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Talquetamab Offers New Hope in Relapsed/Refractory Multiple Myeloma

— Bispecific antibody achieves "incredible" response rates over 70% in heavily pretreated patients

MedpageToday

NEW ORLEANS -- Talquetamab had substantial antitumor effects in patients with heavily pretreated relapsed or refractory multiple myeloma, a researcher reported here.

In a 288-patient, phase I/II study that assessed the agent's efficacy with two different dosing regimens -- 0.4 mg/kg weekly and 0.8 mg/kg every other week -- response rates were 74.1% and 73.1%, respectively, according to Ajai Chari, MD, of the Tisch Cancer Institute at Mount Sinai in New York City.

Chari called the results with talquetamab, a novel, off-the-shelf bispecific antibody against the target GPRC5D, "incredible." He also pointed out that these rates included very good partial responses or better in almost 60% of patients in each dosing group, "demonstrating a high depth of response."

"To put this into context, historically for novel agents to get approved in myeloma by accelerated approval, we needed a response rate of 20% to 30%, " Chari said during a press briefing at the American Society of Hematology (ASH) annual meeting. "Now we are saying [percentages in the] 70s is the new 20s to 30s."

Chari added that these response rates were consistent across important subgroups, including stage III disease, baseline cytogenetic risk, number of prior therapies, and refractoriness to prior therapy. Even patients with extramedullary disease achieved a response rate of about 50%, he noted.

Chari and colleagues analyzed a third arm of 51 patients who had progressed after treatment with T-cell redirection therapies, which Chari called a "new unmet need" in myeloma. These patients received either of the dosing schedules and had a response rate of 62.7%, with 72.2% and 44.4% rates for patients with prior CAR T therapy and bispecific antibody treatment, respectively.

"It looks like they are seeing responses, even in people who are heavily pretreated ... and with other agents similar to it," said ASH press conference moderator Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle. Patients who are penta-refractory often have inferior outcomes, which makes the current data "quite exciting," she said. These patients are refractory to the five most active multiple myeloma drugs: proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis); immunomodulatory drugs (IMiDs) lenalidomide (Revlimid) and pomalidomide; and the anti-CD38 monoclonal antibodies.

Chari also reported that among patients randomized to the 0.4-mg (n=143) and 0.8-mg (n=145) regimens, median progression-free survival was 7.5 months and 11.9 months, respectively, with a median duration of response of 9.3 months and 13.0 months.

"And impressively, those patients who had a [complete response] or better, which means we completely eradicated the disease, we don't even know how long the remissions last," he said. "So, this is really life changing for these patients."

The MonumenTAL-1 study included 339 patients. Of those, 74 were from the pivotal phase I dose-escalation trial, the results of which were simultaneously published in the . The phase I study showed response rates ranging from 64%-70%.

Eligibility criteria included patients with measurable disease, and in the phase I portion of the study patients had to have progressed on, or were intolerant, to all established therapy, and have an ECOG performance status of 0-1. Patients in the phase II study had to have at least three prior lines of therapy, including a proteasome inhibitors, IMiD, and anti-CD38 antibody, and an ECOG status of 0-2.

Patients were typical of those with relapsed/refractory disease, Chari said, with a median age of 67. About 60% of patients considered high-risk in some way (extramedullary disease, high-risk genetics, and stage III myeloma). These patients also had a median of five lines of prior therapy over the 6.7 years since their diagnosis.

He pointed out that almost all patients were refractory to a CD38 monoclonal antibody, while three-quarters were triple-class exposed/refractory. "And almost every single patient was progressing on their last line of therapy," he added. "So this is a tough population of patients who have exhausted a lot of the available therapies. In spite of that, we saw this impressive response rate."

As for safety, Chari noted that as a first-in-class agent targeting a novel target, talquetamab has a different safety profile.

High-grade adverse events (AE) were uncommon, he said, and when seen were typically hematologic AEs. Most high-grade AEs were cytopenias and were mostly limited to the first few cycles of treatment.

Infections occurred in 57.3% and 50.3% of patients in the 0.4-mg and 0.8-mg dosing regimens, respectively, with grade 3/4 rates of 16.8% and 11.7%.

Chari also noted that 9.1% and 11.0% patients had COVID-19, respectively, with two patients dying from that infection.

About three-quarters of patients experienced cytokine release syndrome, while 60% experienced skin-related AEs, such as rash, and about about half reported taste changes and nail disorders.

Discontinuation due to AEs occurred in 4.9% and 6.2% of 0.4-mg and 0.8-mg dosing regimens, respectively.

Talquetamab developer Janssen/Johnson & Johnson submitted a on Friday for the agent as treament for relapsed or refractory multiple myeloma.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was supported by Janssen Research and Development. Some co-authors are company employees.

Chari disclosed relationships with Amgen, Bristol Myers Squibb, Celgene, GSK, Janssen Pharmaceuticals, Karyopharm Therapeutics, Novartis, Pharmacyclics, Sanofi, Seattle Genetics, Takeda.

Co-authors disclosed multiple relationships with industry.

Primary Source

American Society of Hematology

Chari A, et al "Talquetamab, a G protein-coupled receptor family C group 5 ember D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Phase 1/2 results from MonumenTAL-1" ASH 2022; Abstract 157.

Secondary Source

New England Journal of Medicine

Chari A, et al "Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma" N Engl J Med 2022; DOI: 10.1056/NEJMoa2204591.