Two new bispecific antibodies—teclistamab and talquetamab—have been shown to be active in relapsed or refractory multiple myeloma when used in combination, including in patients with extramedullary disease, without compounding toxicity. Results of two clinical trials with these two agents were presented at the 2023 ASCO Annual Meeting.1,2
RedirecTT-1: Combination of Teclistamab and Talquetamab
Teclistamab, which targets B-cell maturation antigen (BCMA), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma. Talquetamab is a bispecific antibody targeting G protein–coupled receptor family C group 5 member D (GPRC5D) and has shown efficacy in heavily pretreated patients. Both drugs also target CD3. [Editor’s Note: On August 9, 2023, the FDA granted accelerated approval to talquetamab-tgvs for the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior therapies (including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody).]
The phase Ib RedirecTT-1 trial of 93 patients evaluated these two bispecific antibodies in combination in patients with previous exposure to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody (ie, triple-class–exposed). Almost two-thirds (66%) were refractory to five classes (ie, penta-refractory); 38% had extramedullary disease, and 33% had high-risk cytogenetics.
The overall response rate to the combination was 86.6% across all dose levels and 96.3% in patients treated with the recommended phase II regimen (teclistamab at 3.0 mg/kg plus talquetamab at 0.8 mg/kg every 2 weeks), including complete responses in 40.2% and 40.7%, respectively. In patients with extramedullary soft-tissue plasmacytomas, 85.7% responded to the recommended dose, with 28.6% being complete responses.
“This is the first time that results of two bispecific antibodies used in combination have ever been reported in hematologic malignancies,” said Yael C. Cohen, MD, of Tel-Aviv Sourasky (Ichilov) Medical Center and Sackler School of Medicine at Tel Aviv University in Israel. Dr. Cohen noted that the overall response rate with teclistamab plus talquetamab is similar to that seen with chimeric antigen receptor (CAR) T-cell therapies.
Median time to response was 2.0 months. With 13.4 months of median follow-up, the median duration of response was not reached; median progression-free survival was 20.9 months across all dose levels and not estimable on the phase II regimen.
“The safety profile of the combination was consistent with that of monotherapies, with no new or additive toxicities,” Dr. Cohen said. Grade 3 or 4 treatment-related adverse events were observed in 88.2% of patients, leading to death in six (6.5%) altogether but in one (2.9%) receiving the phase II dose. Although approximately three-quarters of patients developed cytokine-release syndrome, there were no deaths or treatment discontinuations because of this side effect. As seen in the monotherapy studies, infections were observed in 83.9% of patients (52.7% were grade 3 or 4).
“These results support the initiation of larger studies with the combination of teclistamab and talquetamab,” Dr. Cohen said. She noted the study will expand to include more patients with extramedullary disease.
TRIMM-2: Talquetamab Plus Daratumumab
In another combination study in multiple myeloma, talquetamab was given with daratumumab, based on the possible synergistic immunomodulatory effects of these two agents together. The combination, involving talquetamab in two different doses, was evaluated in the TRIMM-2 study of 64 patients previously treated with at least three lines of therapy (> 60% penta-refractory). Updated results were reported by Bhagirathbhai R. Dholaria, MBBS, of Vanderbilt University Medical Center, Nashville.2
Bhagirathbhai R. Dholaria, MBBS
Patients received talquetamab at 0.4 mg/kg weekly or talquetamab at 0.8 mg/kg every 2 weeks. Both were paired with daratumumab at 1,800 mg weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and monthly for cycle 7 and beyond.
With a median follow-up of more than 16 months, the objective response rate was 71.4% with talquetamab at 0.4 mg/kg weekly and 84.0% with talquetamab at 0.8 mg/kg every 2 weeks (plus daratumumab). In patients with prior T-cell redirection therapy (CAR T-cell or bispecific antibody), response rates were 66.7% and 78.9%, respectively, Dr. Dholaria reported.
Median duration of response was not reached with 0.4 mg/kg and was 20.3 months with 0.8 mg/kg. Almost 81% of responders and 93% of complete responders were still responding at 12 months, including 88% of those with prior T-cell redirection therapy. Of 19 patients who switched to less-frequent dosing, 94% remained in response. Median progression-free survival was not reached with 0.4 mg/kg and was 19.4 months with 0.8 mg/kg, yielding 12-month progression-free survival rates of 77.4% and 67.4%, respectively, and an overall survival rate of around 92% for each regimen.
Skin, nail, and oral toxicities were common but mostly low grade. Adverse events led to dose reductions of talquetamab in 16.9% of patients, and one patient discontinued the drug because of a toxic skin eruption. Cytokine-release syndrome was mostly confined to step-up and cycle 1 dosing, and none led to treatment discontinuation. Infections were generally low grade, although 13.7% of the arm given 8 mg/kg of talquetamab developed grade ≥ 3 pneumonia (one case was fatal). No reduction in total CD19 B cells was observed in either dosing cohort, which may partially explain the relatively low infection rate, he suggested.
“With long-term follow-up, no increased toxicities were observed, and talquetamab plus daratumumab remained clinically manageable.... Talquetamab may be a versatile combination partner for daratumumab, with the ability to use every-2-week dosing at initiation and potentially less-frequent dosing schedules thereafter,” Dr. Dholaria said.
DISCLOSURE: Dr. Cohen reported financial relationships with Janssen, Amgen, GlaxoSmithKline, Medisone, NeoPharma, and Takeda. Dr. Dholaria reported financial relationships with ADC Therapeutics, Arivan Research, Beam Therapeutics, Boxer Capital, Ellipses, Gamida Cell, Janssen Oncology, Jazz Pharmaceuticals, Pluristem Therapeutics, Adaptive Biotechnologies, Curio Science, MJH Healthcare Holdings, Wiley, Iovance Biotherapeutics, and Syndax.
REFERENCES
1. Cohen YC, Morillo D, Gatt ME, et al: First results from the RedirecTT-1 study with teclistamab plus talquetamab simultaneously targeting BCMA and GPRC5D in patients with relapsed/refractory multiple myeloma. 2023 ASCO Annual Meeting. Abstract 8002. Presented June 3, 2023.
2. Dholaria BR, Weisel K, Mateos MV, et al: Talquetamab plus daratumumab in patients with relapsed/refractory multiple myeloma: Updated TRIMM-2 results. 2023 ASCO Annual Meeting. Abstract 8003. Presented June 3, 2023.
