Talquetamab/Daratumumab Combination Appears Safe in Patients With Anti-CD38–Refractory Myeloma

Results from the phase 1b TRIMM-2 study (NCT04108195) showed early onset and durable deep responses with talquetamab and daratumumab and hyaluronidase-fihj (Darzalex Faspro) in heavily pretreated patients who were anti-CD38 refractory to multiple myeloma, according to data presented during the European Hematology Association 2022 Congress held in June.¹ At a median follow-up of 5.1 months, the objective response rate (ORR) was 80.4% (n = 41) in response-evaluable patients (n = 51). The rate of complete response (CR) or better was 29.4% (n = 15) with the combination, and the rate of very good partial response (VGPR) or better was 62.7% (n = 32). The ORR in patients with prior anti-CD38 exposure was 77.3% (n = 34/44) (TABLE ¹).

“Data from TRIMM-2 support the use of talquetamab and daratumumab as a novel immunotherapy-based approach for the treatment of patients with anti–CD38–exposed myeloma,” lead study author Niels van de Donk, MD, PhD, professor of hematology and cancer immunology at Vrije Universiteit Amsterdam and a hematologist at VU University Medical Center in Amsterdam, Netherlands, said in the presentation.

Talquetamab is a first-in-class, off-theshelf, T-cell–redirecting, bispecific antibody that targets GPRC5D and CD3 receptors. As a human IgG1k monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, daratumumab monotherapy elicits T-cell expansion and has enhanced T-cell cytotoxic potential.

The combination of talquetamab and daratumumab has the potential to demonstrate synergistic clinical activity, and preclinical studies have shown that the addition of daratumumab enhanced talquetamabmediated lysis of multiple myeloma cells.

The open-label, multicenter, multicohort trial enrolled adult patients with multiple myeloma diagnosed according to International Myeloma Working Group criteria. Patients must have received at least 3 prior lines of therapy or be double refractory to a proteasome inhibitor and an immunomodulatory drug (IMiD). Treatment with an anti-CD38 monoclonal antibody was permitted if it was administered at least 90 days prior to enrollment.

In part 1, investigators identified the recommended phase 2 dose (RP2D) of the combination. In part 2, the safety of the regimen was characterized at the RP2D. Antitumor activity, pharmacokinetic (PK), and pharmacodynamic (PD) activity also were assessed.

Talquetamab was administered subcutaneously at a dose of 800 μg/kg every 2 weeks (n = 44) or 400 μg/kg every week (n = 14). Daratumumab was administered according to the approved subcutaneous schedule, at a dose of 1800 mg every week for the first 2 cycles, every 2 weeks in cycles 3 through 6, and monthly thereafter.

Step-up dosing was used for talquetamab, and premedications including steroids were limited to step-up doses and the first full dose of talquetamab.

Regarding patient demographics and patient characteristics, the median number of prior lines of therapy received in the 400-μg/kg and 800-μg/kg cohorts were 6 (range, 4-16) and 5 (range, 2-14), respectively. Most patients were refractory to CD38 antibodies, namely 78.6% and 75.0%, respectively. In addition, 57.1% and 63.6% of patients, respectively, were triple-class refractory. Penta-refractory disease was present in 35.7% and 27.3% of patients, respectively.

Van de Donk also stated that approximately 50% of patients in both cohorts had prior BCMA-targeted therapy: an antibodydrug conjugate, chimeric antigen receptor T-cell therapy, or a bispecific antibody.

The median follow-up in the 400-μg/kg cohort was 6.7 months. In this cohort of response-evaluable patients (n = 14), the ORR was 71.4%; 28.6% of patients experienced CR or VGPR.

The median follow-up in the 800-μg/kg cohort was 4.2 months. In this cohort of response-evaluable patients (n = 37), the ORR was 83.8%; 29.7% and 35.1% of patients achieved a CR or VGPR or better, respectively.

The time to first confirmed response in both cohorts was 1.0 month (range, 0.9-6.5).

Notably, the median duration of response was not reached, and at a median follow-up of 6.5 months (range, 1.6-19.6) in responders (n = 41), 90.2% remained on treatment.

