Linvoseltamab Demonstrates Deep, Durable Responses in R/R Myeloma Ahead of FDA Action Date

The investigational BCMA- and CD3-targeted bispecific antibody linvoseltamab (REGN5458) produced deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma, including those with high-risk features, according to Suzanne Lentzsch, MD, PhD.¹

Longer-term findings from the phase 1/2 LINKER-MM1 study (NCT03761108) were presented at the 2024 EHA Hybrid Congress. At a median follow-up of 14.3 months, the overall response rate (ORR) was 71% in patients treated with the 200 mg dose of linvoseltamab, with 50% of patients achieving a complete response (CR) or better. The stringent CR and CR rates were 44.4% and 5.1%, respectively. Additionally, among patients who experienced a CR or better and were minimal residual disease (MRD) evaluable, 93% of were MRD negative (n = 26/28).¹

Moreover, linvoseltamab induced deep and durable responses in high-risk subgroups. Patients at least 75 years of age (n = 31) achieved an ORR of 71% with a CR or better rate of 54.8%. In patients with a high-risk cytogenetics (n = 46), the ORR was 67%, of which 47.8% were a CR or better. Patients with baseline extramedullary plasmacytomas and paramedullary plasmacytomas (n = 36) had an ORR of 58% and a CR or better rate of 27.8%.

In February 2024, linvoseltamab was granted FDA priority review for the treatment of adult patients with relapsed/refractory multiple myeloma who have progressed on or after 3 or more prior lines of therapy. The FDA has set a target action date of August 22, 2024.²

“If linvoseltamab is approved [by the FDA], it will be interesting [to see] how we choose and select the best bispecific antibody among the 3 or 4 available, if the bispecific antibody [ABBV-383] is also FDA approved,” Lentzsch stated during an interview with OncLive^®.

In the interview, Lentzsch discussed the current arsenal of bispecific antibodies in relapsed/refractory multiple myeloma, expanded on efficacy and safety outcomes with linvoseltamab in the LINKER-MM1 study, and highlighted next steps planned for the agent’s development.

Lentzsch is a professor of medicine and director of the Multiple Myeloma and Amyloidosis Program at Columbia University Herbert Irving Comprehensive Cancer Center, in New York, New York.

OncLive: What does the current arsenal of bispecific antibodies in relapsed/refractory multiple myeloma look like?

Kamdar: Over the last couple years, bispecific antibodies targeting BCMA and CD3 on T cells is a very attractive tool to treat relapsed/refractory multiple myeloma. There has been an avalanche of bispecific antibodies, and we [currently] have 2 bispecific antibodies approved by the FDA: teclistamab [Tecvayli] and elranatamab-bcmm [Elrexfio]. In the United States, we have the [investigational] bispecific antibody linvoseltamab being tested in clinical trials for relapsed/refractory multiple myeloma.

What should be known about the design of the LINKER-MM1 study, as well as the methods that were utilized?

LINKER-MM1 is a phase 1/2 clinical trial that [is currently investigating] the bispecific antibody linvoseltamab as monotherapy. Patients who were relapsed/refractory and [been previously] exposed to a proteasome inhibitor [PI], an immunomodulatory drug [IMiD], and a CD38 monoclonal antibody were eligible for this trial. Patients received a weekly dosage of linvoseltamab after 2 step-up doses.

After 14 weeks of weekly treatment, the treatment [move] to biweekly treatment. If patients had a very good partial response or better after 24 weeks of treatment, they could switch to a monthly treatment. [Overall], this was a very convenient regimen for patients.

What patients were enrolled on this phase 1/2 trial of linvoseltamab?

This was a heavily pretreated patient population. Patients had received a median of 5 to 16 prior lines of treatment. These were the patients who had no other options and were also older. The median age was 70 years, and 26.5% of patients were over 75. Additionally, 39.3% of patients had high risk cytogenetics. Those with [extramedullary plasmacytomas and paramedullary] and ISS stage IIII [disease] were also included on the clinical trial. All patients received 200 mg of linvoseltamab.

What efficacy outcomes with liso-cel in the overall population? Did these vary across subgroups and high-risk disease features?

Responses were excellent; 71% of patients achieved an ORR, which is stunning given the fact that this patient population was heavily pretreated. Moreover, 50% of these patients [achieved] a CR. Of those patients achieving a CR, 93% went into MRD negativity. Importantly, we also saw excellent response rates in high-risk subgroups. For instance, in patients with extramedullary multiple myeloma, we saw [a CR rate] of 27.8%. Patients with high-risk cytogenetics and older patient populations also had excellent response rates. Altogether, these are very encouraging data.

There was also an excellent duration of response [with linvoseltamab]. The [median] progression-free survival was not reached in all patients or in patients who achieved a CR. The overall survival [OS] was 31.4 months for the general patient population. In patients who achieved a CR, the median OS was not reached.

What were the most common toxicities associated with linvoseltamab, and what should be known about the risk of cytokine release syndrome (CRS) and infection?

The most common adverse effects [AEs] included CRS, neutropenia, and anemia. CRS occurred in 46.2% of patients but was mainly grade 1/2. Only 1% of patients had a grade 3 or higher CRS. There were no grade 4 CRS [events observed].

In terms of neutropenia and anemia, we saw grade 3/4 neutropenia in [41.9%] of the patients. Also, [30.8%] of the patient had grade 3/4 anemia, a known AE. [However], what we are concerned about [with] bispecific antibodies is the rate of infections. [A total of] 74.4% of the patients had an infection, and 35.9% of the patients had a grade 3/4 infection. That means higher grade or more serious infections requiring intravenous antibiotics and hospital admissions.

There were also data looking at the infection rate and the development over the time of treatment. We observed that in the first 3 months of treatment, the infection rate [in the overall population] was 21.4%. However, it decreased after 1 year of treatment to 6.6%. It is encouraging that patients [achieving a response] can do very well in terms of infection, for instance, with longer time of treatment and appropriate support.

Based on these findings, what next steps are planned for the investigation of linvoseltamab?

There are currently some additional studies ongoing. First, [we are evaluating] whether we can [administer] linvoseltamab as a subcutaneous infusion. That would make it very easy to give to our patients. Also, there are several studies [ongoing] to test the combination of linvoseltamab with other approved multiple myeloma drugs. [This includes] PIs and IMiDs, but also other antibodies used in [the disease].

What are the potential implications for this research on treatment selection in multiple myeloma?

As of now, linvoseltamab is not approved for the treatment of [patients with] multiple myeloma. It [has been] submitted to the [FDA] and we will see whether this will be the third BCMA-targeted bispecific antibody that is approved. As of now, it does not change practice because we have our 2 currently approved bispecific antibodies [to use].

References

1. Lentzsch S, Bumma N, Lee H, et al. Linvoseltamab in patients with relapsed/refractory multiple myeloma in the LINKER-MM1 study: Depth and durability of response at 14-month median follow-up. Presented at the European Hematology Association (EHA) 2024 Hybrid Congress; Madrid, Spain; June 13-16, 2024. S212.
2. Linvoseltamab BLA for treatment of relapsed/refractory multiple myeloma accepted for FDA priority review. News Release. Regeneron. February 21, 2024. Accessed August 14, 2024.https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-treatment-relapsedrefractory-multiple-myeloma