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

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Hans Lee, MD, discusses updated data from the LINKER-MM1 study in heavily pretreated relapsed/refractory multiple myeloma.

Hans Lee, MD

Hans Lee, MD

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
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