Linvoseltamab Demonstrates Potential for Early Intervention in High-Risk Smoldering Multiple Myeloma

A BCMA-directed therapy such as linvoseltamab-gcpt (Lynozyfic) may represent an opportunity for early intervention in the management of high-risk smoldering multiple myeloma, offering the potential to delay or even prevent progression to multiple myeloma, according to Paula Rodriguez-Otero, MD, PhD.1

Currently, linvoseltamab is FDA approved 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, based on data from the phase 1/2 LINKER-MM1 trial (NCT03761108).2

Findings from the phase 2 LINKER-SMM1 trial (NCT05932680) demonstrated the potential of this agent earlier in context of smoldering myeloma, showing that at a median follow-up of 3.9 months among evaluable patients (n = 19) achieved an overall response rate (ORR) of 100%, including a very good partial response (VGPR) or better rate of 73.7% and a complete response (CR) or better rate of 36.8%.1 In the safety run-in cohort (n = 6; median follow-up, 12.7 months), 83.3% of patients achieved CR or better, and all 12 patients with evaluable samples achieved minimal residual disease (MRD) negativity at 10⁻⁶ sensitivity.

In an interview with OncLive®, Rodriguez-Otero, a consultant hematologist and deputy professor at Clínica Universidad de Navarra in Pamplona, Spain, discussed the rationale for targeting BCMA in high-risk smoldering multiple myeloma, the early efficacy and safety findings from LINKER-SMM1, and the potential implications of linvoseltamab for disease interception and prevention of progression to active myeloma.

OncLive: What was the rationale for evaluating linvoseltamab in high-risk smoldering myeloma?

Rodriguez-Otero: [Linvoseltamab] is a bispecific antibody targeting BCMA that has shown high and deep responses in the setting of triple-class–exposed, relapsed/refractory multiple myeloma. The idea of evaluating it in an earlier, very early precursor population such as high-risk smoldering myeloma is that eventually, if we treat high-risk smoldering [disease], where the immune system may be more functional and fit, with a high-potency drug such as [linvoseltamab], we may be able to completely eradicate the clone and eventually prevent the evolution from smoldering to active myeloma.

Linvoseltamab is a T-cell–redirecting therapy. It’s a bispecific antibody that targets BCMA on the myeloma [cell] side and CD3 on the T-cell side. With this dual binding, it will activate and redirect the T cells against the myeloma cells, inducing T-cell–directed killing of myeloma cells.

What was the design of this study and the characteristics of the patient population?

This is a phase 2, open-label study that is evaluating [linvoseltamab] in high-risk smoldering multiple myeloma. Patients were enrolled if they had a diagnosis of smoldering multiple myeloma within 5 years of study entry and met one of the high-risk criteria, either by 2020 International Myeloma Working Group [IMWG] criteria.

Patients were treated with linvoseltamab using 3 step-up doses: in week 1, 1 mg; in week 2, 4 mg; and then in week 3, 25 mg. [Linvoseltamab] at 200 mg, which is the approved dose, was then given every month for a duration of 2 years.

The study had two different parts. Part 1, which is a safety run-in phase, involved 6 patients, and the key primary end point was safety. Then there was part 2, which is the expansion phase that aimed to enroll 34 patients, for a total of 40. The primary end point of part 2 is an efficacy measure in terms of complete response rate by IMWG criteria and MRD negativity at 1 and 2 years.

What efficacy results were observed in this analysis?

The efficacy of linvoseltamab in this population is quite remarkable. We have 19 out of the 24 patients that are evaluable for response, and the ORR was 100%.

If we look at the disease-evaluable population, among these 19 patients, the median follow-up is only 3.9 months. Still, the CR [or better] rate is not that high, at 36.8%, and [the] VGPR or better rate is 73.7%.

If we take a look at the safety run-in portion of the study, which includes the patients who were enrolled first, with a median follow-up that is now over 1 year, we do see a higher proportion of CRs; 83% of the patients in this cohort achieved a CR or better, so we are seeing a deepening of responses over time.

We also have 12 patients that were evaluable for MRD. MRD in this study is collected at the time of VGPR or better. Among these 12 patients with samples available for MRD, all of them were MRD negative at 10-6.

How was the safety profile of linvoseltamab in this study?

The safety [data show] that, as expected, the incidence of all-grade treatment-emergent adverse [effects (AEs)] is important, but we do see a lower rate of grade 3 or 4 AEs compared [with] what we've seen in the relapsed/refractory setting.

For example, [regarding] neutropenia, which is the most frequent hematologic AE we see, grade 3/4 neutropenia is seen in less than 40% of patients. Cytokine release syndrome [CRS] is seen in only 40% of patients. All of the [instances of CRS] were grade 1, except one [AE] that was grade 2, after the first step-up dose of 1 mg.

All CRS [effects], as expected, occurred during the step-up phase or after the first full dose, with only one patient developing one CRS [effect] on cycle 2, day 1. We haven't seen immune effector cell–associated neurotoxicity syndrome so far in the study.

Regarding infections, which we know are a great concern in the setting of BCMA-directed therapies, the incidence of grade 3/4 infections in this study is very low, with only three infections that were grade 3: one Salmonella infection, one Staphylococcus bacteremia, and one COVID-19 infection. All of them were classified as grade 3 because they required IV antibiotics.

Other than that, there were no discontinuations and no deaths due to AEs. Overall, we see what appears to be a better safety profile, particularly concerning the low incidence of grade 3 or higher infections with [linvoseltamab] in this early setting, compared to the relapsed/refractory myeloma population.

Based on these early findings, what are the next steps for evaluating this regimen in high-risk smoldering multiple myeloma?

This is still very preliminary data, so we need to first fully enroll the study. There are only seven patients left to enroll so far, so we are still working to generate more data. The data look very encouraging, and we believe that this could be a good platform to try to prevent the evolution from high-risk smoldering into active disease, but we need more follow-up and a larger cohort of patients. The idea is really to go into a phase 3, randomized trial of linvoseltamab compared with daratumumab [Darzalex], which we know is probably going to be a new standard in this population.

References

1. Rodriguez-Otero P, Lieonart JJB, Clavero ME, et al. Safety and efficacy of linvoseltamab (LINVO) in patients (Pts) with high-risk smoldering multiple myeloma (HR-SMM): first results from the Phase 2 LINKER-SMM1 trial. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-68.
2. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed October 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma