乌鸦传媒

SAN DIEGO -- More than 70% of patients with heavily pretreated multiple myeloma responded to an investigational bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, results from a prospective trial showed.

Overall, 71% of patients achieved a partial response (PR) or better with linvoseltamab, including complete responses (CRs) in 46%. Responses deepened over time, including patients who switched from 2-week to 4-week dosing after 24 weeks.

Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) had yet to be reached after a median follow-up of 11.1 months, reported Sundar Jagannath, MD, of the Icahn School of Medicine at Mount Sinai in New York City, at the American Association for Cancer Research annual meeting.

"Linvoseltamab demonstrated high efficacy in patients with relapsed/refractory multiple myeloma, including those in prespecified high-risk subgroups," said Jagannath. "The most common treatment-emergent adverse events were cytokine release syndrome [CRS] -- only one patient with grade 3, neutropenia (40% grade 3/4), and anemia (31% grade 3/4). Infection frequency and severity decreased over time, including patients with responses of CR or better. The phase III LINKER-MM3 trial is ongoing in patients with relapsed/refractory multiple myeloma."

New treatment options for relapsed/refractory myeloma are needed, said invited discussant Faith Davies, MD, of NYU Langone Health in New York City. As the three "pillars" of treatment -- immunomodulators, proteasome inhibitors, and monoclonal antibodies -- have moved into the first-line setting, newer patients are developing resistance.

"We're gaining a new problem, which is how do we treat triple-class-refractory patients," said Davies.

Two previous studies, one retrospective and one prospective, have provided some context for evaluating new therapies for relapsed/refractory myeloma. The studies showed response rates of 31% to 40%, median PFS of 3.4 to 6 months, and median OS of 9 to 12 months.

By comparison, linvoseltamab produced a 71% overall response rate (ORR) in a study population that included patients who were over the age of 75 (30%) and African American (20%). Many of the patients had extramedullary disease and high-risk genetics.

"Despite some of these high-risk features, we see a very impressive overall response rate of 71%, really quite a dramatic improvement in clinical efficacy," said Davies.

CRS was predictable in its severity and timing, requiring a 24-hour hospitalization during two step-up doses, she continued. In contrast, some of the other new bispecific antibodies used in hematology may necessitate hospitalization for as long as 7 to 14 days.

Infection is a second major concern in heavily treated myeloma patients, Davies noted. With linvoseltamab, the rate of infection decreased over time, including a dramatic decrease after a switch to once-monthly dosing.

Bispecific antibodies offer an effective, off-the-shelf treatment for patients with previously treated myeloma, Jagannath acknowledged during his review of background information. Currently available BCMA/CD3 agents produce response rates in the range of 60-65%. As Davies noted, linvoseltamab required two 1-day hospitalizations for step-up dosing, allowing for monthly treatment of patients who achieved deep responses.

Jagannath reported findings from the phase I/II trial evaluating a 200-mg dose of linvoseltamab in patients with multiple myeloma that had progressed during or after three or more lines of therapy (and triple refractory). Patients began treatment with weekly infusions to week 14, then every 2 weeks. Patients who achieved very good partial response (VGPR) or better after 24 weeks transitioned to dosing every 4 weeks.

The primary endpoints were safety and ORR, and secondary endpoints included DOR, PFS, and OS.

Data analysis included 117 patients who had a median age of 70. Median treatment exposure was five prior lines of therapy and a range of two to 16. Two-thirds of the patients were at least quad-refractory, and 28% were at least penta-refractory.

The 71% ORR included stringent CR in 41% of patients, CR in 5%, VGPR in 16%, and PR in 9%. The results included 56 patients who switched to dosing every 4 weeks. Among 27 patients assessed for minimal residual disease (MRD) status, 25 were MRD negative.

High response rates were observed across most prespecified subgroups, with the exception of those with extramedullary disease at baseline (~50% response rate), bone marrow plasma cell >50% (~50%), and soluble BCMA ≥400 ng/mL (~60%).

Median time to response (≥PR) was 1 month, and 2.6 months for ≥VGPR, and 7.9 months for ≥CR. Jagannath said 14 of 29 patients with VGPR improved to ≥CR after switching to dosing every 4 weeks. The probability of maintaining a response at 12 months was 78%, while the probability of being progression-free and alive at 12 months was 68.8%, and being alive at 12 months was 74.5%.

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