Linvoseltamab Produces Durable Responses in Relapsed/Refractory Multiple Myeloma

The bispecific antibody linvoseltamab (REGN5458) elicited early signals of efficacy in patients with relapsed/refractory multiple myeloma, according to Hans Lee, MD, who added that the drug’s toxicity profile, particularly the rate of associated cytokine release syndrome (CRS), is tolerable and manageable.

The phase 1/2 LINKER-MM1 trial (NCT03761108) evaluated the efficacy and safety of the bispecific antibody linvoseltamab in patients with relapsed/refractory multiple myeloma. The phase 2 portion of this study optimized dose selection with 2 linvoseltamab dose cohorts: a 50 mg cohort and a 200 mg cohort. In the 50 mg cohort (n = 104), at a median follow-up of 7.7 months (range, 0.3-31.3), the overall response rate (ORR) was 50%, including a stringent complete response (sCR) rate of 14%, a complete response (CR) rate of 7%, a very good partial response (VGPR) rate of 20%, and a partial response (PR) rate of 9%. In the 200 mg cohort (n = 117), at a median follow-up of 5.6 months (range, 0.2-28.2), the ORR was 71%, including an sCR rate of 16%, a CR rate of 14%, a VGPR rate of 29%, and a PR rate of 12%.¹

“These results support the continued development of linvoseltamab in multiple myeloma,” Lee said in an interview with OncLive® during the 2023 ASCO Annual Meeting.

The upcoming phase 3 LINKER-MM3 trial (NCT05730036) will investigate the efficacy of linvoseltamab vs elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone in patients with relapsed/refractory multiple myeloma.² The primary end point of this trial is progression-free survival (PFS), with ORR, minimal residual disease (MRD) negativity rate, and overall survival serving as key secondary end points. 

In the interview, Lee discussed unmet needs in patients with relapsed/refractory multiple myeloma; highlighted key efficacy and safety findings from the LINKER-MM1 trial; and how these data may inform the future of the multiple myeloma treatment paradigm.

Lee is an associate professor and director of Multiple Myeloma Clinical Research in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What was the rationale for LINKER-MM1?

Lee: The LINKER-MM1 trial is a phase 1/2 trial with linvoseltamab in [patients with] relapsed/refractory multiple myeloma. Linvoseltamab is a bispecific antibody that targets BCMA on myeloma cells and CD3 on T-cell receptors. There’s been encouraging efficacy and safety [data] with linvoseltamab, with data presented at previous congresses.

The rationale for the phase 2 part of the LINKER-MM1 trial was to evaluate 2 different [doses of] linvoseltamab, 50 mg and 200 mg, to optimize dose selection. At the 2023 ASCO Annual Meeting, we presented for the first time the initial results of the fully enrolled phase 2 part of the study in both the 50 mg and 200 mg cohorts.

What patients were enrolled in this trial?

The key eligibility criteria of the phase 2 part of the LINKER-MM1 trial were patients with relapsed/refractory multiple myeloma with progression on or after at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Unique to this trial, patients could also be enrolled if they were triple-class refractory, regardless of their lines of prior therapy.

What were the efficacy findings from this trial?

In the 50 mg dose cohort, the ORR was 50%. In the recommended 200 mg dose cohort, the ORR was 71%, with a VGPR or better rate of 59% and a CR or better rate of 30%. Notably, 66% of patients dosed in the 200 mg cohort remained on trial at the time of the data cutoff in February 2023.

Among patients with an sCR or CR, across [patients in the] 50 mg and 200 mg cohorts with evaluable MRD data, 54.3% of patients were MRD negative. Responses appear to be durable and deepened with time. The 6-month probability of maintaining a response in the 200 mg cohort was 83.6%.

At a median follow-up of 7.7 months in the 50 mg cohort, the median PFS was 7.9 months. At a median follow-up of 5.6 months in the 200 mg cohort, the median PFS had not been reached. The 6-month probability of PFS was 72.7% in the 200 mg cohort.

What is the safety profile of linvoseltamab in this population?

The most common adverse effect [AE] across the trial, between the 50 mg and 200 mg cohorts, was CRS, which occurred in 54.8% of patients in the 50 mg cohort and 45.3% of patients in the 200 mg cohort. Among patients in the 200 mg cohort, most of the CRS was grade 1 in severity. [A total of] 35.0% of these patients had grade 1 CRS, 9.4% of these patients had grade 2 CRS, and there was a single grade 3 event. When CRS occurred, it typically occurred rapidly, within a day of dosing, and resolved within 24 hours. Hospitalization for CRS monitoring was only required for 24 hours after the initial 2 step-up doses on week 1 day 1 and week 2 day 1 because of the rapid onset and resolution of CRS.

Another important AE with bispecific antibodies in general is infection risk. This is an AE of special interest across bispecific antibodies as a drug class. The rates of infection seemed to be similar between the 50 mg and 200 mg cohorts. The rates of infection were [61.5% and 59.8% in the 50 mg and 200 mg cohorts, respectively], and the [rates] of grade 3 or grade 4 infections were [34.6% and 36.8% in the 50 mg and 200 mg cohorts, respectively].

How do these findings support the further investigation of linvoseltamab in patients with relapsed/refractory multiple myeloma?

The LINKER-MM1 trial demonstrated that linvoseltamab has high efficacy in heavily pretreated patients with multiple myeloma, with rapid and durable responses [seen with] the data so far. Importantly, responses were seen in historically high-risk subgroups, including patients with high-risk cytogenetics and patients with high baseline disease burden.

Also encouraging with linvoseltamab were the relatively low rates of CRS, [which was] mostly grade 1 in nature and severity. This limited the amount of hospitalization patients required for CRS monitoring, with only a 24-hour hospitalization [period] after each of the first 2 doses.

A phase 3 study comparing linvoseltamab with a standard-of-care [SOC] triplet-based regimen will be initiated shortly in [patients with] early relapsed/refractory multiple myeloma.

What other multiple myeloma research sparked your interest at the 2023 ASCO Annual Meeting?

Some anticipated data were the [phase 3] CARTITUDE-4 trial [NCT04181827] data showing the benefits of earlier CAR T-cell therapy with ciltacabtagene autoleucel [cilta-cel; Carvykti] vs SOC triplet-based therapy. There was a significant PFS benefit in patients who received cilta-cel vs SOC multiple myeloma therapies. This highlights the importance and applicability of applying some of these novel approaches, such as bispecific antibodies and CAR T-cell therapies, in earlier lines of therapy. These are exciting data.

Disclosures: Dr Lee reports consulting or advisory roles with Allogene Therapeutics, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Karyopharm Therapeutics, Legend Biotech, Monte Rosa Therapeutics, Oncopeptides, Pfizer, Sanofi, and Takeda; as well as research funding from Amgen, Celgene, GlaxoSmithKline, Janssen, Regeneron, and Takeda.

References

1. Lee HC, Bumma N, Richter JR, et al. LINKER-MM1 study: linvoseltamab (REGN5458) in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8006. doi:10.1200/JCO.2023.41.16_suppl.8006
2. A study to learn how linvoseltamab (REGN5458) will work compared to the elotuzumab, pomalidomide, and dexamethasone (EPd) combination, in participants with relapsed/refractory multiple myeloma (LINKER-MM3). ClinicalTrials.gov. Updated June 18, 2023. Accessed August 9, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05730036