Linvoseltamab Impresses in LINKER-MM1 Study of Patient With Pretreated Myeloma

Hans C. Lee, MD

Results from the phase 2 LINKER-MM1 study (NCT03761108) show that linvoseltamab (REGN5458) elicited an objective response rate (ORR) of 71% at the recommended dose of 200 mg for patients with relapsed/refractory multiple myeloma, according to a presentation at the 2023 ASCO Annual Meeting.¹

Two doses of linvoseltamab, a BCMA/CD3 bispecific, were explored in the phase 2 study, with activity seen at both doses. At the 200-mg dose, responses consisted of a stringent complete response (CR) for 16% of patients, 14% had a CR, 29% had a very good partial response (VGPR), and 12% experienced a partial response (PR). Median progression-free survival (PFS) for this dose level was not yet reached, with a 6-month estimated PFS rate of 72.7%.

“Early, deep, and durable responses were observed in patients who were mostly triple refractory,” said lead investigator Hans C. Lee, MD, from The University of Texas MD Anderson Cancer Center. “At the recommended dose of 200 mg, linvoseltamab is efficacious and showed generally manageable safety in patients with relapsed/refractory multiple myeloma, supporting continued development.”

In the phase 2 study, 104 patients received treatment with 50-mg linvoseltamab and 117 received the 200-mg dose. In both arms, step up dosing was used in week 1 and 2 to minimize toxicity. In week 1 on day 1, linvoseltamab was administered at 5 mg. On week 2, day 8 of treatment, this was stepped up to 25 mg. Hospitalization was required for 24 hours surrounding the administration of the step-up dosing. In cycle 1 to 3 (weeks 3 to 14), linvoseltamab was administered weekly, which changed to every 2 weeks in cycles 4 and 5. In the 50 mg arm, treatment persisted at twice weekly for the remainder of the study whereas in the 200 mg arm, those achieving a VGPR or better were reduced to every 4 weeks for cycle 6 onward.

In the 200-mg arm, the median age of patients was 70 years, with 26.5% age 75 or older. ECOG performance status was 0 (28.2%) or 1 (71.8%) and the ISS stage was I (38.5%), II (37.6%), III (18.8%), or missing (5.1%). Extramedullary plasmacytomas were present for 13.7% of patients and 35.9% had high-risk cytogenetics. The bone marrow plasma cell percentage was 50% or more for 22.2% of patients and was missing for 24.8%. The median number of prior lines of therapy was 5 (range, 2-14), and all patients were triple-class exposed, with 95.7% being quad-exposed. Three-fourths were penta-exposed (75.2%) and nearly a quarter were also penta-refractory (23.9%). Most patients were triple-refractory (73.5%) and most were refractory to their last line of therapy (76.9%).

The median duration of follow-up in the 50 mg arm was 7.7 months. In the 200 mg arm, the median duration of follow-up was 5.6 months. At the 50 mg dose of linvoseltamab, the ORR was 50%, which consisted of a stringent CR for 14% of patients, 7% had a CR, 20% had a VGPR, and 9% experienced a PR. “Based on earlier results, responses may deepen over time,” Lee said.

The probability of maintaining a response was 83.6% at 6 months and 79.2% at 12 months. The median duration of response is not yet reached. Minimal residual disease (MRD) data, tested at a sensitivity of 10-5 using clonoSEQ and Euroflow, were available for 46 patients across doses who achieved a CR or stringent CR. Of these patients, 54.3% were MRD-negative.

ORR remained consistent across subgroup populations, including those at high-risk, noted Lee. Moreover, across each subgroup, the 200 mg dose was consistently associated with a higher ORR. In those age 75 and older (n = 31), the ORR with linvoseltamab was 67.7%. Those with high cytogenetic risk (n = 42) had an ORR of 61.9% with linvoseltamab. Moreover, in patients with a baseline soluble BCMA of <400 ng/mL (n = 57), the ORR was 84.2%, in those with a baseline soluble BCMA of 400 ng/mL or more (n = 51) the ORR was 54.9%.

Patients in the 50 mg arm were able to dose escalate to 200 mg, if they progressed within 4 to 12 weeks of initiating therapy. Of those who escalated (n = 8), most experienced a VGPR (75%). The median time to VGPR in this group was 3.7 months.

The estimated 6-month PFS rate in the 50 mg arm was 54.6% and the median PFS was 7.9 months. The estimated 3-month PFS rates were 79.6% and 59.4%, in the 200-mg and 50-mg linvoseltamab arms, respectively.

In the 200 mg cohort, the most common treatment-emergent adverse events (TEAEs) were hematologic. The most common grade 3/4 events were neutropenia (30.8%), anemia (23.9%), thrombocytopenia (13.7%), and lymphopenia (11.1%). Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was experienced by 5.9% of patients across doses, with most occurring during the step-up dosing. TEAEs led to treatment discontinuation for 16.2% of patients in the 200 mg arm. TEAEs leading to death occurred for 7 patients in the 50 mg arm and for 6 in the 200 mg arm. None were considered related to linvoseltamab, according to the treating physician.

The most common non-hematologic TEAE in the 200-mg cohort was cytokine release syndrome (CRS), which occurred in 45.3% of patients. This was followed by cough (33.3%), fatigue (32.5%), and diarrhea (32.5%). The median time to CRS was 14.8 hours in the 200 mg arm, and the duration of CRS was 16.5 hours. There was 1 grade 3 event (0.9%), with the remainder being grade 1 or 2 in severity. Tocilizumab was administered for 13.7% of patients.

“You have to be careful with cross trial comparisons, but the level of CRS is not the same we see with CAR T cells,” said ASCO discussant Ravi Vij, MD, of Washington University School of Medicine. “One thing we see with bispecifics is the time spent in the hospital. Having a fast solution of CRS may be an advantage.”

Other TEAEs of interest included infection, which occurred in 59.8% of patients in the 200 mg arm. In the 200 mg arm, grade 3 or greater infections were experienced by 36.8% of patients, with the leading being pneumonia (13.7%). Opportunistic infections occurred in 7.7% of patients in the 200 mg cohort, with most being grade 3 or greater in severity. There were 3 patients with Pneumocystis jirovecii pneumonia, for which prophylaxis had not been required.

The 200 mg dose of linvoseltamab is being further explored in the phase 3 LINKER-MM3 trial for patients with relapsed/refractory multiple myeloma (NCT05730036). The single agent is being compared with elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone. The study plans to enroll 286 participants.

_REFERENCES:

_{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}