New Agent Shows Early Promise in Triple-Class Refractory MM

San Diego — The bispecific antibody linvoseltamab (Regeneron) can induce deep and durable responses in patients with relapsed or refractory multiple myeloma, according to results from the phase 1/2 LINKER-MM1 trial. 

Overall, linvoseltamab demonstrated “high efficacy in patients with late-stage” disease, including those with high-risk features, said study investigator Sundar Jagannath, MD, from Mount Sinai Hospital, New York City, who presented the results at the American Association for Cancer Research 2024 annual meeting. 

However, five patients died from treatment related infections and one from treatment related renal failure, Jagannath reported.

Proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies are the current pillars of multiple myeloma treatment. 

Their increasing use in earlier lines of treatment has led to resistance, creating a challenge for patients who become refractory to all three classes of drugs, explained Faith Davies, MD, director of the Center for Blood Cancers at New York University in Manhattan, during a discussion at the meeting.

There’s currently no standard of care for triple-class refractory multiple myeloma, but Davies said one could be emerging: Bispecific antibodies, such as linvoseltamab, that target B-cell maturation antigen on the surface of multiple myeloma cells and CD3 receptors on the surface of T cells. 

A total of 117 patients in the single arm LINKER-MM1 trial were infused with 5 mg of linvoseltamab on day 1, 25 mg on day 8, then 200 mg once a week to week 14, followed by 200 mg every 2 weeks to week 23. Patients moved on to monthly dosing at that point if they had at least a very good partial response. Median exposure to linvoseltamab was 47.5 weeks. 

Eighty-two percent of participants were at least triple-class refractory. More than a quarter were aged ≥ 75 years, and 17.1% were Black individuals, reflecting multiple myeloma demographics. 

The overall response rate in the 17.9% of subjects with stage III disease was 62%, with complete responses in 43%; among the 16.2% with extramedullary plasmacytomas, overall response rate was 53% with complete responses in 26%. 

The median overall response rate across the study population was 71% at a median follow-up of 11.1 months, including complete responses or better in 46%; the median duration of response was not reached. The probability of progression free and overall survival at 1 year were 69% and 75%, respectively. 

Among bispecific antibodies already on the US market for relapsed/refractory multiple myeloma, teclistamab and elranatamab had overall response rates of 63% and 61%, respectively, in similar phase 2 testing, Jagannath noted.

Davies emphasized additional potential advantages for linvoseltamab. While step-up dosing of other bispecifics requires up to 48 hours in the hospital due largely to the risk of cytokine release syndrome (CRS), step-up dosing of linvoseltamab requires just 24 hours because CRS with the agent is mostly grade 1/2 and has a median onset of 11 hours.

Also, patients who have deep responses at 6 months have the option of once monthly dosing. 

Almost three quarters of subjects developed infections, which were grade 3/4 in 34%. Their frequency and severity decreased after 6 months coincident with monthly dosing.

Almost half of patients developed CRS but there was only one grade 3 case and no grade 4/5s. CRS occurred mostly during step-up dosing, and just over half of cases required supportive measures. There were nine cases of immune effector cell-associated neurotoxicity syndrome, all concurrent with CRS and infusion-related reactions.

A phase 3 trial, LINKER-MM3, is underway for linvoseltamab. A Food and Drug Administration approval decision is expected in August.

With linvoseltamab making its way to the bispecific market, we have a class of drugs that can induce really deep responses and minimal residual disease negativity in triple-class refractory multiple myeloma patients, raising the possibility of a new standard of care, Davies said.

The study was funded by Regeneron and included employees. Jagannath and Davies are consultants for Regeneron and other companies. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.