Linvoseltamab Elicits Deep, Durable Responses in R/R Multiple Myeloma

The bispecific antibody linvoseltamab induced durable responses in patients with relapsed or refractory multiple myeloma, including those with high-risk features, according to updated data from the phase 1/2 LINKER-MM1 study (NCT03761108) presented during the 2024 EHA Congress.¹

At a median follow-up of 14.3 months, linvoseltamab, when administered at a dose of 200 mg, elicited an objective response rate (ORR) of 71% in evaluable patients (n = 117), with 50% of patients achieving a complete response (CR) or better. When broken down further, 44.4% of patients experienced a stringent CR, 5.1% of patients had a CR, 13.7% of patients had a very good partial response (VGPR), and 7.7% of patients experienced a partial response (PR) to treatment.

Notably, high response rates were observed across prespecified high-risk subgroups, including those aged 75 years or older (n = 31; ORR, 71.0%; ≥ CR, 54.8%), those with high cytogenetic risk (n = 46; ORR, 67.0%; ≥ CR, 47.8%), those with stage III disease (n = 21; ORR, 61.9%), those with extramedullary disease at baseline (n = 19; ORR, 52.6%), and those who were triple refractory (n = 19; ORR, 73.7%). Deep responses were also observed in patients with extramedullary plasmacytomas plus paramedullary disease (n = 36; ORR, 58%) and those who were Black or African American (n = 20; ORR, 85%); respective CR or better rates in these groups were 27.8% and 45.0%, respectively.

Responses deepened over time. The median time to a PR or better was 1 month (range, 0.5-6.3), the median time to a VGPR or better was 2.6 months (range, 0.7-15.7), and the median time to a CR or better was 8.5 months (range, 1.6-14.1). After at least 24 weeks of treatment, 58 patients in the phase 2 portion of the trial switched to receive the agent on an every-4-weeks dosing schedule, and responses continued to deepen. Notably, 65% of 31 patients with VGPR achieved a CR or better after switching to the every-4-weeks schedule.

“At a median follow-up of 14.3 months, linvoseltamab demonstrated high efficacy in patients with late-stage, relapsed/refractory multiple myeloma, including those in prespecified high-risk subgroups,” Suzanne Lentzsch, MD, PhD, professor of clinical medicine and director of the Multiple Myeloma and Amyloidosis Program at the College of Physicians and Surgeons of Columbia University Medical Center and NewYork-Presbyterian Hospital, in New York, New York, said in a presentation of the data. “…[The] safety profile [of the agent] is acceptable, and the most common treatment-emergent adverse effects [TEAEs] were cytokine release syndrome [CRS,] neutropenia, and anemia.”

For patients with heavily pretreated multiple myeloma, BCMAxCD3 bispecific antibodies represent off-the-shelf treatment options that have been shown to elicit ORRs ranging from 61% to 63%. The investigational, fully human BCMAxCD3 antibody linvoseltamab requires 2 1-day hospitalizations but can provide a monthly dosing option to those who achieve deep responses, Lentzsch said.

The safety and efficacy of the agent is under evaluation in patients with active multiple myeloma after progression on or following at least 3 lines of treatment, including a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted antibody, or that was double- or triple-class refractory. On LINKER-MM1, study participants were hospitalized for 24 hours and given intravenous (IV) linvoseltamab at 5 mg on day 1 and 25 mg on day 8 for weeks 1 to 2. For weeks 3 to 14, the bispecific antibody was given at a dose of 200 mg once weekly. The agent was then given every 2 weeks for weeks 16 through 23. Those who achieved a VGPR or better who had received treatment for at least 24 weeks transitioned to a dosing schedule of every 4 weeks.

The primary end point for phase 1 of the study was safety; for phase 2, the primary end point was ORR by independent review committee. Secondary end points included ORR (phase 1), safety (phase 2), duration of response, minimal residual disease (MRD), progression-free survival (PFS), and overall survival (OS).

In the 200 mg cohort (n = 117), the median patient age was 70 years (range, 37-91) with 26.5% of patients aged 75 years or older. Approximately half of patients were male (54.7%) and most were White (70.9%) and had an ECOG performance status of 1 (72.6%). Regarding disease stage per International Staging System, 41.9% of patients had stage I disease, 35.0% of patients had stage II disease, 17.9% of patients had stage III disease, and this information was missing for 5.1% of patients. Additionally, 16.2% of patients had extramedullary plasmacytomas and 39.3% of patients had high-risk cytogenetics.

More than half of patients previously underwent autologous transplant (65.8%). The median number of prior lines of therapy was 5, (range, 2-16). All patients were at least triple-class exposed, 95.7% of patients were at least quad exposed, and 76.9% of patients were at least penta exposed. With regard to refractory status, 82.1% of patients were at least triple refractory, 65.8% of patients were at least quad refractory, 28.2% of patients were at least penta refractory, and 85.5% of patients were refractory to their last line of therapy.

