More Than 70% of Heavily Pretreated Patients Taking Talquetamab for Multiple Myeloma See Responses That “Deepen Over Time”

More than 70% of patients with multiple myeloma had responses—and about a quarter had complete responses—to the bispecific antibody talquetamab, even after progressing on a half-dozen other treatments—which for some included chimeric antigen receptor (CAR) T-cell therapy.

Ajai Chari, MD, professor of medicine and director of clinical research in the Multiple Myeloma Program, Mount Sinai, New York, New York, presented combined results from phase 1 and 2 from the MonumenTAL-1 study (NCT03399799) today at the American Society of Hematology (ASH) Meeting and Exposition in New Orleans, Louisiana. Results from phase 1 were simultaneously being published in The New England Journal of Medicine.¹

The combined data, which involved 288 patients with a median of 5 prior lines of therapy, produced overall response rates of 74.1% for patients treated a dose of 405 µg/kg weekly and 73.1% for patients treated with 800 µg/kg every 2 weeks, with a median duration of response of 9 months or longer. Both these doses were given subcutaneously.

Chari emphasized during his presentation that the time response was relatively short, a little more than a month to the first response and a median of 2.2 to the best response for a lower dose tested, given weekly, and 2.7 months for a larger dose, given every 2 weeks.²

“This means that three-quarters of these patients are looking at a new lease on life,” said Chari. “We’re hoping that this will soon become available so that patients can benefit.”

These “incredible” responses were maintained across important subgroups, including high-risk patients; even patients with extramedullary disease saw response rates of 50%. “We don't even know how long the remissions last. So, this is really life changing for these patients,” he said during a press briefing.

Talquetamab is being developed by Janssen, which paid for the study.

As the investigators explain in the NEJM article, the explosion of treatment options in multiple myeloma means patients are living longer, but the downside is that nearly all will relapse. Thus, the field remains on the hunt for new therapies. The authors state that patients who are “triple-class-refractory,” meaning they are refractory after receiving a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody, have a poor prognosis.

The arrival of CAR T-cell therapies in multiple myeloma—idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), is an important advance, but brings with it the need to address patients who fail these treatments. Also, the customized nature of CAR T-cell therapy brings its own challenges, as some clinicians have reported manufacturing issues create difficulty in delivering these therapies to multiple myeloma patients who could be candidates.

Talquetamab, an off-the-shelf product, targets both CD3 and a G protein–coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. It works by redirecting T cells to mediate killing of GPRC5D-expressing myeloma cells.

“A substantial percentage of patients with relapsed or refractory multiple myeloma who received talquetamab had a response, and the responses continued to deepen over time,” the investigators wrote in the NEJM article.

“As a bispecific antibody, talquetamab can be readily available off the shelf with convenient subcutaneous administration, so that potential delays, attrition, and the burden associated with generating patient-specific CAR T-cell therapy can be avoided,” they said. “Talquetamab therapy also led to responses in patients who had received previous T-cell–redirecting therapies targeting BCMA. “These findings suggest that an effective immune response can be mounted against a different antigen even after previous exposure and disease progression with T-cell therapy.”

Multiple doses. The phase 1 data outlined in the NEJM article first examined multiple doses of talquetamab, either intravenously weekly or every other week in doses ranging from 0.5 to 180 µg per kilogram of body weight, or subcutaneously weekly, every other week or monthly, in doses from 5 to 1600 µg per kilogram. Patients in phase 1 had received a median of 6 prior lines of therapy or could not receive standard therapies without unacceptable side effects.

For this portion of the study, the primary end points were the frequency and type of dose-limiting toxic effects, adverse events (AEs), and laboratory abnormalities; these were used to pinpoint which doses would be evaluated in the next phase. For phase 2, the doses selected were 405 µg per kilogram weekly and 800 µg given every other week.

For phase 1, the median age of the patients receiving an intravenous dose was 65 years, with 31% over age 70; the median age receiving a subcutaneous dose was 64 years, with 28% over age 70. For the combined phase 1/2 study, the median age was 67.

Black patients made up 14% of the enrollment in the intravenous group and 10% of the enrollment in the subcutaneous group; these rates are nearly on par with Black representation in the overall US population but below the share of Black patients with multiple myeloma, which is about 20%, according to the International Myeloma Foundation. For the combined phase 1/2 data, the share of Black patients dropped to 8.4% for the 405 µg dose and 6.2% for the 800 µg dose.

Presentation at ASH. Chari’s presentation revealed combined results from phase 1 and phase 2 for the first time. A total of 143 patients received the 405 µg/kg weekly dose, while 145 patients received the 800 µg/kg biweekly dose. More than 92% of patients at both doses in the combined phase 1/2 population had received an anti-CD38 monoclonal antibody; 74.1% of the lower dose were triple-class refractory, as were 69% of those receiving the larger dose.

In the combined phase 1/2 group, at the 405 µg dose, 23.8% of patients achieved a stringent complete response, 9.8% saw a complete response, 25.9% saw a very good partial response, and 14.7% saw a partial response. At the 800 µg dose, 20.0% saw a stringent complete response, 12.4% saw a complete response, 24.8% had a very good partial response, and 15.9% had a partial response.

Duration of response was 7.5 months (95% CI, 5.7-9.4) for the 405 µg dose and 11.9 months (8.4-NE) for the 800 µg dose.

Patient safety. Common AEs were cytokine release syndrome (CRS), seen in 32.2% and 31.7% of the patients in the 2 dose levels, which was less than half of the overall CRS rate seen in the overall phase 1 study. Changes to patients’ nails and skin were common toxic effects, both in phase 1 and in the combined phase 1/2 data. In the phase 1/2 data, infections were seen in 57.3% and 50.3% of the lower and higher doses, respectively; grade 3/4 events occurred in 16.8% and 11.7% at the 2 doses.

The toxicity profile is key, especially the lack of cytopenias, Chari said. “This is very important for myeloma, the number one cause of morbidity and mortality in these patients is infection, and some of the other agents that are generating a lot of interest have significant infectious complications.”

Five patients in the lower dose group and 4 in the higher dose group died of an opportunistic infections; 13 patients total developed COVID, and 2 patients died from COVID. But Chari emphasized that patients showed some ability to develop antibodies following vaccination, which is important for patient safety.

Chari noted that a phase 3 study is ongoing (NCT05455320) evaluating talquetamab against approved therapies, and multiple phase 1 studies are studying its use in combination with other agents.

References

1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-Cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. Published online December 10, 2022. DOI: 10.1056/NEJMoa2204591
2. Chari A. Talquetamab, a G protein-coupled receptor family C Group 5 member D x CD3 bispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from the MonumenTAL study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition. December 10-13, 2022; New Orleans, LA. Abstract 157.