Commentary

Article

Decreasing Grade 3/4 Infections, Limited Hospitalizations Underscore Potential for Linvoseltamab in R/R Myeloma

Author(s):

Sundar Jagannath, MBBS, discusses linvoseltamab and expands on key efficacy and safety findings from the LINKER-MM1 trial in patients with relapsed/refractory multiple myeloma.

Sundar Jagannath, MBBS

Sundar Jagannath, MBBS

The BCMA- and CD3-directed bispecific antibody linvoseltamab (REGN5458) demonstrated potential benefit for patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy with a decreasing rate of grade 3/4 infections at 6 months and beyond observed. Sundar Jagannath, MBBS, added that in addition to this decreasing rate of infections, 24-hour hospital stays were required only during the 2 step-up doses in the phase 1/2 LINKER-MM1 trial (NCT03761108).

Findings from the trial presented during the 2024 AACR Annual Meeting showed that patients treated with the 200 mg dose of linvoseltamab during phases 1 and 2 (n = 117) experienced an objective response rate (ORR) of 71% per independent review committee (IRC) assessment. Responses included a stringent complete remission (CR) rate of 41%, a CR rate of 5%, a very good partial response (VGPR) rate of 16%, and a PR rate of 9%. This translated to a CR or better rate of 46% and a VGPR or better rate of 62%.

“I'm very encouraged about this [bispecific] antibody and its safety profile, as well as the fact that [patients need] to be admitted [to the hospital] for only 2 24-hour [periods during step-up dosing]. The grade 3/4 infection rate drops below 5% after 6 months, which is very positive for this molecule,” Jagannath said in an interview with OncLive®.

In the interview, Jagannath discussed the background of linvoseltamab, expanded on key efficacy and safety findings from LINKER-MM1, and detailed the next steps for investigating this agent in patients with relapsed/refractory multiple myeloma. Jagannath serves as the director of the Center of Excellence for Multiple Myeloma and as a professor of Medicine, Hematology and Medical Oncology at The Tisch Cancer Institute of Mount Sinai in New York, New York.

OncLive: What is linvoseltamab’s mechanism of action, and what is the rationale for investigating its use in difficult-to-treat patients with relapsed/refractory multiple myeloma?

Jagannath: Linvoseltamab is a fully human bispecific antibody that binds to BCMA and CD3, thereby bringing the patient's own T cells close to the cancer cell. That causes destruction of the cancer cells by the patient's own immune cells.

There are 2 approved [BCMA/CD3-directed] bispecific antibodies [for the treatment of patients with relapsed/refractory multiple myeloma (teclistamab-cqyv [Tecvayli] and elranatamab-bcmm [Elrexfio])], so we [know] that these are effective drugs. The uniqueness of linvoseltamab is that it is a fully human antibody, so anti-drug antibody generation is very low.

Additionally, the adverse effect (AE) profile [of linvoseltamab] is excellent, such that a patient has to be admitted [to the hospital] for only the step-up dosing. The step-up dosing is done weekly, [starting with] 5 mg on day 1 and 25 mg on day 8. After those doses, patients stay in the hospital for 24 hours. When they go on to week 3 to receive the 200 mg dose, they are not admitted, and cytokine release syndrome [CRS] has been manageable.

What were the characteristics of the patients enrolled to LINKER-MM1?

The total number of patients [who received] the 200 mg dose [of linvoseltamab during the phase 1 or 2 portions] was 117. The median age [on the trial]–which is common in this population–was 70 years [range, 37-91], and 26.5% of the patients were over the age of 75. [Additionally,] 17.1% of the patients were African American. The study, as it was conducted, reflects the United States population. Therefore, it meets the external validity criteria. [If] the FDA [looks at this study to support potential approval], they can say, ‘Yes, what we found on the study could be reproduced in the population at large because the study reflects [the real-world population].’

