Talquetamab in R/R MM: Updates from the MonumenTAL trials

G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising immunotherapy target for patients with multiple myeloma (MM) due to its high expression on malignant plasma cells.¹ Talquetamab is an investigational bispecific T-cell engager antibody targeting both the GPRC5D and CD3 molecules for the treatment of patients with relapsed/refractory (R/R) MM.¹ As a result of encouraging phase I and II trial results, a biologics license application for the bispecific antibody talquetamab was submitted to the U.S. Food and Drug Administration (FDA) on December 9, 2022.

Recently, the final analysis results of the phase I MonumenTAL-1 trial investigating the dose escalation of talquetamab were published in the New England Journal of Medicine by Ajai Chari et al.¹ This was shortly followed by a presentation of the combined phase I and II results at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition by Chari.² Prospective phase III trials were also presented at the congress. Below, we summarize results from the phase I and II parts of the MonumenTAL-1 trial, as well as outline future phase III studies.

MonumenTAL-1: Final phase I results¹

The Multiple Myeloma Hub previously reported the study protocol and patient characteristics from the phase I trial. MonumenTAL-1 is an ongoing phase I/II study of talquetamab in patients with R/R MM (NCT03399799). The key objective is to evaluate the efficacy and safety of the recommended phase II dose.

Overall, 232 patients with no prior exposure to T-cell redirecting therapies received talquetamab intravenously (n = 102) and subcutaneously (n = 130). The final response rates from talquetamab are shown in Figure 1. The median time to response and median duration of response for patients treated with 0.4 mg/kg was 0.9 months and 10.2 months, respectively. In contrast, the median time to response and median duration of response for patients treated with 0.8 mg/kg was 1.2 months and 7.8 months, respectively.

Figure 1. Best response rates for patients treated with 0.4 mg/kg and 0.8 mg/kg of talquetamab*

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Chari, et al.¹

The most common adverse events (AEs) of any grade at the 0.4 mg/kg dose level were anemia and neutropenia at 60% and 67%, respectively. Likewise, the most common AEs of any grade for 0.8 mg/kg were anemia and neutropenia at 43% and 36%, respectively. Rates of any grade cytokine release syndrome for the 0.4 mg/kg dose and 0.8 mg/kg dose were 77% and 80%, respectively. The rate of any grade infection for 0.4 mg/kg was 47% and 34% for 0.8 mg/kg.

Combined analysis of phase I and II²

The final response rates for the combined analysis of patients treated with 0.4 mg/kg and 0.8 mg/kg of talquetamab in both the phase I and II parts of the trial are shown in Figure 2.

Figure 2. Combined response rates of patients treated with 0.4 mg/kg and 0.8 mg/kg of talquetamab from phases I and II* 

CR, complete response; ORR, overall response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Chari.²

The overall response rate was similar in both the 0.4 mg/kg and 0.8 mg/kg cohorts and was consistent across subgroups:

• Triple-class refractory: 72.6% and 71.0%, respectively
• Penta-class refractory: 71.4% and 70.6%, respectively

The median time to first response with the 0.4 mg/kg and 0.8 mg/kg doses was 1.2 months and 1.3 months, respectively. The median time to best response with the 0.4 mg/kg and 0.8 mg/kg doses was 2.2 months and 2.7 months, respectively.

Most high-grade AEs were cytopenias but were generally limited to the first treatment cycle. The most common AEs of Grade 3 or 4 in ≥20% of patients at both dose levels are summarized in Table 1 and the most common AEs of any grade in the entire cohort are presented in Table 2.

Table 1. Most common AEs in ≥20% of patients at both dose levels*

The rate of any grade infection at the 0.4 mg/kg dose level was 57.3% compared with 50.3% for the 0.8 mg/kg dose level. Overall, there were low rates of Grade 3 or 4 non-hematologic AEs and only treatment discontinuation in 4.9% of patients treated at 0.4 mg/kg and 6.2% treated at 0.8 mg/kg. No deaths were reported due to drug-related AEs.

MonumenTAL-3³

MonumenTAL-3 is an ongoing phase III trial (NCT05455320) of talquetamab + daratumumab ± pomalidomide compared with daratumumab + pomalidomide + dexamethasone in patients with R/R MM who had received ≥1 prior line of therapy. The study is currently recruiting patients with a target enrolment of 810 patients globally and will be randomized at a 1:1:1 ratio. The eligibility criteria are as follows:

• Measurable and progressive disease
• ≥18 years old
• Eastern Cooperative Oncology Group performance status 0–2
• Must have received ≥1 prior line of therapy including a proteasome inhibitor and lenalidomide

The primary endpoint is progression-free survival defined by the International Myeloma Working Group. Secondary endpoints include efficacy, biomarkers analysis, safety, and patient-reported outcomes.

MonumenTAL-5⁴

MonumenTAL-5 is an ongoing phase III trial (NCT05461209) of talquetamab monotherapy versus belantamab mafodotin in patients with R/R MM who have previously had ≥4 lines of therapy. The study is currently recruiting patients with a target enrollment of 216 patients and the eligibility criteria are as follows:

• ≥18 years old
• Measurable disease
• Eastern Cooperative Oncology Group performance status 0–2
• ≥4 lines of prior therapy
• Progressive disease on or after last regimens

The primary objective is to investigate the efficacy and safety of talquetamab monotherapy versus belantamab mafodotin in patients with R/R MM.

Patients will be randomized at a 1:1 ratio for treatment with either 0.8 mg/kg of talquetamab every 2 weeks or 2.5 mg/kg of belantamab mafodotin every 3 weeks. The primary endpoint of the trial is overall response rate and progression-free survival. Secondary endpoints include overall survival, complete response, and very good partial response or better. Enrollment for the study began in October 2022.

Conclusion

Combined results from the phase I and II parts of the MonumenTAL-1 study highlight the overall promising efficacy with a manageable safety profile of talquetamab at both dosing levels in heavily pretreated patients with R/R MM. This has presented a rationale for further investigation, as shown by the prospective phase III trials currently in the stage of enrollment.