Q&A With Hans Lee, MD: Linvoseltamab Approval Offers New Off-the-Shelf Option for Heavily Pretreated Multiple Myeloma

The FDA has approved linvoseltamab-gcpt (Lynozyfic; Regeneron), a B-cell maturation antigen (BCMA) bispecific antibody, for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.¹

The July 2, 2025, approval was supported by data from the ongoing phase 1/2 LINKER-MM1 trial (NCT03761108).²

Hans Lee, MD | Image: SCRI

In an interview with The American Journal of Managed Care (AJMC), Hans Lee, MD, a LINKER-MM1 investigator and director of myeloma research at Sarah Cannon Research Institute in Nashville, Tennessee, highlighted the key findings of the trial, which he conducted when he was director of multiple myeloma clinical research at The University of Texas MD Anderson Cancer Center in Houston. In addition to discussing how the approval may influence clinical decision-making for patients with heavily pretreated multiple myeloma, Lee reviewed forthcoming trial results and noted that new data were presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Hematology Association (EHA) 2025 Congress.

This transcript was lightly edited.

AJMC: Please summarize the key findings of the LINKER-MM1 trial and how they supported the FDA’s recent approval of linvoseltamab.

Lee: The LINKER-MM1 study was a phase 1/2 study that evaluated the drug linvoseltamab, which is a BCMA bispecific antibody for the treatment of relapsed/refractory multiple myeloma. Specifically, the trial enrolled [patients with] heavily pretreated myeloma with at least 3 prior lines of therapy who were triple-class exposed. This means patients were exposed to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, or were triple-class refractory, regardless of lines of prior therapy.

A total of 117 patients enrolled in the study and received a 200-mg, FDA-approved dose of linvoseltamab. The drug showed a very high overall response rate of 71%. Not only were the response rates very high, but the depth of response was also very impressive, with a complete response rate or better of 52%.

This translated into durability response as well. At the last data cutoff of a median follow-up of approximately 21 months, the median progression-free survival had not been reached yet, and the median duration of response was approximately 29 months.

In terms of the safety profile of linvoseltamab, the most common adverse effect is cytokine release syndrome [CRS]. This is common with [chimeric antigen receptor T-cell] therapies and bispecific T-cell antibodies. The total incidence of CRS is relatively low—a 46% incidence of CRS, with the majority being grade 1, some grade 2, and very rarely grade 3.

The other [adverse effect] to be mindful of is the infection risk. Infections are common in patients receiving BCMA bispecific antibodies, although the rates of infections decrease with time. After 6 months of treatment on linvoseltamab in the clinical trial with de-escalation [of] the frequency of dosing, the rates of infection of grade 3 or higher decreased to 5% to 8%.

AJMC: What does this approval mean for patients with heavily pretreated multiple myeloma, and how do you see it shaping clinical decision-making going forward?

Lee: The approval of linvoseltamab is important because it provides a very highly effective off-the-shelf therapy for the treatment of relapsed/refractory multiple myeloma. Although there are several other BCMA bispecific antibodies currently approved by the FDA for patients in this population, linvoseltamab has some differentiating characteristics that I think will be beneficial to patients.

First, it has a different administration route. It is intravenously given instead of subcutaneously given. I think this impacts the kinetics of the onset of CRS and its resolution. What this ultimately translates into is that there are fewer hospitalization requirements for the administration of linvoseltamab compared [with] the other BCMA bispecific antibodies.

There are hospitalization requirements for the first 2 doses. The first 2 step-up doses [are] dosed 1 week apart, but the hospitalization requirement is only 24 hours. Basically, a 24-hour hospitalization for dose 1 and step-up dose 2, and all outpatient thereafter.

Second, what was very interesting about the LINKER-MM1 study was that there was a prospective de-escalation of the frequency of dosing built into the study. Patients receive weekly linvoseltamab for the first 3 cycles but then [are] de-escalated to every other week dosing for cycles 4 and 5 and then de-escalated even further to every 4-week dosing starting [with] cycle number 6 if a patient achieves a very good partial response or better.

Again, a very prospective, more patient-friendly dosing schedule to, ultimately, every 4-week dosing, which is much better for our patients.

AJMC: What practical considerations should clinicians keep in mind as they begin incorporating linvoseltamab into their treatment approach?