The data cutoff date for the results reported during the 2024 EHA Congress was January 6, 2024. Additional data indicated that of patients who achieved a CR or better with linvoseltamab and who were evaluable for MRD, defined as having a threshold of 10-5 by EuroFlow or clonoSEQ, 93% were MRD negative.

For all patients, the median PFS was not yet reached (NR; 95% CI, 17.3-not evaluable [NE]). In those who achieved a CR or better, the median PFS was also NR (95% CI, NE-NE). For all patients, 70.0% (95% CI, 60.1%-78.0%) had a probability of being free of disease progression at 1 year; in those with a CR or better, this rate was 96.3% (95% CI, 86.0%-99.1%). In all patients, the median OS was 31.4 months (95% CI, 21.6-NE); in those who had a CR or better, the median OS was NR (95% CI, NE-NE). Moreover, 75.3% (95% CI, 66.0%-82.3%) of all patients had a probability of survival at 12 months; this rate was 100.0% for those with a CR or better.

The median exposure to 200 mg of linvoseltamab was 53.0 weeks (range, 1.0-167.0). Any-grade TEAEs were experienced by all patients, and these effects were grade 3 or 4 for 73.5% of patients. The most common hematologic TEAEs reported in 20% or more of patients were neutropenia (any grade, 42.7%; grade 3/4, 41.9%) and anemia (38.5%; 30.8%). The most common non-hematologic TEAEs experienced by 20% or more of patients included CRS (any grade, 46.2%; grade 3/4, 0.9%), diarrhea (37.6%; 1.7%), cough (36.8%; 0%), fatigue (33.3%; 0%), arthralgia (29.9%; 0%), hypokalemia (24.8%; 3.4%), headache (23.1%; 0.9%), nausea (23.1%; 0%), COVID-19 (22.2%; 9.4%), back pain (20.5%; 2.6%), and dyspnea (20.5%; 0.9%).

Immune effector cell–associated neurotoxicity syndrome occurred in 7.7% of patients (grade 1, 2.6%; grade 2, 2.6%; grade 3, 2.6%) and all events occurred concurrently with CRS or infusion-related reactions. Six patients experienced TEAEs that resulted in death within 30 days of their last dose of treatment (infection, n = 5; renal failure, n = 1).

Of the 46% of patients who experienced CRS, 35% had a grade 1 event, 10% had a grade 2 event, and 1% had a grade 3 event. The median time to first CRS onset was 11 hours (range, –1.1-183.6), and the median duration of CRS was 15.6 hours (range, 1.0-96.0). Twenty-five percent of patients received supportive measures to treat the toxicity; 19% received tocilizumab (Actemra), 11% had corticosteroids, 8% received oxygen, 1% were given vasopressors, and 9% received IV fluid bolus. “CRS occurred mostly during step-up dosing of linvoseltamab,” Lentzsch noted.

Infections occurred in 74.4% of patients, and they were grade 3 or 4 for 35.9% of patients. Opportunistic infections were reported in 10.3% of patients who received the agent at 200 mg; 6.0% of these infections were grade 3 or 4. The most common infections experienced by 4% or more of patients included upper respiratory tract infection (grade 1, 1.7%; grade 2, 13.7%; grade 3, 1.7%; grade 4, 0%), COVID-19 (2.6%; 7.7%; 6.8%; 0%), pneumonia (0%; 1.7%; 14.5%; 0%), sinusitis (0%; 10.3%; 0%; 0%), urinary tract infection (0%; 7.7%; 1.7%; 0%), COVID-19 pneumonia (0%; 1.7%; 3.4%; 0%), Escherichia urinary tract infection (0%; 3.4%; 1.7%; 0%), Candida infection (1.7%; 2.6%; 0%; 0%), nasopharyngitis (3.4%; 0.9%; 0%; 0%), Pneumocystis jirovecii pneumonia (0%; 0.9%; 1.7%; 0.9%), and Rhinovirus infection (2.6%; 1.7%; 0%; 0%).

“Infection frequency and severity decreased over time, including in patients with a CR or better,” Lentzsch said.

The open-label, randomized, phase 3 LINKER-MM3 trial (NCT05730036) will compare the safety and efficacy of linvoseltamab with the combination of elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone in patients with relapsed or refractory multiple myeloma.²

References

1. Lentzsch S, Bumma N, Lee HC, 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: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S212.
2. A trial to learn how well linvoseltamab works compared to the combination of elotuzumab, pomalidomide and dexamethasone for adult participants with relapsed/refractory multiple myeloma (LINKER-MM3). ClinicalTrials.gov. Updated June 7, 2024. Accessed June 17, 2024. https://clinicaltrials.gov/study/NCT05730036