A new therapy, known as a bispecific antibody, that causes the immune system to kill the cancer cells bone marrow was successful in 73 percent of patients in two clinical trials, according to researchers at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.
Talquetamab binds to both T cells and multiple myeloma cells and targets T cells — white blood cells that can be recruited to fight disease — to kill multiple myeloma cells. Researchers have described this strategy as “taking your army straight to the enemy.”
The results of the study were published in the scientific journal New England Journal of Medicine.
Talquetamab: some details on the new experimental therapy
The success of standard immunotherapy, called talquetamab, has also been seen in patients whose tumors were resistant to all approved multiple myeloma therapies. It uses a different target than other approved therapies: a receptor expressed on the surface of cancer cells known as GPRC5D.
Talquetamab was tested in Phase 1 and Phase 2 studies. The Phase 1 study established two recommended doses that were tested in the Phase 2 study. Phase 2 study results were reported on Saturday, December 10 at the meeting American Society of Hematology Annual. All of the study participants had previously been treated with at least three different therapies without achieving durable remission, suggesting that talquetamab could offer new hope to patients with difficult-to-treat multiple myeloma.
“That means nearly three-quarters of these patients are looking at a new lease on life,” said Ajai Chari, MD, director of clinical research in the multiple myeloma program at the Tisch Cancer Institute and lead author of both studies. “Talquetamab induced a substantial response among patients with heavily pretreated, relapsed or refractory multiple myeloma, the second most common blood cancer. It is the first bispecific agent that targets the GPRC5d protein in patients with multiple myeloma.”
Nearly all myeloma patients who receive standard therapies relapse continuously. Patients who relapse or become resistant to all approved multiple myeloma therapies have a poor prognosis, so further treatments are urgently needed. This study, while an early-stage study designed to detect tolerability and find a safe dose, is an important step in meeting that need.
This Phase 1 clinical trial enrolled 232 patients at multiple cancer centers around the world between January 2018 and November 2021. Patients received a variety of doses of talquetamab intravenously or injected under the skin; future studies will focus only on doses given under the skin weekly or every two weeks.
Efficacy and safety results from the Phase 1 study were validated in the Phase 2 study presented at ASH. The Phase 2 study included 143 patients treated with a weekly dose and 145 patients treated with a higher twice-weekly dose.
The overall response rate in these two groups was about 73%, said Dr. chari. The response rate was maintained in all subgroups examined, with the exception of patients with a rare form of multiple myeloma that also extends to organs and soft tissues. More than 30% of patients in both groups had a complete response (no detection of specific myeloma markers) or better, and nearly 60% had a “very good partial response” or better (indicating that the cancer was substantially reduced but not necessarily declining to zero).
The median time to a measurable response was approximately 1.2 months in both dose groups and the median duration of response to date is 9.3 months with weekly dosing. The researchers are continuing to collect data on the duration of response in the group that received 0.8 mg/kg every other week and for patients in both dose groups who had a complete response or better.
Side effects were relatively frequent, but typically mild. About three-quarters of the patients experienced cytokine release syndrome, which is a constellation of symptoms including fever that is common with immunotherapies. About 60% experienced skin-related side effects such as rashes, about half reported taste changes, and about half reported nail complaints. The researchers said that very few patients (5 to 6%) discontinued treatment with talquetamab due to side effects.
The response rate observed in the study, which Dr. Chari explained is superior to that of most currently available therapies, suggesting talquetamab could offer a viable option for patients whose myeloma has stopped responding to most available therapies, offering the potential to extend life and benefit from other new and future therapies as they are developed.
Talquetamab is a bispecific humanized monoclonal antibody against human CD3, a T-cell surface antigen, and member D of group 5 of the human G protein-coupled receptor C family (GPRC5D), a tumor-associated antigen (TAA ), with potential antineoplastic activity.
Talquetamab had moderate side effects. A low white blood cell count (neutropenia) occurred in 42% of patients and a cytokine release syndrome (CRS) in 64%. CRS was low-grade with no associated mortality. The phase study confirmed a 70% response rate in patients with advanced disease.
Following administration, talquetamab binds to both CD3 on T cells and GPRC5D expressed on some tumor cells. This results in cross-linking of T cells and tumor cells and induces a potent cytotoxic response of T lymphocytes (CTLs) against tumor cells expressing GPRC5D. GPRC5D is overexpressed on some cancers, such as multiple myeloma, while minimally expressed on normal, healthy cells and plays a key role in tumor cell proliferation.
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