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As of January 28, 2022, 167 patients with RRMM across Phase 1 and 2 have received at least one dose of REGN5458. Median age was 64 (range 41-90), 49% of patients were male, patients had a median of 6 prior lines of therapy, and 90% were at least triple class refractory (refractory to a PI, IMiD, and anti-CD38 therapy); prior exposure to BCMA-targeting agents was excluded (except BCMA antibody-drug conjugates). High-risk cytogenetic features were present in 13.6% of patients while 18.6% were stage 3 per revised International Staging System (R-ISS); 40% had bone marrow plasmacytosis >50%.

Across both phases, 164 (98.2%) patients experienced treatment-emergent adverse events (TEAEs) for whom 78.4% were Grade (G) 3 or higher TEAEs. The most common hematologic TEAEs were anemia 36.5% (≥G3 29.9%), neutropenia 28.7% (27.5%) and thrombocytopenia 21% (16.2%). The most common non hematologic TEAEs reported (≥ 30%) were CRS 47.9% (G1 36.5%, G2 10.8%, and one patient with G3 0.6% [observed in the context of infection]) and fatigue 34.1%. Five patients (3%) discontinued REGN5458 due to treatment related adverse events (TRAEs), there were no treatment discontinuations due to CRS.

ORR was higher for phase 1 patients treated at ≥200 mg dose levels (N=24) as compared to that for patients treated at doses <200 mg (N=49), 75% versus 40.8%. This observation was consistent across patient subgroups by cytogenetic risk, R-ISS stage, prior therapy, and bone marrow plasmacytosis level. Responses deepened over time with 37.5% of patients with ≥CR. Median DOR has not been reached. Based on the overall benefit/risk profile, the RP2D was determined to be 200mg.

Results were presented today at the American Society of Hematology (ASH) Annual Meeting from the first two dose groups (3 mg and 6 mg weekly doses).

• Patients had a median of seven lines of prior systemic therapy, and all had failed CD38 antibody treatment.
• Responses were observed in 4 of 7 (57%) patients, including 3 of 4 (75%) in the 6 mg dose group.
• In the 6 mg dose group, 2 patients (50%) were also minimal residual disease (MRD) negative, meaning that no cancer cells were detectable in their bone marrow.

Results: As of February 28, 2023, 117 MM pts enrolled into the 200 mg cohort; median age was 70 (range: 37–91) with 26% ≥75, 26% were non-white, 14% had extramedullary (excluding paramedullary) plasmacytomas ≥2 cm, 36% had a high-risk cytogenetics, 22% had bone marrow plasma cells ≥50%, and 74% were ≥triple-class refractory. Median duration of follow-up was 5.6 months (interquartile range [Q1–Q3]: 3.02–8.34) ORR was 71% with ≥complete response (CR) rate of 30%. Responses deepen over time: median time to ≥partial response (PR) was 0.95 months (Q1–Q3: 0.76–1.87); median time to ≥VGPR was 1.87 months (0.79–3.55); and median time to ≥CR was 5.32 months (3.71–7.69). Moreover, high ORR and high rates of ≥CR were observed in many subgroups of difficult-to-treat MM pts. Specifically, ORR and ≥CR rates were: 70% and 29% in pts with ≥triple-class refractory disease; 68% and 26% in pts ≥75 years old; 62% and 26% in pts with high cytogenetic risk; and 47% and 18% in pts with International Staging System stage III. High rates of overall response and ≥CR were also observed in patients with high tumor burden as determined by various measures including bone marrow plasmacytosis ≥50% (50% and 31%) and soluble BCMA at baseline ≥ 0.4mg/L (55% and 25%). Kaplan-Meier (KM) estimated median duration of response was not reached (NR) (95% confidence interval [CI] non-evaluable [NE], NE), and probability of response at 12 months was 79% (95% CI 63, 89). KM estimated median PFS was NR (95% CI NE, NE) and probability of PFS at 12 months was 66% (95% CI 52, 77).

TEAEs occurred in all patients with Grade [Gr] ≥3 in 79%. The most common TEAE was cytokine release syndrome (any grade: 45%, Gr3-4: 1%, Gr5: 0; tocilizumab was utilized to treat these symptoms in 16 [13.7%] pts). Other common TEAEs were cough (33%, 0, and 0), neutropenia (32%, 31%, and 0), diarrhea (32%, 2%, and 0), and fatigue (32%, 0, and 0). Rate of infections of any grade was 59.8% with ≥Gr3 in 36.8%. The most common infections were pneumonia (any grade 17.1%, ≥Gr3 13.7%), upper respiratory tract infection (12.0%, and 2.6%), and COVID-19 (12.0%, 5.1%). Opportunistic infections (any grade) were observed in 9 (7.7%) pts including 7 (6.0%) pts ≥Gr3. Twenty-six of 117 (22%) pts were treated with intravenous immunoglobulin.

