Analyzing Long-Term Follow-Up Results From MonumenTAL-1 in Multiple Myeloma

The panel.

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Binod Dhakal, MD, MS, an associate professor of medicine at the Medical College of Wisconsin, and Leonid Shunyakov, MD, an oncologist/hematologist at Citizens Memorial Hospital, discussed the application of talquetamab-tgvs (Talvey) in relapsed/refractory multiple myeloma. The discussion, part of a Between the Lines® program hosted by CancerNetwork®, centered on updated results from the phase 1/2 MonumenTAL-1 trial (NCT03399799; NCT04634552) shared at the meeting.1

Talquetamab has a unique place in the treatment paradigm for multiple myeloma as it is the only approved bispecific antibody targeting GPRC5D for relapsed/refractory multiple myeloma. Regarding this mechanism of action, Dhakal said, “The exact function and mechanism of this target is not understood; however, we know it is expressed heavily on the malignant plasma cells, much more than the normal plasma cells.”

Updated Efficacy

With an extended median follow-up ranging from 30 to 38 months, the trial’s results continued to demonstrate consistent or improved efficacy and safety outcomes.

Patients in the trial were assigned to 1 of 3 treatment cohorts: the first (weekly dosing) enrolled patients who were naive to T-cell redirection therapy (TCR) and received 0.4 mg/kg of subcutaneous talquetamab once weekly (n = 143), the second (every 2-week dosing) enrolled patients who were TCR-naive who were administered 0.8 mg/kg of subcutaneous talquetamab once every 2 weeks (n = 154), and the third (prior TCR weekly and every 2-week dosing) enrolled patients who received prior TCR and were administered either 0.4 mg/kg once weekly or 0.8 mg/kg once every 2 weeks (n = 78).

In the first cohort, the overall response rate (ORR) was 74.1%, with a complete response (CR) or better rate of 32.9%, a very good partial response (VGPR) rate of 26.6%, and a PR rate of 14.7%. In the second cohort, the ORR was 69.5%, with a CR or better rate of 40.3%, a VGPR rate of 18.8%, and a PR rate of 10.4%. In the third cohort, the ORR was 66.7%, with a CR or better rate of 42.3%, a VGPR rate of 12.8%, and a PR rate of 11.5%.

Notably, however, in the first and second cohorts, the patients were naive to TCR, whereas in the third cohort, they received prior TCR. Shunyakov said, “It’s pretty incredible to see that the response rate in patients who had prior exposure to T-cell–redirected therapy is about the same as in patients who are naive to TCR.”

Further, the median duration of response (DOR) was 9.5 months (95% CI, 6.7-13.4) in the first cohort, 17.5 months (95% CI, 12.5-25.1) in the second cohort, and 19.2 months (95% CI, 8.1-24.7) in the third cohort.

“If you look at the durability of response, that is where the significance of this product comes in,” said Dhakal. “If you look at the 0.8 mg/kg [subcutaneous] every other week, your median DOR is almost 18 months. That is quite impressive.”

He emphasized the similarity in DORs between the second cohort, which did not receive prior TCR, and the third cohort, which did. Shunyakov agreed that the positivity of these results, especially in the prior TCR cohort, was impressive. With these high and durable responses in this group of patients with an unmet need for new therapies, it is crucial to consider talquetamab for treatment, according to Dhakal.

Dhakal also pointed out that data from the benchmark studies from when CAR T-cell therapies were initially developed—the MAMMOTH and LocoMMotion (NCT04035226) studies—showed an overall survival (OS) of less than a year.

MonumenTAL-1 data significantly improved on that by showing prolonged survival in the same unexposed patient population and also in patients with prior exposure to T-cell–directed therapies.

The findings showed a median OS of 34.0 months (95% CI, 25.6-not estimable [NE]) in the first cohort, not reached (95% CI, NE-NE) in the second cohort, and 28.3 months (95% CI, 19.5-NE) in the third cohort. The respective 36-month OS rates were 49.3% (95% CI, 40.4%-57.6%), 60.8% (95% CI, 51.5%-68.8%), and 44.6% (95% CI, 31.4%-57.0%).