Lee: There are a couple of aspects around this question. I think the first aspect is that as clinicians get prepared to incorporate linvoseltamab into their clinical practice, there is this concept of step-up dosing that’s common with all BCMA bispecific antibodies, where a patient may receive a low dose of 5 mg for the first dose, a second intermediate step-up dose of 25 mg 1 week thereafter, and the first target dose of 200 mg on week 3.

Again, there is a 24-hour hospitalization recommendation for the initial first 2 step-up doses. During this period, there is also monitoring for CRS, potential [immune effector cell–associated neurotoxicity syndrome], and other immune effector cell [adverse] effects.

The risk for CRS is low, and the majority of CRS is really grade 1, which is fever and easily manageable, but these are things that clinicians need to be mindful of when initially dosing linvoseltamab.

On the back end, the thing to keep in mind is the potential risk for infections. As with other BCMA bispecific antibodies, there are higher rates of infection, perhaps compared with some other standard myeloma therapies. Being very vigilant and proactive about infection mitigation strategies [is necessary].

This would include [intravenous immunoglobulin], for instance, as primary prophylaxis to mitigate the risk of infection. To keep the [immunoglobin G] levels more than 400, infection prophylaxis with valacyclovir [or] acyclovir for shingles prophylaxis or [varicella-zoster virus] prophylaxis, as well as [Pneumocystis jirovecii pneumonia] prophylaxis, is mandatory for patients receiving this drug.

AJMC: Looking ahead, what role do you see linvoseltamab playing in the multiple myeloma treatment landscape, whether in earlier lines of therapy, as part of combination strategies, or beyond?

Lee: Linvoseltamab is being studied in multiple settings in multiple myeloma through various clinical trials. Probably most importantly, the LINKER-MM3 [NCT05730036] study is a phase 3 randomized study evaluating linvoseltamab vs a standard-of-care therapy, elotuzumab [Empliciti] plus pomalidomide [Pomalyst] and dexamethasone.³ This is the confirmatory phase 3 study that will support the accelerated approval of linvoseltamab from the LINKER-MM1 study.

Linvoseltamab is also being studied in newly diagnosed myeloma. The phase 1/2 LINKER-MM4 [NCT05828511] study is looking at linvoseltamab as a monotherapy, both in transplant-eligible and transplant-ineligible [patients with multiple] myeloma.⁴ Generally speaking, we have a lot of optimism that BCMA bispecifics will be utilized in the frontline setting eventually in patients with multiple myeloma, given their high efficacy in relapsed/refractory disease. That’ll be a very important study, and we look forward to seeing the readout of those initial results, hopefully soon.

Also, linvoseltamab is being studied in combination as well. In myeloma, we often combine active drugs with other active drugs. The phase 1 LINKER-MM2 (NCT05137054) study is a very important study, again, looking at linvoseltamab in combination with other agents active in multiple myeloma.⁵ Initial results of several arms of the LINKER-MM2 study, for instance, linvoseltamab in combination with carfilzomib [Kyprolis] and in combination with bortezomib [Velcade], were presented at this year’s ASCO⁶ and EHA meetings.

It’s safe to combine linvoseltamab with these agents, and early efficacy is also being demonstrated. Again, there are a lot of clinical trials combining linvoseltamab in multiple settings in multiple myeloma, and I think this will be very important in the coming years to see these results.

References

1. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed July 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma.
2. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(22):2702-2712.doi:10.1200/JCO.24.01008
3. Weisel K, Hungria V, Quach H, et al. PB2133: trial I progress: LINKER-MM3, a phase 3, open-label randomized study of linvoseltamab vs elotuzumab, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Hemasphere. 2023;7(suppl 3):e465366a. doi:10.1097/01.HS9.0000975296.46536.6a
4. A window of opportunity trial to learn if linvoseltamab is safe and well tolerated, and how well it works in adult participants with recently diagnosed multiple myeloma who have not already received treatment (LINKER-MM4). ClinicalTrials.gov. Updated April 25, 2025. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT05828511
5. A study to examine the effects of novel therapy linvoseltamab in combination with other cancer treatments for adult patients with multiple myeloma that is resistant to current standard of care treatments (LINKER-MM2). ClinicalTrials.gov. June 24, 2025. Accessed July 22, 2025. https://clinicaltrials.gov/study/nct05137054
6. Rodríguez-Otero P, Delimpasi S, Oriol A, et al. Linvoseltamab (LINVO) + bortezomib (BTZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): First results from the LINKER-MM2 trial. J Clin Oncol. 2025;43(suppl 16):7510. doi:10.1200/JCO.2025.43.16_suppl.7510