Another important aspect is that the study required the patient to have had 3 or more prior lines of therapy and should have been exposed to the 3 classes; an immunomodulatory drug [IMiD], a proteasome inhibitor, and daratumumab [Darzalex]. The phase 1 portion allowed patients who were double refractory, and the phase 2 portion allowed [patients who were] triple-class refractory. This is important because 100% of the patients were triple-class exposed, because that was the study design, and 82.1% of the patients were triple-class refractory. This was a highly heavily pretreated population.

The study had patients who had more than 50% plasma cell infiltration in the bone marrow [23.1%]. The median soluble BCMA level was 368.0 ng/mL [range, 18.7-4430.0], and soluble BCMA reflects tumor burden. It was a high tumor burden population for the majority of patients. [The study included] patients with extramedullary disease [16.2%], which was adjudicated by the IRC. This was a patient population that would meet the external validity criteria for the FDA.

What were the key efficacy findings presented at the 2024 AACR Annual Meeting?

The primary objective for phase 2 was ORR, and the ORR, which was adjudicated by the IRC, was 71%. More importantly, 46% of patients were in CR or better, and 62% of the patients had a VGPR or better. The PR [rate] was only 9%. These were deep responses.

In those patients [with a CR or better] who were evaluable for minimal residual disease [MRD], 25 out of 27 patients [92.6%] were MRD-negative. [A meeting of the FDA’s Oncologic Drugs Advisory Committee on April 12, 2024] adjudicated the inclusion of MRD as one of the end points in the early approval of drugs [in multiple myeloma] for FDA. We had ORR and CR, but we wanted MRD. Therefore, having 25 out of 27 patients achieve MRD negativity speaks to the potency of this drug.

What safety data were seen in this trial?

In the class of BCMA-directed bispecific antibodies, there are 3 things we need to know. One, which is unique to this class, is CRS. The second is low blood counts, especially neutropenia and anemia, which should be kept in mind. The third [is infection]. Because of the neutropenia, the fact that this [agent] is BCMA-directed, and normal plasma cells also express BCMA, there is a profound depletion of the plasma cell component. [Because of this depletion,] patients don’t make antibodies in response to an infection quickly. Therefore, [risk of] infection becomes an important aspect.

In this regard, the neutropenia and anemia were as expected. Seventy-three percent of patients did experience [any-grade] infections, [and 43% had] grade 3/4 infections. We are giving this antibody over a period of time, and the uniqueness of this study is that this antibody is initially given once per week for the first 14 weeks, then it is automatically reduced to every 2 weeks [from weeks 16 to 23]. At 24 weeks, in patients who achieved VGPR or better, dosing was reduced to once every 4 weeks.

When we look at how infections happened and when they happened, this study was well designed from that point of view. We saw infections during the first 6 months. [In months 0 to 3, the rate of] any-grade infections was 53%. As soon as you move past the 6 months, the infection rate drops to [31.4% for months 6 to 9,] 23.4% for months 9 to 12, and only 17.8% for months 12 to 15. If you look at the grade 3/4 infection rate, which is what we are all concerned about, the grade 3/4 infection rate was 21.4% in months 0 to 3 and 22.0% in months 3 to 6], and it precipitously drops to about 4.3% in months 6 to 9.

[The infection data are important because] the responses were all very rapid. The PR is achieved within 4 weeks or within the first month; VGPR is achieved very quickly, within 2 months or thereabout. By 6 months, most of the patients are in VGPR and able to convert to treatment once every 4 weeks, so the infection [rate drops]. The study was designed well, and patients were allowed to [take a] a prophylactic antibiotic.

What are the next steps for investigating linvoseltamab in patients with relapsed/refractory multiple myeloma?

The phase 3 LINKER-MM3 trial [NCT05730036] is ongoing, [evaluating linvoseltamab vs elotuzumab (Empliciti) plus pomalidomide (Pomalyst) and dexamethasone] in [patients with] relapsed/refractory multiple myeloma. Looking at how the other bispecifics have done in phase 3 studies, especially BCMA-directed bispecifics, [linvoseltamab should] do well.

Reference

Jagannath S, Richter J, Dhodapkar MV, et al. Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody in patients with relapsed or refractory multiple myeloma, including difficult-to-treat subgroups. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT001.

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