Linvoseltamab Continues to Elicit Durable Efficacy in High-Risk Relapsed/Refractory Multiple Myeloma

Treatment with linvoseltamab (REGN5458) led to deep responses in patients with relapsed or refractory multiple myeloma, including those with heavily pretreated, high-risk disease who had progressed on or after at least 3 or more lines of therapy or were triple class refractory, according to Hans Lee, MD. Lee added that these responses deepened over time and a manageable safety profile was maintained for patients who were treated with the BCMA-CD3 bispecific antibody.

At the 2023 ASH Annual Meeting, Lee and colleagues shared data from a longer follow-up of the first-in-human, dose escalation/expansion, phase 1/2 LINKER-MM1 study (NCT03761108) at a median of 8 months. At the recommended dosage of 200 mg, patients treated with linvoseltamab (n = 117) experienced an overall response rate (ORR) of 69%. Notably, 59% of these responses were very good partial responses (VGPR) or higher, 39% of which were complete responses (CRs).1 Further, the median time to VGPR was 2.6 months and the median time to CR was 7.6 months.²

Additional data from a Regeneron press release showed that at a median follow-up of 11 months, responses continued to deepen, with a 71% ORR comprised of a 46% CR rate.²

“This [data] supports the continued development of linvoseltamab in relapsed/refractory multiple myeloma and other areas of multiple myeloma, including earlier relapsed/refractory multiple myeloma in newly diagnosed patients,” Lee said.

The phase 3 confirmatory trial, LINKER-MM3 (NCT05730036), is currently enrolling patients to receive linvoseltamab vs elotuzumab (Empliciti) in combination with pomalidomide (Pomalyst) and dexamethasone.³

In an interview with OncLive^®, Lee discussed updated data from the LINKER-MM1 study in heavily pretreated relapsed/refractory multiple myeloma and highlighted the benefits of a step-up dosing schedule and rapid de-escalation approach. Lee is the director of Multiple Myeloma Clinical Research and is an associate professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, in Houston.

OncLive: What was the rationale for this research?

Lee: At this year’s ASH meeting, we presented updated data from the LINKER-MM1 study which looks at linvoseltamab, a BCMA bispecific T-cell antibody, in relapsed/refractory multiple myeloma. BCMA is shown to be a very important target in relapsed/refractory multiple myeloma with multiple studies showing the effectiveness of BCMA-targeted immunotherapies.

What’s important about this update from the LINKER-MM1 study is that it shows more mature data with longer follow-up. It’s also the first time that the primary end point of ORR as adjudicated by the independent review committee [IRC] is being reported.

What patient population was evaluated in this study?

In the LINKER-MM1 study patients with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy and were triple-class exposed to a proteasome inhibitor, an immune modulator drug, an antiCD38 monoclonal antibody, or had triple-class refractory disease regardless of lines of prior therapy received, were enrolled.

In the 200 mg cohort, which is the recommended phase 2 dose of linvoseltamab, 117 patients received a 200 mg dose. Patients received a median of 5 prior lines of therapy and 80% were triple-class refractory, 27% were over the age of 75, and 39% had high-risk cytogenetics. This is a very heavily pretreated relapsed/refractory multiple myeloma patient population that was enrolled in the LINKER-MM1 study.

What results were presented at the 2023 ASH Annual Meeting?

At the 2023 ASH meeting, with a median follow-up of 8 months, the ORR as adjudicated by the IRC was 69%, with the majority of patients attaining a VGPR or better at 59%. Also, with longer follow-ups, continuous deepening, and durability of responses [was noted]. The estimated 9-month durability response was 87% and the estimated 9-month progression-free survival was 73% with this longer follow-up with this data cut.

There were no new safety signals observed with this longer follow-up of linvoseltamab in the LINKER-MM1 study. The most common non-hematologic adverse event [AE] was cytokine release syndrome [CRS], which occurred in 46% of patients with the majority being grade 1 AEs. In terms of infections, there is approximately a 35% to 37% grade 3 or higher infection rate with linvoseltamab in this patient population [and any grade infections occurred at a rate of 73%].

How do you foresee these results impacting treatments for this patient population?

We’re very encouraged by the continued efficacy and encouraging safety of linvoseltamab in relapsed/refractory multiple myeloma with longer follow-up in the LINKER-MM1 study.

Some of the key differentiating factors of linvoseltamab include the weekly step-up dosing with a 5 mg dose given on week 1 day 1, a 25 mg dose given at week 2 day 1, and weekly dosing thereafter given for cycles 1 through 3 on a 28-day cycle. This is followed by de-escalation of the frequency of dosing for cycles 4 and 5 and further de-escalation of dosing in a response-adapted approach in patients attaining a VGPR or better to every 4 weeks.

This rapid de-escalation of the frequency of dosing along with limited hospitalization requirements for CRS monitoring, and the low CRS rates, make it a very promising approach for the treatment of relapsed/refractory multiple myeloma.

[More data] from the LINKER-MM1 study was published [in late 2023], which is an even later data cut than what was shared at the ASH meeting. This was an 11-month median follow-up time, which demonstrated an even higher ORR adjudicated by an independent review committee of 71% and a complete response rate of 46%. With longer follow-up, we’re seeing very high efficacy, durability of responses, and encouraging safety signals.

What would be your main takeaway message for colleagues?

The LINKER-MM1 study data with longer follow-up demonstrates the very strong efficacy of linvoseltamab in heavily pretreated relapsed/refractory multiple myeloma with a convenient step-up dosing schedule that limited hospitalization, with only 24 [hour] hospitalizations during the step-up dosing period in the first 2 [step-up] doses [needed]. Rapid de-escalation of the frequency of dosing in a response-adapted approach with relatively low CRS rates [was observed].

References

1. Jagannath S, Richter J, Dhodapkar MV, et al. Patterns of response to 200 mg linvoseltamab in patients with relapsed/refractory multiple myeloma: longer follow-up of the LINKER-MM1 study. Blood. 2023;142(suppl 1):4746. doi:10.1182/blood-2023-177968
2. American Society of Hematology 2023 investor event. Regeneron Pharmaceuticals, Inc. December 14, 2023. Accessed February 2, 2024. https://investor.regeneron.com/static-files/cb093452-9e37-41b0-9d52-c53b9275e99e
3. Linvoseltamab receives EMA filing acceptance for treatment of relapsed/refractory multiple myeloma. News release. Regeneron. February 2, 2024. Accessed February 2, 2024. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-receives-ema-filing-acceptance-treatment