Linvoseltamab Adds Highly Effective Option in Later-Line Multiple Myeloma

The FDA approval of linvoseltamab-gcpt (Lynozyfic) in patients with relapsed/refractory multiple myeloma represents a significant advance in the treatment landscape, as it provides an effective therapy with increased accessibility compared with other available treatments, according to Hans Lee, MD; and Nisha Joseph, MD.

“This approval provides a highly effective, off-the-shelf agent for the treatment of [patients with] relapsed/refractory multiple myeloma,” Lee said. “There are some characteristics [that distinguish] linvoseltamab from other B-cell maturation antigen [BCMA] bispecific antibodies that will hopefully improve the access of this drug compared with some of the other agents that are available. In particular, there’s a lower hospitalization requirement for linvoseltamab, especially during this type of dosing, compared with some of the other agents.”

On July 2, 2025, the FDA granted accelerated approval to linvoseltamab for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1 The approval was supported by data from the phase 1/2 LINKER-MM1 study (NCT03761108).

Data from LINKER-MM1 revealed that patients who received the BCMA-directed CD3 T-cell engager (n = 80) experienced an objective response rate (ORR) of 70% (95% CI, 59%-80%), with a complete response (CR) or better rate of 45% (95% CI, 34%-57%).2 Patients also had stringent CRs (39%), CRs (6%), very good partial responses (VGPRs; 19%), and partial responses (6%). The median duration of response was not reached (NR; 95% CI, 12 months-not evaluable).

Lee is the director of myeloma research at the Sarah Cannon Research Institute in Nashville, Tennessee. Joseph is an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia.

In an interview with OncLive®, Lee and Joseph highlighted the potential clinical effects of the approval, additional findings from LINKER-MM1, and the future of linvoseltamab in multiple myeloma.

OncLive: What were the key design characteristics of LINKER-MM1?

Joseph: LINKER-MM1 looked at linvoseltamab monotherapy at 50 mg and 200 mg. What’s unique about this drug is the step-up [dosing] is different than what we see with other bispecific antibodies. It’s given weekly, and the patient receives 2 ramp-up doses at 5 mg and 25 mg, and then the full dose weekly for the first 14 weeks. This could then go to every other week, and then at week 24, for patients who had achieved a VGPR or better, there is an option to go to monthly dosing.

In my practice, we are giving a majority of these bispecifics [in this manner]. It’s great to see proof of concept in a clinical trial. [This approach] not only improves the tolerability of the drug, but we’re seeing that we don’t lose that efficacy benefit.

What were the efficacy data reported with linvoseltamab in LINKER-MM1?

Lee: The 200-mg dose is the FDA-approved dose of linvoseltamab, and that’s in the package label. The ORR, which was the primary end point of the study, was 70% but what was striking was the depth of response. Forty-five percent of patients had a CR or better. We’ve had longer follow-up of this trial reported at recent meetings, and at the last data cutoff, the median progression-free survival was NR. It was also striking that we saw very high response rates in historically difficult-to-treat subgroups, including patients with extramedullary disease, high-risk cytogenetics, and high baseline BCMA levels.

Are there any patient subgroups that would not be a good fit for this agent based on its safety profile?

Joseph: In general, when I consider bispecific antibodies, I think about those initial toxicities during the step-up phase, and then more long-term toxicities. When we’re initially starting the drug and doing the ramp-up, we worry about cytokine release syndrome [CRS], fever, and immune effector cell–associated neurotoxicity syndrome [ICANS]. In general, we don’t see a high rate of ICANS with bispecific antibodies, but it’s there.

Long term, when you’re continually dosing patients, the things that we worry about are cytopenias and infections. When we looked at linvoseltamab, there was nothing that negatively stood out. CRS was predominantly grades 1 and 2 and is lower than what we saw with the other bispecific antibodies, which is also important when we look at operationalizing the drug and getting it into the community. We’ve learned that the use of prophylactic tocilizumab [Actemra] during ramp-up dosing with bispecific antibodies can lower the rate of CRS. I know from speaking to community providers that managing the initial CRS is sometimes a concern.

Because the ramp-up is weekly, that lends itself to be an easier drug for our community partners to ramp up in the clinic. The majority of ICANS was early grade. In terms of infections, the grade 3/4 infection rate was a bit lower than what we saw with some of the other BCMA bispecific antibodies. When you’re looking at those rates, particularly of high-grade infections in these early-phase studies, something to keep in mind is that we’ve learned a lot about how to mitigate and manage those infections in the clinic. It’s not something I think of as a rate-limiting step. These are patients with relapsed/refractory multiple myeloma who are at higher risk for infection, and we’re giving them a T-cell redirecting therapy. We know there’s going to be a risk of infection, but we’ve learned how to reduce that risk for our patients.

Lee: We can give [these types of agents] as a general drug class to most of our patients, regardless of age. An interesting aspect of LINKER-MM1 was that over 25% of patients were over the age of 75 [years]. This is proof of concept that age is just a number, and this fits an unmet need, particularly in [older] patients who may not be candidates for CAR [chimeric antigen receptor] T-cell therapies. This is an off-the-shelf therapy that’s immediately available to patients.

How do you envision linvoseltamab fitting into the treatment paradigm of later-line multiple myeloma?

Lee: Right now, we’re a bit constrained by the label. Although there are other BCMA bispecific antibodies currently FDA approved in this context, there are potential advantages of using linvoseltamab in this patient population, again, including the relatively easier step-up dosing schedule requiring limited hospitalization, the aggressive, rapid de-escalation, and the frequency of dosing that was studied prospectively in LINKER-MM1. If a patient has advanced disease characteristics, this is potentially an area where I might lean toward linvoseltamab, given the strong efficacy data seen in these patient populations.

Joseph: When thinking about a bispecific vs CAR T-cell therapy, in general, the data in terms of sequencing look better with CAR T-cell therapy before bispecific antibodies. But that’s a patient-specific conversation, particularly in these later lines. Oftentimes with bispecifics vs CAR T-cell therapy, there’s this concept of 1 and done, but that’s not the case. There’s a lot more to it to get a patient through CAR T-cell therapy on the front and back ends. When we’re thinking about linvoseltamab, after that initial ramp-up period, that’s a once-a-month visit. Even for an older patient who doesn’t live close to the center, that can be quite feasible for patients and quite effective. The toxicity, overall, considering some of the toxicity risk upfront with CAR T-cell therapy, is much less.

What are the next steps for the further development of linvoseltamab?

Lee: Linvoseltamab is being studied in other contexts of multiple myeloma, beyond LINKER-MM1. There is the ongoing [phase 3] LINKER-MM3 study [NCT05730036] of linvoseltamab vs elotuzumab [Empliciti], pomalidomide [Pomalyst], and dexamethasone, which is the standard-of-care [SOC] triplet in relapsed/refractory multiple myeloma. This confirmatory study would support the accelerated approval of linvoseltamab.

We also have the [phase 1/2] LINKER-MM4 study [NCT05828511], which is studying linvoseltamab monotherapy in newly diagnosed patients, and the [phase 1b] LINKER-MM2 study [NCT05137054] of linvoseltamab with SOC myeloma therapy. There is a lot to come, and I believe linvoseltamab is a drug that’s going to be used across the myeloma disease spectrum as these studies mature.

References

1. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed September 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma
2. Lynozyfic. Prescribing information. Regeneron Pharmaceuticals, Inc; 2025. Accessed September 5, 2025. https://www.regeneron.com/downloads/lynozyfic_fpi.pdf