Talquetamab’s Late Toxicities Characterized by Oral and Skin AEs

Bispecific T-cell engagers are providing a new approach to treating relapsed/refractory multiple myeloma. These agents are now being used as an alternative to chimeric antigen receptor (CAR) T-cell therapies or in sequence with them. In a virtual Case-Based Roundtable event for oncologists in North Carolina and Virginia, Christopher J. Ferreri, clinical assistant professor in the Department of Hematologic Oncology and Blood Disorders at Atrium Health Levine Cancer Institute, discussed the tolerability profile of talquetamab (Talvey), a therapy that has some overlap in toxicities with other approved agents but also presents its own unique challenges in management that can be approached with prophylaxis, supportive care, and dose reductions.

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CASE SUMMARY

• A 72-year-old man was diagnosed 6 years ago with multiple myeloma, 60% plasma cells, and translocation 14;20.
• Medical history: respiratory infections (2 episodes of pneumonia and multiple episodes of bronchitis over prior 10 years)
• The patient received 5 prior lines of therapy, most recently B-cell maturation antigen (BCMA)-directed CAR T-cell infusion.
• He now presented with progressive disease (increased free light chain, creatinine 2.3 mg/dL)
• ECOG performance status: 2
• Talquetamab was initiated via step-up dosing (0.8 mg/kg every 2 weeks).
• During admission, he experienced grade 1 cytokine release syndrome (CRS) after the second step-up dose.
• He also reported altered taste and dry mouth during step-up dosing.
• By end of the first month of treatment, the patient achieved stringent complete response (sCR), but is experiencing the following adverse events (AEs):
• Oral: complete loss of taste and dry mouth
• Skin: dry skin, skin exfoliation on hands and feet
• Nails: ridging and peeling

Targeted Oncology: What are the early-presenting toxicities associated with talquetamab?

Christopher J. Ferreri, MD: The early toxicities, CRS and ICANS [immune effector cell–associated neurotoxicity syndrome], can be logistically challenging based on your system, but generally, it has a much easier profile to manage than CAR T cell therapy. With the MonumenTAL-1 study [NCT04634552], you saw CRS incidence in the low 70% overall, but the majority of that being grade 1, a little under 20% being grade 2, and 1 or 2 cases being grade 3, less than 2%.¹ It almost always happens during the step-up dosing schema.

The first full dose is the last dose of the step-up regimen. If you go to subsequent full doses or maintenance doses, you see less than 3% CRS after that. Even then, [it’s unclear if a] fever was truly CRS or if it was an infection that wasn't diagnosed. If you're worried about the logistics of your practice, but if somebody else does the step-up dosing, then after that, you shouldn't need to be dealing with CRS or ICANS. Neurotoxicity or ICANS occurs relatively uncommonly in less than 10% of patients and tends to happen very early within the step-up dosing as well.

Infection risk is a big point of conversation. When we talk about BCMA-directed bispecifics, that is the main toxicity consideration. When you follow any patient with myeloma for over a year, it's hard not to have some sort of infection, but the ones that we get concerned about are grade 3 or higher requiring hospitalization or intravenous antibiotics. At this amount of follow-up, there was around 20%, lower than what we had seen with BCMA-targeted bispecifics.²

What are the toxicities specific to targeting GPRC5D?

GPRC5D, the target protein, is an orphan G protein-coupled receptor. We don’t know exactly what its endogenous ligand or role is, but we know that it is expressed on malignant plasma cells more so than normal plasma cells, making it a good target for myeloma. But it's also expressed on keratinized tissues. We primarily see this with oral and cutaneous AEs. In the trial, they reported an incidence of 72% of dysgeusia.² The rate of some degree of taste alteration or loss that we see in our practice is essentially 100%. Many patients will develop a dry mouth and sometimes some oropharyngeal dysphagia related to those symptoms. When those symptoms are more severe and it impacts oral intake, you can see weight loss; 40% of patients had weight loss on the study.³ That is not always a bad thing, depending on where the patient's starting, but grade 3 weight loss was seen in 3% of patients and led to discontinuation in 1%.

