In the phase I/II MonumenTAL-1 trial, the novel bispecific antibody talquetamab produced responses in more than 70% of heavily pretreated patients with multiple myeloma.1 Of note, the safety profile confirmed results of the phase I portion of the study (recently published in TheNew England Journal of Medicine),2 and the risk of infections while on treatment was quite low, according to Ajai Chari, MD, Professor of Medicine and Director of Clinical Research, Tisch Cancer Institute at Mount Sinai, New York.
“These responses [to talquetamab] are incredible, and they were maintained in subgroups, including in more than 60% of patients with prior T-cell–redirecting therapy.”— AJAI CHARI, MD
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“This is really life-changing for these patients,” Dr. Chari commented at a press briefing. “This was a tough population of patients who had exhausted a lot of the available therapies. Despite that, we saw this impressive response rate of about 74%. To put this into context, for novel agents to gain accelerated approval in myeloma, we historically saw response rates of 20% to 30%. Now, we are saying that 70% is the new 30%. These responses are rapid and deep, and they were maintained in subgroups, including in more than 60% of patients with prior T-cell–redirecting therapy. This is important because patients continue to progress on approved CAR T-cell [chimeric antigen receptor] therapy and bispecifics, all of which target the B-cell maturation antigen (BCMA) antigen.”
Talquetamab is a first-in-class, off-the-shelf, T-cell–redirecting bispecific antibody that targets not only CD3 receptors but also G protein–coupled receptor family C group 5 member D (GPRC5D). GPRC5D is highly expressed on malignant plasma cells but rarely in normal human tissue.
As recently reported in The New England Journal of Medicine, the phase I dose-finding trial of a variety of doses (both intravenous and subcutaneous) reported objective response rates of 64% to 70% at the recommended phase II doses.2 Dr. Chari presented combined results for 288 patients from phase I and phase II who received talquetamab at one of two recommended phase II doses: 0.405 mg/kg subcutaneously per week or 0.8 mg/kg subcutaneously every other week.
Patients had received a median of five prior lines of therapy, 79% had undergone stem cell transplantation, and approximately 60% had high-risk features. Most had disease that was refractory to anti-CD38 antibodies, and almost three-quarters had disease that was refractory to the three major classes of drugs.
High Response Rates Across the Board
Response (the primary endpoint for phase II) was observed in 74.1% of patients receiving 0.4 mg/kg weekly and in 73.1% of those receiving 0.8 mg/kg every 2 weeks. Complete or stringent complete responses were achieved by 33.6% and 32.4%, respectively, and very good partial responses or better were achieved in 59.4% and 57.2%, Dr. Chari reported.
“Response was consistent across subgroups, including baseline stage III disease, baseline cytogenetic risk, number of prior therapies, refractoriness to prior therapy, and belantamab exposure. Patients with baseline plasmacytomas had slightly lower response rates of apprxomiately 50%, though still encouraging in such high-risk patients,” he added.
Median progression-free survival was 7.5 months, and treatment at both doses led to durable responses. For patients achieving complete or stringent complete responses, median duration of response was not reached with either dose. For all responders, median duration of response was 9.3 months with the weekly dose of 0.4 mg/kg and 13.0 months with the every-2-week dose of 0.8 mg/kg. The median time to a measurable response was approximately 1.2 months in both dosing groups.
Dr. Chari emphasized the rapidity with which responses were achieved with the dose intensity (ie, the dose or frequency) used in this study and suggested that if talquetamab were moved into earlier lines, the doses may be lower. “When you have these heavily pretreated patients who are looking at hospice, you need rapid disease control. Once you’ve done that, you can back off a little. As we move it earlier, we may be able to use less dose-intensive schedules in combination [with other agents] to minimize adverse effects.”
In the study, there were 51 patients who had previously received therapies that redirect T cells, including 71% with prior CAR T-cell therapy and 35% with prior bispecific antibody therapy. These patients were younger and had a higher prevalence of a high-risk feature. The response rate in this subset was 62.7%, and median duration of response was 12.7 months.
Safety Profile
Most high-grade adverse events were cytopenias, which were generally limited to the first few treatment cycles. These adverse events included grade 3 or 4 anemia (25%–31%), neutropenia (22%–31%), lymphopenia (25%–26%), and thrombocytopenia (17%–20%).
Grade 3 or 4 infections occurred in 17% receiving 0.4 mg/kg weekly and 12% receiving 0.8 mg/kg every 2 weeks. COVID-19 was contracted by 9% of those given the weekly dosing and 11% of those given every-2-week dosing; cases were mostly mild, although two patients died. Approximately 10% of patients received intravenous immunoglobulin support.
KEY POINTS
- The novel bispecific antibody talquetamab targets GPRC5D and CD3 receptors in multiple myeloma.
- In the phase I/II MonumenTAL-1 trial of heavily pretreated patients, treatment with a weekly dose and an every-2-week dose resulted in responses in more than 70% of patients overall and in more than 60% who had received other bispecific antibodies.
- In contrast with other bispecific antibodies, treatment was associated with a low rate of infection.
“Infections are the number one cause of morbidity and mortality in these patients. Some of the other new agents in this multidrug refractory space are associated with significant infectious complications, upward of 45% grade 3 or 4. Here, the rates of grade 3 or 4 infections were 12% and 17%,” he noted. “And, although 10% in both cohorts had COVID-19, there were just two deaths…. By contrast, with BCMA bispecifics, we are seeing a lot of COVID-related deaths…. It’s a tragic thing to have a patient with myeloma in a stringent complete remission with no detectable disease die of COVID or some other infection. That’s not what we are seeing with talquetamab. Moreover, the favorable infectious profile and minimal cytopenias makes this agent an ideal one to study in combination with other antimyeloma therapies.”
As for other adverse events, there were some skin and nail toxicities and some dysgeusia, but these side effects were reported to be low grade and manageable with supportive care and dose adjustments. Cytokine-release syndrome was generally low grade and confined to the first dose. Approximately 5% of patients discontinued treatment due to an adverse event.
An ongoing phase III study is evaluating talquetamab vs approved therapies. Additional phase I studies are evaluating the drug in combination with other agents, including daratumumab, teclistamab-cqyv, lenalidomide, and checkpoint inhibitors.
DISCLOSURE: Dr. Chari has received research funding from Janssen; has served as a consultant for Janssen, Celgene/BMS, Amgen, Millennium/Takeda, Antengene, and Secura Bio; has received honoraria from Janssen, Celgene/BMS, Amgen, Karyopharm, Sanofi Genzyme, Millennium/Takeda, Antengene, Shattuck Labs, Genentech, AbbVie, Oncopeptides, and Secura Bio; and has participated on data safety monitoring boards for Janssen, Celgene/BMS, Amgen, Karyopharm, Sanofi Genzyme, Shattuck Labs, Genentech, AbbVie, Oncopeptides, and Secura Bio.
REFERENCES
1. Chari A, Touzeau C, Schinke C, et al: Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Phase 1/2 results from MonumenTAL-1. 2022 ASH Annual Meeting and Exposition. Abstract 157. Presented December 10, 2022.
2. Chari A, Minnema MC, Berdeja JG, et al: Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med 387:2232-2244, 2022.