Conclusions: Linvoseltamab 200 mg induced deep responses in patients with RRMM including those with high-risk myeloma and high tumor burden, and deepened responses over time while maintaining a generally manageable safety profile. More mature data with longer follow-up will be reported at the meeting.

As of data cut-off (June 10, 2021), 68 pts were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3–400 mg. The median age at enrollment was 64 years (range, 41‒81) and 20.6% pts were ≥75 years. As per Revised International Staging System, stage was 1, 2 or 3 in 14.7%, 60.3% and 23.5% of pts respectively. Pts had a median of 5 prior lines of systemic therapy (range, 2–17) with the majority of pts (51.5%) being penta-refractory (see Table). The median duration of follow-up was 2.4 months (range, 0.1–20.8).

Treatment-emergent adverse events (TEAE) were reported in 66 pts (97.1%), and Grade (Gr) ≥3 TEAEs in 52 (76.5%) pts. The most frequent TEAEs were fatigue in 29 pts (42.6%), Gr 1/2 in 26 pts (38.2%), Gr 3 in 3 pts (4.4%); cytokine release syndrome (CRS) in 26 pts (38.2%), CRS was Gr 1 in 23 pts (33.8%) and Gr 2 in 3 pts (4.4%). No pt had Gr ≥3 CRS or discontinued treatment due to CRS. There were no Gr ≥3 neurotoxicity events. Nausea was reported in 22 pts (32.4%). The severity of nausea was Gr 1 in 23.5% of pts and Gr 2 in 8.8% of pts.

Treatment-related adverse events (TRAE) were reported in 56 patients (82.4%). The most frequent hematologic TRAE was neutropenia in 11 pts (16.2%), with Gr ≥3 severity in 9 of these pts (13.2%). The most frequent non-hematologic TRAEs were CRS (38.2%) and fatigue (20.6%). The safety profile was consistent across all dose levels, and there was no correlation between CRS and the full dose of REGN5458.

Responses were observed at all dose levels. Amongst pts treated at the 96 and 200 mg dose levels, the response rate was 73.3% (11/15). Across all dose levels, 92.6% (n=25) of all responders achieved at least a very good partial response and 48.1% (n=13) of responders had a complete response (CR) or stringent CR. Pts without extramedullary plasmacytomas (EMP) responded more frequently than those with EMP. The Kaplan–Meier estimated median DOR was not reached and the probability of DOR ≥8 months was 92.1% (95% confidence interval: 72.1, 98.0), with responses ongoing up to 19 months at the latest data cut-off.

Disease response was not impacted by level of BCMA expression in the core biopsy, as assessed by immunohistochemistry.

Results indicated that 95% (n = 18) of 19 patients who responded to treatment experienced a very good partial response (VGPR) or better and 42% achieved a complete response (CR) or a stringent CR (sCR).

At a median follow-up of 2.6 months, patients who received the agent at a dose of 3 mg, 6 mg, or 12 mg (n = 24; dosing levels [DL] 1-3) experienced an overall response rate (ORR) of 29.2%; 20.9% of these responders experienced a CR or sCR, while 4.2% had VGPR or better and 4.2% achieved a partial response (PR).

The ORR was higher among those who received REGN5458 at a dose of 24 mg or 48 mg (n = 17; DL 4-5), at 41.2%, with 11.8% of patients collectively experiencing a CR (11.8%)/sCR (5.9%) and 23.5% of patients achieving a VGPR. Patients who received 96 mg (n = 8; DL 6), the highest dose of the antibody evaluated on the trial, experienced the highest ORR, at 62.5%; all of these patients had a VGPR.