Safety Report

In terms of safety, the combination was tolerable and displayed a safety profile that was comparable to each agent alone.

Hematologic adverse effects (AEs) occurring in at least 20% of patients in the 400-μg/kg arm included anemia (any grade, 57.1%; grade 3/4, 35.7%), thrombocytopenia (any grade, 42.9%; grade 3/4, 28.6%), neutropenia (any grade, 35.7%; grade 3/4, 28.6%), and lymphopenia (any grade, 57.1%; grade 3/4, 57.1%).

A lower incidence of these AEs occurred in the 800-μg/kg arm: anemia (any grade, 43.2%; grade 3/4, 18.2%), thrombocytopenia (any grade, 34.1%; grade 3/4, 15.9%), neutropenia (any grade, 31.8%; grade 3/4, 20.5%), and lymphopenia (any grade, 15.9%; grade 3/4, 15.9%).

One patient discontinued talquetamab because of grade 2 toxic skin eruption.

Cytopenias were predominantly seen in step-up and cycle 1 and 2 doses; these events resolved in most cases.

Nonhematologic AEs in the 400-μg/kg arm were cytokine release syndrome (CRS; grade 1, 57.1%; grade 2, 14.3%), dysgeusia (any grade, 71.4%), dry mouth (any grade, 71.4%), skin exfoliation (any grade, 50%), pruritus (any grade, 42.9%), headache (any grade, 21.4%), back pain (any grade, 21.4%), arthralgia (any grade, 28.6%), cough (any grade, 28.6%), dizziness (any grade, 35.7%), nausea (any grade, 35.7%), weight decrease (any grade, 42.9%), decreased appetite (any grade, 21.4%; grade 3/4, 7.1%), and oropharyngeal pain (any grade, 21.4%).

In the 800-μg/kg arm, investigators also reported CRS (grade 1, 52.3%; grade 2, 25.0%), dysgeusia (any grade, 59.1%, grade 3/4, not applicable), dry mouth (any grade, 40.9%), skin exfoliation (any grade, 29.5%), pruritus (any grade, 22.7%), headache (any grade, 25.0%), back pain (any grade, 25.0%; grade 3/4, 2.3%), arthralgia (any grade, 20.5%), cough (any grade, 20.5%), dizziness (any grade, 18.2%), nausea (any grade, 18.2%), weight decrease (any grade, 15.9%), decreased appetite (any grade, 20.5%), and oropharyngeal pain (any grade, 20.5%).

Most patients had skin- and/or nail-related AEs (81.0%), most commonly skin exfoliation; 13.8% had grade 1/2 nail disorders, and rashes were mostly grade 1/2. Moreover, 5.2% of patients had grade 3 maculopapular rash, and all cases resolved with steroids; most were able to be rechallnged with the combination.

Notably, 53.4% of patients had infections; 17.2% were grade 3 or higher in severity.

One patient died because of treatmentrelated pneumonia.

Regarding CRS, the time to onset was 3 days (range, 2-4) in the 400-μg/kg cohort and 2 days (range, 1-4) in the 800-μg/kg cohort; the median duration in both arms was 2 days. Most patients received supportive care in the 400-μg/kg (64.3%) and 800-μg/kg (68.2%) cohorts, and no discontinuations occurred because of this toxicity.

Two patients had immune effector cell–associated neurotoxicity syndrome, both of which were grade 1 and resolved within 1 day.

Van de Donk also reported that PK and PD analyses indicated that the combination led to T-cell activation and induction of CD38+ and CD8+ T cells. “The efficacy and pharmacodynamic profile of talquetamab plus daratumumab suggest that higher response rates may be observed in patients who are not refractory to anti-CD38 treatment,” van de Donk said.

Other talquetamab-based regimens that include combinations with daratumumab, IMiDs, teclistamab, and/or a PD-1 inhibitor are being evaluated in phase 1 studies (NCT05050097; NCT04586426; NCT05338775).

_REFERENCE:

_{1. 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: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria, and Virtual. Accessed July 8, 2022. https://bit.ly/3uyrIcu}