“In terms of overall survival, [these] data [are] unprecedented,” Shunyakov added.

In cohorts 1, 2, and 3, respectively, the median progression-free survival (PFS) was 7.5 months (95% CI, 5.7-9.4), 11.2 months (95% CI, 7.7-14.6), and 7.7 months (95% CI, 4.1-14.5).

Both clinicians also discussed the heavily pretreated patient population of the trial, as having 3 or more therapies was a requirement to enroll in phase 2; in the TCR-naive population, the median number of lines of therapy was 5, and in the TCR-exposed population, it was 6. Considering the positive data, even in this population, Shunyakov said it would be good to consider moving talquetamab up and treating patients with it as soon as possible. Dhakal highlighted that, as with most highly effective therapies, if you move them earlier, they will elicit better responses.

He also noted that, as patients require more lines of therapy, they are more likely to drop out of treatment, so waiting to administer it may be inadvertently preventing many patients from having the opportunity to receive this therapy.

The Dosing Schedule

With the trial broken down into 3 cohorts, several trends were noticeable. The first Shunyakov mentioned was how the weekly dosing schedule in the first cohort elicited higher responses, whereas the biweekly dosing schedule from cohort 2 demonstrated prolonged OS and PFS.

This likely means that biweekly dosing was better tolerated, and thus, patients can stay on treatment longer and continue to derive benefit. In his practice, Shunyakov has been administering talquetamab in the biweekly dosing schedule, almost from the beginning.

They do this because talquetamab can lead to mucositis, skin problems, and weight loss, which can become serious issues if they overadminister the drug.

Dhakal also uses the 0.8-mg/kg biweekly dosing schedule because it is convenient for the patient, and if the patient maintains their response, they may change to monthly dosing. According to him, no observable difference exists between the weekly and biweekly schedules regarding controlling the disease.

“There are no clinical predictors that will help you choose one dose vs another, but 0.8 mg/kg seems to be more friendly for the patient,” said Dhakal.

Shunyakov also stated that, in patients with prior exposure to BCMA, his next choice for therapy would be to target GPRC5D.

Updated Safety Profile

At the extended follow-up, the safety profile remained consistent with what was previously seen. Discontinuation rates due to adverse events (AEs) remained low, and no new discontinuations were observed due to GPRC5D-related AEs. However, a new safety signal, ataxia/balance disorders, was identified in association with talquetamab and had a low prevalence in MonumenTAL-1. The most common AEs of grades 3 and 4 were cytopenias, and there were no reported treatment-related deaths due to talquetamab.

Both doctors emphasized the infection-related AEs. Any-grade and grade 3/4 infections occurred in 61% and 23% of cohort 1, 71% and 21% of cohort 2, and 78% and 26% of cohort 3, respectively.

Although these rates are significant, Shunyakov compared them with the infection rates of BCMA-directed bispecific antibodies, which are close to 70% for any grade and 50% for grades 3/4. As he said, talquetamab is favorable. He attributed this to the mechanism of action of talquetamab because it primarily targets multiple myeloma cells rather than other plasma cells, which have very minimal or no effect on the healthy B lymphocytes. He added that he may even prefer talquetamab before a BCMA-
directed bispecific antibody due to the lower rate of infections.

For prophylaxis, although patients who receive BCMA-
directed bispecific antibodies almost always receive intravenous immunoglobulin replacement therapy, when patients who received talquetamab are several months into treatment, their immunoglobulin levels increase in most cases. In other words, most patients receiving talquetamab receive prophylaxis early on in treatment but may discontinue it later.

The new safety signal, ataxia/balance disorders, was also a point of conversation. Although neither doctor has seen it in practice yet, they have made it a point to tell their patients that it is a potential new toxicity that can be debilitating, even if it only occurs in less than 1% of patients.

Reference

Rasche L, Schinke CD, 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