Talquetamab Plus Daratumumab Produces Potent Responses in R/R Multiple Myeloma

Bhagirathbhai R. Dholaria, MBBS

Talquetamab plus daratumumab (Darzalex) displayed high response rates regardless of 0.4 mg/kg or 0.8 mg/kg dosing in combination with daratumumab (Darzalex) in patients with heavily pretreated relapsed/refractory multiple myeloma, irrespective of prior treatment with CD38-directed therapy and T-cell redirection therapy, according to updated findings from the phase 1 TRIMM-2 trial (NCT04108195) that were presented at the 2023 ASCO Annual Meeting.

Median follow-up in the 0.4-mg/kg (n = 14) and 0.8-mg/kg (n = 50) cohorts was 16.8 months (range, 1.9-31.0) and 15.0 months (range, 1.0-23.3), respectively. Median time to first response was 1.0 month in both cohorts. The objective response rates (ORRs) were 71.4% and 84.0%, respectively. In the 0.4-mg/kg cohort, 57.1% of patients experienced very good partial response (VGPR) or better (stringent complete response [sCR], 28.6%; CR, 14.3%; VGPR, 14.3%; partial response [PR], 14.3%). In the 0.8-mg/kg cohort, the VGPR or better rate was 74.0% (sCR, 36.0%; CR, 16.0%; VGPR, 22.0%; PR, 10.0%).

“Talquetamab, targeting the novel antigen GPRC5D, combined with daratumumab is an off-the-shelf immunotherapy regimen that shows deep and durable responses in patients with relapsed/refractory multiple myeloma,” lead study author Bhagirathbhai R. Dholaria, MBBS, assistant professor of medicine in the Department of Medicine and Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee, said in a presentation of the data.

Talquetamab is a T-cell redirecting bispecific antibody that targets GPRC5D. Coupled with daratumumab, the combination was hypothesized to result in enhanced immunomodulatory activity.

To be eligible for enrollment, patients had to have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) or were double refractory to a PI and IMiD and had not received CD38-directed therapy in 90 days or less.

In the study, talquetamab was administered at 0.4 mg/kg or 0.8 mg/kg subcutaneously every week or every 2 weeks, respectively. Patients received daratumumab at 1800 mg subcutaneously, weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks in cycles 7 and beyond.

The key objectives for parts 1 and 2 of the trial were to identify the recommended phase 2 dose (RP2D) and the safety at the RP2D, respectively. Antitumor activity was also observed.

Early data from the trial were presented at the 2022 EHA Congress and showed that at a median follow-up of 6.7 months and 4.2 months in the 0.4-mg/kg and 0.8-mg/kg cohorts, respectively, the ORRs were 71.4% and 83.8%, respectively.²

Additional results that were presented at the 2023 ASCO Annual Meeting, which had an additional 5 months of follow-up, showed that when broken down by status to prior CD38-directed therapy, the ORRs in the 0.4-mg/kg cohort were 100%, 63.6%, and 63.6% in the CD38-naïve (n = 3), exposed (n = 11), and refractory (n = 11) populations, respectively. In the 0.8-mg/kg cohort, the ORRs were 100% (n = 5/5), 82.2% (n = 37/45), and 80.0% (n = 32/40), respectively. “Promising responses [were] observed in high unmet need subgroups [with] every-2-week dosing,” Dholaria said.

Among patients who had prior T-cell redirection therapy (n = 6) in the 0.4-mg/kg cohort, the ORRs were 50.0% and 80.0% in those who received prior CAR T-cell therapy (n = 2) and prior bispecific antibody therapy (n = 5), respectively. In the 0.8-mg/kg cohort, the ORRs were 88.9% (n = 8/9) and 70.0% (n = 7/10), respectively.

The median duration of response was not reached in the 0.4-mg/kg cohort and was 20.3 months in the 0.8-mg/kg cohort. The proportion of responders who remained in response at 1 year was 80.9%, 93.3% of which had a CR or higher. This rate was 88.4% in patients who received prior T-cell redirection therapy and 94.1% in those who switched to less frequent dosing.

A total of 65.4% of responders remained on treatment, 63.6% of which had prior exposure to a CD38-directed antibody and 61.5% of which were refractory to prior CD38-directed therapy.

Additional results indicated that the median progression-free survival was not reached (range, 2.73-not evaluable [NE]) in the 0.4-mg/kg cohort and was 19.4 months (range, 12.5-NE) in the 0.8-mg/kg cohort. The 12-month PFS rates were 77.4% (95% CI, 44.9%-92.1%) and 67.4% (95% CI, 52.3%-78.6%), respectively. Median overall survival (OS) was not reached in either cohort. The 12-month OS rates were 92.3% (95% CI, 56.6%-98.9% and 91.5% (95% CI, 78.8%-96.7%) in the 0.4-mg/kg and 0.8-mg/kg cohorts, respectively.

Regarding safety, no additive toxicity occurred, according to Dholaria. Regarding nonhematologic toxicity, skin, nail, and oral adverse effects (AEs) were common but mostly low grade. AEs leading to talquetamab dose reductions and discontinuations occurred in 16.9% and 1.5% (n = 1, toxic skin eruption) of patients, respectively.

“[The] safety profile of the combination [was] consistent with monotherapies, with low rates of talquetamab discontinuation due to AEs,” Dholaria said.

Rashes were managed with topical corticosteroids or short course oral corticosteroids. Dysgeusia and dry mouth were managed with mouth washes, saliva stimulants, or dose modifications. Among the 76.9% of patients who experienced dysgeusia, 6.2% required dose reduction with talquetamab.

The occurrence of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome was comparable to that of talquetamab monotherapy. Notably, CRS was limited mostly to step-up and cycle 1 dosing. No grade 3/4 CRS or CRS leading to treatment discontinuation occurred. Less than 5% (4.6%) of patients experienced ICANS, and all events were grade 1/2 and resolved in 1 to 2 days.

Of 80.0% of patients with grade 3/4 AEs, 60.0% were hematologic. Grade 3/4 neutropenia occurred in less than 30% of patients in both cohorts, and cytopenia was predominantly limited to step-up and cycle 1 and 2 dosing, resolving in most patients.

Infections were mostly low grade. Pneumonias comprised most high-grade infections; one fatality due to treatment-related pneumonia occurred at the 0.8-mg/kg dose. Most patients (75.0%) were likely to experience grade 3 or higher infection within the first 6 months of treatment. A total of 10.8% of patients had opportunistic infections and 3.1% had cytomegalovirus reactivation.

Most patients (95.4%) received antibacterial, antifungal, or antiviral prophylaxis. Notably, 35.4% of patients had immunoglobulin (IgG) levels below 500 mg/dL at baseline and 86.2% post baseline; 33.8% of these patients received intravenous immunoglobulin.

The combination was also found to be B-cell sparing. No reduction in the total CD19 B cells occurred in both cohorts, which Dholaria noted may partially explain the low rate of grade 3/4 infections.

“Talquetamab may be a versatile combination partner, with every 2-week dosing at initiation and potentially less frequent dosing schedules thereafter,” Dholaria concluded. “Ongoing combination studies include RedirecTT-1, TRIMM-2, and MonumenTAL-3.”

References

1. Dholaria BR, Weisel K, Manteos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16):8003. doi:10.1200/JCO.2023.41.16_suppl.8003
2. van de Donk NWCJ, Bahlis N, Mateos MV, et al. Novel combination immunotherapy for the treatment of relapsed/refractory multiple myeloma: updated phase 1b results for talquetamab (a GPRC5D x CD3 bispecific antibody) in combination with daratumumab. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S183.