From the cutaneous side of things, rash happens about one-third of the time, typically managed with topical corticosteroids, or if it's more diffuse, you can use a short course of oral corticosteroids. Often that will resolve and not recur with retreatment, but sometimes it is a persistent issue. Nobody in the study stopped because of a rash. Outside of developing a rash, patients often develop dry skin and sometimes associated pruritus with that. The nail [AEs] are mostly cosmetic. It's ridging and appearance changes. Occasionally, when severe, some patients’ nails will fall off and regrow and then advance again. This is an important thing to be aware of.

There are GPRC5D-targeted CAR T cells in development as well. When data were first published, the clear dose-limiting toxicity of a CAR T cell against this target was an atypical central nervous system AE. It was cerebellar dysfunction. Initially, this wasn't seen with talquetamab, and it's still not common. But across the trial portfolio looking at talquetamab, in MonumenTAL-1 in less than 1% but it has been observed in both the real-world setting and across other studies.⁴ It is not common, but can be severe and debilitating if a patient develops ataxia and cerebellar symptoms, and it is a reason to stop the drug until that resolves if it does occur.

CASE UPDATE

• The following supportive care was provided to help the patient with AEs:
• CRS (grade 1): 1000 mg acetaminophen

• Dermatologic: heavy moisturizing cream, ammonium lactate 12% lotion to hands and feet twice daily, nail hardener, topical vitamin E oil, triamcinolone 0.025% ointment

• Oral: Dexamethasone/nystatin oral rinse, diet changes, dose reduction (cycle 6, 800 mg dropped to 400 mg), schedule modification (monthly dosing)
• He remained in a sCR on monthly dosing. His taste changes were intermittent and grade 1 or less.
• Skin exfoliation resolved during cycle 2
• Nail changes continued

How do patients respond when treated for cutaneous and oral AEs?

Once the peeling of the skin of the hands and feet stops, it usually is a one-time thing, unless a patient has a long pause and restarts the drug. For the oral AEs, they can modify the diet to softer foods, maybe some lozenges, less dry foods, things like that. Sometimes patients try dexamethasone or Nystatin oral rinses; others will recommend OTC Biotène mouthwash.

Ultimately, this patient had a dose reduction from 0.8 mg/kg down to [0.4 mg/kg]. Other options are schedule modifications of dosing it less frequently, such as monthly. For this patient, he maintains an sCR. He's decreased his dosing frequency down to once a month, and his taste changes have improved. They're not completely gone, but they’re intermittent or not always persistent. Skin exfoliation has not recurred, and he still has some minor nail changes. I would say that description is relatively common.

What is the infection profile with talquetamab?

Looking at infectious complications, the longer you follow these patients, the more infections that will occur. But grade 3 or higher was in the 20% [range]; it's over 50% for patients with BCMA bispecifics.⁵ We did see a few opportunistic infections. In this study, essentially 15% of patients were getting intravenous immunoglobulin prophylaxis.⁶ That is probably on the low side compared with what we're doing for our patients treated with talquetamab; most patients develop hypogammaglobulinemia.

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_{DISCLOSURES: Ferreri previously reported consulting or advisory role for Sanofi and Janssen; stock/other ownership in Affimed Therapeutics.}

_REFERENCES:

_{1. Talvey. Prescribing information. Janssen Pharmaceutical Companies; 2023. Accessed September 4, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761342s000lbl.pdf}

_{2. Chari A, Krishnan A, Rasche L, et al. Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab. Clin Lymphoma Myeloma Leuk. 2024;24(10):665-693.e14. doi:10.1016/j.clml.2024.05.003}

_{3. Rasche L, Schinke C, Touzeau 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. Presented at: European Hematology Association 2024 Congress; Madrid, Spain; June 13-16, 2024. Abstract P915.}

_{4. Chari A, Touzeau C, Schinke C, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1-2 study. Lancet Haematol. 2025;12(4):e269-e281. doi:10.1016/S2352-3026(24)00385-5}

_{5. Rasche L, Schinke C, Touzeau C, et al. Efficacy and safety from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Analyses at an extended median follow-up. J Clin Oncol. 2025;43(suppl 16):7528. doi:10.1200/JCO.2025.43.16_suppl.7528}

_{6. Rodríguez-Otero P, Schinke C, Chari A, et al. Analysis of infections and parameters of humoral immunity in patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with talquetamab (tal) monotherapy in MonumenTAL-1. J Clin Oncol. 2025;41(suppl 16):8020. doi:10.1200/JCO.2023.41.16_suppl.8020}