Results: As of January 6, 2024, median duration of safety follow-up of the 117 patients with MM enrolled in the 200 mg dosing cohorts was 14.3 months. In the full population of patients treated with 200 mg linvoseltamab, ORR was 70.9%, with 49.6% reaching a complete response or better; median Kaplan-Meier (KM) estimated DOR was 29.4 months (95% confidence interval [CI] 19.2– non-evaluable [NE]); median PFS was not reached (NR; 95% CI 17.3 months–NE) with 70% estimated probability of PFS at 12 months; median OS was 31.4 months (95% CI 21.6–NE) (Bumma et al. JCO 2024). KM estimated median DOR in patients who transitioned to Q4W was NR (95% CI 19.2 months–NE). Efficacy per BMPC level was as follows: in patients with <50% BMPC (n=65), ORR was 78.5% and KM-estimated median DOR, PFS, and OS were NR (95% CI 29.4 months–NE), NR (95% CI NE–NE); and 31.4 months (95% CI 21.6–NE), respectively. In patients who had ≥50% BMPC (n=28), ORR was 50% and KM estimated median DOR, PFS, and OS were 19.2 months (95% CI 11.6–NE), 17.3 months (95% CI 2.5–NE); and NR (95% CI 10.2 months–NE), respectively. Efficacy per refractory status was as follows: in patients with triple-class refractory disease (n=19) ORR was 73.7% and KM-estimated median DOR, PFS, and OS were NR (95% CI 11.6 months–NE), NR (95% CI 7.6 months–NE), and 21.6 months (95% CI 12.2–NE), respectively. In patients with penta-class refractory disease (n=33) ORR was 66.7% and KM-estimated median DOR, PFS, and OS were 29.4 months (95% CI 11.2–NE), NR (95% CI 5.4 months–NE), and 31.4 months (95% CI 10.2–NE), respectively. Efficacy per sBCMA level was as follows: in patients with <400 ng/mL sBCMA (n=59), ORR was 83.1% and KM estimated median DOR, PFS, and OS were all NR with 95% CIs of 19.2 months–NE, 19.8 months–NE, and 21.6 months–NE, respectively. In patients with ≥400 ng/mL sBCMA (n=52) ORR was 55.8% and KM estimated median DOR, PFS, and OS were 29.4 months (95% CI 16.6–NE), 17.3 months (95% CI 3.0–NE), and 31.4 months (95% CI 11.7–NE), respectively.

Safety outcomes in the overall population have been previously reported (Bumma et al. JCO 2024). The most common treatment-emergent adverse event (TEAE) was cytokine release syndrome 46.2% any grade. Other common TEAEs were neutropenia (composite); 42.7% any grade, anemia (composite) 38.5% any grade, diarrhea 37.6% any grade, cough 36.8% any grade, and fatigue 33.3% any grade.

Conclusions: Linvoseltamab 200 mg induced prolonged response and survival in patients with RRMM, including those with difficult to treat refractory disease and high tumor burden (high sBCMA concentration or BMPC percentage), while maintaining a generally manageable safety profile. More mature safety and efficacy data with longer follow-up and including MRD data will be presented at the meeting.

The overall response rate (ORR) was 51% among all enrolled patients (n = 73). Among all responders, 86% achieved a very good partial response (VGPR) or better and 43% achieved a complete response (CR) or better.

All-grade treatment-emergent adverse effects (TEAEs) occurred in 100% of patients (grade 3, 42%; grade 4, 33%).

Hematologic TEAEs occurring in at least 20% of patients included anemia (all grade, 32%; grade 3, 23%), lymphopenia (all grade, 23%; grade 3, 10%; grade 4, 10%), neutropenia (all grade, 23%; grade 3, 7%; grade 4, 15%), and thrombocytopenia (all grade, 21%; grade 3, 8%; grade 4, 5%).

Nonhematologic TEAEs occurring in at least 20% of patients included fatigue (all grade, 45%; grade 3, 3%), CRS (all grade, 38%), pyrexia (all grade, 36%; grade 3, 4%), nausea (all grade, 33%), dyspnea (all grade, 26%), diarrhea (all grade, 25%; grade 3, 3%), back pain (all grade, 25%; grade 3, 5%), vomiting (all grade, 25%), pneumonia (all grade, 23%, grade 3, 11%), chills (all grade, 22%; grade 3, 1%), cough (all grade 22%), and headache (all grade, 21%; grade 3, 3%).

Three patients (4%) experienced grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS); notably, no grade 3 ICANS events were reported.

Five (7%) grade 5 AEs occurred due to sepsis (n = 3), COVID-19 (n = 1), and pneumonia (n = 1); all deaths were determined to be unrelated to study treatment.

Across the study population, 38% of patients developed CRS. Most CRS events were grade 1 (n = 25), and only 3 patients (4%) experienced grade 2 CRS; no grade 3 or greater CRS events occurred.