Another BCMA-targeted agent has arrived for the treatment of multiple myeloma.

The new option, Regeneron’s linvoseltamab, has won an FDA approval for treating myeloma patients who have received at least four prior lines of therapy. The company had also requested clearance in some refractory patients who tried three prior lines of therapy, but that population was not included in the drug’s FDA label.

Branded as Lynozyfic, the drug joins two fellow BCMAxCD3 bispecific antibodies, namely Johnson & Johnson’s Tecvayli and Pfizer’s Elrexfio, as well as J&J’s GPRC5DxCD3 T-cell engager Talvey, in the late-line myeloma treatment armamentarium.

Being a latecomer came with some advantages, Andres Sirulnik, M.D., Ph.D., SVP and hematology clinical development unit head at Regeneron, said in a recent interview with Fierce Pharma. Regeneron did a thorough dose-finding process to strike the best efficacy-safety balance as the company learned from evolving data from its competitors, he said.

Regeneron designed its phase 1/2 Linker-MM1 trial with unique dosing regimens. For the higher 200 mg dose of Lynozyfic, patients are allowed to transition to a once-monthly dosing frequency after achieving at least a very good partial response following completion of 24 weeks of therapy.

In contrast, J&J’s Tecvayli can be given on a biweekly basis in patients who have achieved and maintained a complete response or better for at least six months. Elrexfio also boasts a biweekly dosing schedule for responders from week 25 onward.

Results from the linvoseltamab Linker-MM1 study suggest that most patients can achieve the necessary response status to switch to fewer doses. Among 80 patients treated with 200 mg Lynozyfic and who matched the FDA indication, 70% recorded a response, including 64% with at least a very good partial response and 45% a complete response or better. This group of patients had tried a median five prior lines of therapy.

By comparison, Tecvayli’s label shows a 68% overall response rate from the MajesTEC-1 trial, including 63% with a very good partial response or better and 31% a complete response or better. Those numbers were 56%, 50% and 25%, respectively, for Pfizer's Elrexfio in pretreated, BCMA-naïve patients enrolled in the MagnetisMM-3 trial.

And Lynozyfic’s trial participants had a higher tumor burden compared with other competitor studies, Sirulnik noted.

For T-cell engagers, the immune side effect cytokine release syndrome is a known problem. CRS occurred in 46% of 117 patients treated with Lynozyfic at 200 mg in Linker-MM1. Except for one (1%) grade 3 event, all the other cases were grade 1 or 2.

The rates of CRS were higher, at 72% for Tecvayli and 58% for Elrexfio, in the two drugs’ respective trials. In both cases, CRS events were predominantly grade 1 or 2, with fewer than 1% reaching grade 3.

Nevertheless, the FDA has put CRS and neurotoxicity as black box warning items on the labels of all three T-cell engagers, requiring that patients be hospitalized following certain initial step-up doses due to the risks.

Infections represent another major safety concern shared among BCMA bispecifics. In Regeneron’s Linker-MM1 trial, investigators recorded 38% of grade 3 or 4 infections, plus 4% fatal infections. 

Sirulnik argued that it would be difficult to tease out the effect of treatment on infections in patients with heavily pretreated myeloma given that they already have compromised immune systems because of the cancer. The frequency and severity of infections decreased dramatically beyond the initial six months of treatment in the Linker-MM1 study, potentially suggesting that improvements in patients' health could be at play, he said. Still, the hypothesis needs to be validated in a randomized clinical trial, the Regeneron exec stressed.

On that note, Regeneron is conducting the phase 3 Linker-MM3 trial, pitting Lynozyfic against a combination of Bristol Myers Squibb’s Empliciti and Pomalyst with dexamethasone in myeloma patients who have tried one to four prior treatments. The study is fully enrolled, and its results could serve as confirmatory evidence for Lynozyfic’s current accelerated approval.

Lynozyfic’s approval came later than expected after Regeneron’s original application was knocked back by the FDA last year over issues at a contract manufacturer. While the drug was delayed in the U.S., the European Commission approved it in April.

Outside of cancer, Regeneron is in the early stage of testing linvoseltamab together with its Sanofi-partnered blockbuster Dupixent to treat severe food allergies.

Interest has also grown in the industry to direct BCMA T-cell engagers against autoimmune diseases after a 2024 study reported a drug-free complete remission following treatment with Tecvayli in a patient with aggressive refractory systemic lupus erythematosus.

“We have plans, and you’re going to hear about it soon,” Sirulnik said when asked about Regeneron’s plan for studying linvoseltamab in autoimmune disorders.

Meanwhile, another Regeneron bispecific, the CD20xCD3 antibody odronextamab, is taking its own second shot at an FDA approval in previously treated follicular lymphoma (FL). In a pair of high-profile rejections last year, the FDA snubbed the drug in FL and diffuse large B-cell lymphoma (DLBCL) over the progress of phase 3 confirmatory trials.

While awaiting an FDA decision in FL, Regeneron is “contemplating the possibility” of reapplying for accelerated approval in DLBCL, Sirulnik noted, as Roche’s bid to get its own CD20xCD3 bispecific Columvi approved in second-line DLBCL appeared to have hit a setback. If Columvi were to win a full approval based on the phase 3 Starglo trial, the door to an accelerated nod would be closed for odronextamab.