Examining Real-World Approaches for GPRC5D Bispecific in Multiple Myeloma

The introduction of the GPRC5D-targeted bispecific T-cell engager talquetamab (Talvey) adds an alternative target vs B-cell maturation antigen (BCMA) used in chimeric antigen receptor (CAR) T-cell therapy and other approved bispecifics. During a Case-Based Roundtable event in Baltimore, Maryland, Carol Ann Huff, MD, of Johns Hopkins Medicine, and participants discussed real-world data and personal experiences using talquetamab, including the unique tolerability challenges and its use as bridging therapy for CAR T-cell therapy.

DISCUSSION QUESTIONS

• What has been your experience with using talquetamab?​
• Have you seen outcomes similar to what was shown in MonumenTAL-1 (NCT03399799)? Where do they differ?​
• From a sequencing perspective, in what lines of therapy are you most often recommending a GPRC5D-targeted bispecific?

Carol Ann Huff, MD: These are the real-world data looking at talquetamab: these are patients from the TriNetX database of about 426 patients, and the 6-month overall survival was 86%, 12-month [OS] was 70%, and…the 6-month progression-free survival is 56% and 12 months was 45%.¹

Adverse events were slightly lower [than in the trial]. Cytokine release syndrome [CRS] reported was virtually all grade 1, 47% of 54%; 6% grade 2, and then there was a 10% incidence of immune effector cell–associated neurotoxicity syndrome [ICANS]. Forty-one percent of patients in the real-world data received tocilizumab [Actemra], and 18% received steroids. The infection rates were reported to be only 27%, and 18% with grade 3 infections. Weight loss is a challenge, and the mean is 7-kg loss [at 6 months], and we can see a 10 to 15 lb, 7 to 8 kg loss in patients. We try hard to not have that happen.

Gang Chen, MD: If 18% used a steroid, and 41% used tocilizumab, does that mean some providers ordered tocilizumab [but others did not]?

Huff: These are real-world data, so this is simply what’s reported in databases. I would say we don’t use a lot of tocilizumab. We mostly use steroids, and I think you can manage with those. But I think one of the things that will probably potentially help more [oncologists] use these. The more solid tumor bispecifics come out, people will be very comfortable with this, but until then, the data using prophylactic tocilizumab to reduce even those fevers and the phone calls that you might get, and the emergency room visits, I think has value.

One dose of prophylactic tocilizumab when you start drops the CRS rate down to about 15% to 20%, and it’s virtually all grade 1.²

Chen: And are there no issues with insurance?

Huff: Again, I don’t do it myself, but there have been more studies that are coming out showing the benefits of it. I think it will be approved, but I haven’t advocated for it myself, because we just have a different system in place.

Haiyun Wang, MD: We do use it, and so far, we don’t have issues.

Carole Miller, MD: Well, remember, [Maryland is an] all-payer state. If you have a regulated infusion area, it all goes to our total cost of care, which is regulated by the state….

Huff: Has anybody here used talquetamab?

Chen: I have not had personal use, but I have a patient who received it at [the University of] Maryland. It seems like the adverse events [AEs] are more severe than teclistamab [Tecvayli].

Huff: With teclistamab or with the BCMA-targeted bispecifics, the AEs are early potential for CRS, which is all low grade, and cytopenias and infection risk, but there isn’t another unique AE of those BCMA-targeted therapies. The reason that we see the AEs here is because GPRC5D is expressed on epithelial cells, and so it hits the target; it’s just not our intended effect of that. So there are definitely more AEs with talquetamab, or there are these unique AEs with talquetamab….

When you combine talquetamab with other agents such as daratumumab [Darzalex]—there’s the TRIMM-2 trial [NCT04108195]—or combining it with teclistamab or other agents, there do seem to be fewer AEs when it’s given in combination than when it’s given by itself.³ I’m not entirely sure why, but, but those are the reports from the trials that are there.

…[Dr Chen], how’s your patient doing on talquetamab?

Chen: She was not doing well. She is 50 years old and was diagnosed with multiple myeloma at the age of 30. She underwent 2 allogeneic [transplants], teclistamab, and CAR T, everything. She was doing fine, but it doesn’t work for her.

Huzefa Bahrain, MD: I used it as a bridge to CAR T. It did the trick; it helped to get the patient to CAR T.

Huff: You got to CAR T, which is great. That is an increasing use of talquetamab to bridge patients to get them to CAR T. I have done that as well. I personally like to try to collect their T cells and then use the talquetamab, so that I’m taking T cells that haven’t seen any T-cell redirecting therapy, but it’s a nice way of using the immune system, not using the target that you’re going to reinfuse with your CAR T cells.

Bahrain: I’m just curious. Let’s say you take them post treatment. Those T cells you take, are they better equipped to detect the target of GPRC5D because they’ve been exposed to it?

Huff: Probably not, because you’re using the cells, and they’re used up, if you will, and they’re not there. But the nice thing is, we know these therapies are highly effective. So, if you have a patient who’s had 4 prior lines of therapy at this point in time, almost certainly they’ve had bortezomib, carfilzomib [Kyprolis], pomalidomide [Pomalyst], lenalidomide [Revlimid], and anti-CD38, and you’re trying to get them to CAR T.

We do know—we’re not talking CAR T necessarily here—but there’s more toxicity the higher the tumor burden is going into CAR T—more CRS, more ICANS, so we like to optimally cytoreduce patients. If you said, what else could I use that has a 60% to 70% response rate? There’s not really much else that you could use. So, if you can collect those cells and then give those agents, you’ve got a 60% to 70% chance you can get them reduced [and] give the CAR T to come in to consolidate that response.

Haiyun Wang, MD: My patient is getting it as bridging with cells collected.

Carol Ann Huff, MD: That’s what I like to do, collect the cells so…I can get a pure cell population before I’ve utilized some of them with a bispecific. It doesn’t always work that way, but we try to do that.

_{DISCLOSURES: Huff previously reported clinical research support or data safety monitoring board participation with ICON, Janssen Pharmaceutica Products, LP; and advisory board or consulting for Alexion Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Johnson & Johnson, and Legend Biotechnologies.}

REFERENCES

1. Al Hadidi S, Szabo A, Mohan Lal B, et al. Talquetamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J. 2025;15(1):196. Published 2025 Nov 7. doi:10.1038/s41408-025-01386-7

2. Kowalski A, Lykon J, Diamond B, et al. Tocilizumab prophylaxis for patients with multiple myeloma treated with bispecific antibodies. Blood Adv. 2025;9(19):4979-4986. doi:10.1182/bloodadvances.2025016911

3. Chari A, van de Donk NWCJ, Dholaria B, et al. Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study. Blood. 2025;146(24):2902-2913. doi:10.1182/blood.2025029360