make lumps and tumors, biologically, they've changed, and they're more aggressive. In this study, belantamab mafodotin [Blenrep], for the most part, was the prior anti [BCMA therapy], because that's where we were in terms of the drug use.

Ultimately, you can see an overall response rate [ORR] of 74% [in the once-weekly cohort], 69% [in the every-2-weeks cohort], and 66% [in the prior T-cell therapy cohort].² These patients are not supposed to be with us in 5 months. When you go to the higher dose every other month, we see a duration of response of approximately a year and a half. This is helping us get to the next [line of therapy].

What safety outcomes stood out in the MonumenTAL-1 trial of talquetamab?

[In terms of] safety data, what I'll highlight is cytokine release syndrome [CRS]. CRS is not as high as with chimeric antigen receptor [CAR] T-cell therapy. With a CAR T-cell therapy, we expect [the rate of any-grade] CRS to be in the 90th percent. [With talquetamab], we're in the [range of] 70%, so it's definitely [present].² But my question is always going to be: are we talking about a grade 1 adverse event [AE], which is a fever? I can tell the patient to take acetaminophen for a fever. That's manageable. What's harder to manage is the grade 2 and grade 3 CRS, and if you go into the subsets, the majority of these patients are going to [only] have fever.^1,2

What's impressive here are the off-target AEs.² There are not a lot of cytopenias. With a GPRC5D [bispecific]…you can expect them to lose 10% of their body weight, and they don't eat [sufficiently] for approximately a year.… So if you have somebody who's starting with low body weight, this gets pretty [concerning]. After approximately 1 year you start to see that go away. In the clinical trial with the GPRC5D CAR T-cell therapies, that lasts for approximately 1 month and it's gone, so it's interesting. Their nails can become completely brittle…the skin rash is [serious]. It looks like a grade 2 or grade 3 graft-vs-host disease skin rash.

Why is it important to reduce dose intensity of talquetamab?

This is where we are now: do we have to keep pushing so hard on these T cells? Remember, we're causing a lot of T cell exhaustion. Is there a point at which we can drive these patients’ [dose intensity] down? I always tell my patients about the myeloma iceberg. That’s our analogy,when your myeloma gets diagnosed, your disease is up here, and by the time I have you in a partial remission, you're just a bit under the surface, and I'm trying to melt that iceberg as far down as I can get it. Now we have minimal residual disease negativity. So if I have the iceberg melted pretty far down, maybe I don't need to keep [exhausting] these T cells.

[On the MonumenTAL-1 trial], there was a group where they waited to do the dose reduction until they hit their best response, and then they dose reduced. Then in the other group, it was prospective, so the plan was to dose reduce [or reduce dose frequency] based on time of exposure.

[Reported data] are focusing only on the patients who were dose reduced after they had best response.³ We’re not comparing with what we saw in the other group. The patients who hit best response were able to be dose reduced. [Other] patients were never dose reduced, because they didn't hit optimal response. What you can tell is that patients who get a fabulous response [can] ride that out beautifully [with dose reduction], so that's what you want.

This is what's making me think in my practice that if my patients are not [responding], am I going to add something else in? Because there are other clinical trials that you're going to see coming out with the combinations, like talquetamab plus carfilzomib [Kyprolis], talquetamab plus daratumumab [Darzalex], talquetamab plus pomalidomide [Pomalyst] and daratumumab—those kinds of [regimens]. Is that what we're going to start doing next based on response? Some of us are starting to do that; we've agreed as a community, if you don't see that great response by 3 to 6 months, you need to think about adding something in if you can get it.

How did the patients who had dose reductions prospectively perform?

Ultimately…the ORR here was still [nearly] 80% of patients.³ The median progression-free survival was 13 months. They're doing very well. They still had an excellent response even with a prospective dose reduction. For the most part, this is what we're doing in our practice now; we prospectively dose reduce.

Is there a correlation between dose reductions and the toxicities that a patient experiences?

Yes, there is. [In the prospective cohort, dose reductions were] because of toxicity. As you dose reduce, your [skin and oral] toxicities go down, and patients stay on the drug and they're more tolerant of it. What does not get better is the weight loss and the nail toxicity.

REFERENCES:

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

2. Rasche L, Schinke C, Tozeau C, et al. Long-term efficacy and safety results from the phase 1/2 monumental-1 study of talquetamab, a GPRC5D × CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. HemaSphere. 2024;8(suppl_1):P915. doi:10.1002/hem3.104

3. Chari A, Oriol A, Krishnan A, et al. 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. Blood. 2023;142(suppl_1):1010. doi:10.1182/blood-2023-181228