Soluble BCMA Dynamics in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Linvoseltamab in Linker-MM1

Introduction Linvoseltamab, a BCMA×CD3 bispecific antibody, induced deep and durable responses with a generally manageable safety profile in patients with heavily pretreated RRMM in the Phase 1/2 LINKER-MM1 study (NCT03761108) (Lentzch S, et al. EHA 2024). Soluble BCMA is a recognized marker for disease burden in MM, with elevated sBCMA correlating with plasma cell burden and potentially predictive of clinical outcome (Kleber M, et al. J Clin Med. 2021; Ghermezi M, et al. Haematologica 2017). Here, we report baseline (BL) and linvoseltamab treatment-induced changes in concentrations of soluble BCMA (sBCMA) in serum of patients with RRMM. Methods Patients in LINKER-MM1 received step-up doses during Weeks 1-2 and full doses from Weeks 2-3 onward, depending upon the cohort. The Phase 1 dose-escalation part comprised 9 dose levels from 3-800 mg, with intravenous linvoseltamab administered weekly (QW) to Week 16 and once every 2 weeks (Q2W) thereafter. The Phase 2 dose-expansion part included 2 dose cohorts (50 mg and 200 mg), with patients receiving linvoseltamab QW through Week 14 (5/25 mg step-up followed by either 50 mg or 200 mg), then Q2W thereafter. In the 200 mg Phase 2 cohort, patients reaching very good partial response or better received linvoseltamab once every 4 weeks (Q4W) after Week 24. Total sBCMA was measured in serum samples (unbound sBCMA and sBCMA bound to linvoseltamab) using a validated enzyme-linked immunosorbent assay. Results Analysis of sBCMA included 281 patients (Phase 1: n=73; Phase 2, 50 mg: n=104; Phase 2, 200 mg: n=104). In LINKER-MM1, median (range) BL sBCMA concentrations were 387 ng/mL (17-10,200) compared with ~30 ng/mL in healthy individuals (Chen H, et al. Leuk Res. 2019). In general, patients with lower BL sBCMA had higher response rates compared with patients with higher BL sBCMA, which is consistent with reported literature (Kleber M, et al. J Clin Med. 2021). Objective response rate (ORR) was higher in the 200 mg dose cohort compared with the 50 mg cohort in both high and low BL sBCMA groups in Phase 2 patients. Post-treatment, total sBCMA initially increased after linvoseltamab dosing, likely reflecting linvoseltamab binding to sBCMA and slower elimination of the drug-ligand complex vs unbound sBCMA; sBCMA concentrations peaked at ~Week 5, then typically declined below BL (to levels similar to those observed in healthy individuals), likely reflecting decreased production of sBCMA consistent with reduced disease burden due to the effect of linvoseltamab treatment. This is also reflected by post-treatment reductions in concentrations of serum free light chain in the same patients. In the 50 mg and 200 mg Phase 2 cohorts, respectively, median (range) sBCMA (ng/mL) was 370 (26.1-10,200) and 363 (18.7-4430) at BL, 1150 (13.5-5950) and 1260 (18-15,500) at Week 5, 473 (7.6-5240) and 440 (5.1-18,100) at Week 8, declined below BL in both cohorts to 74 (2.9-2800) and 103 (2-10,200) at Week 12, and was 10 (0-820) and 13 (2-943) at Week 24. Further evaluation in the 50 mg and 200 mg cohorts between responders (≥ partial response) and non-responders (stable disease or progressive disease) at Week 12 showed that the median nadir of sBCMA (compared with BL) was lower in responders vs non-responders in both dose groups. Median sBCMA concentrations remained low in patients who transitioned from Q2W to Q4W dosing, indicating continued disease control. Conclusions Consistent with earlier findings (Boyapati A, et al. IMS 2023), linvoseltamab treatment resulted in a high ORR across BL sBCMA concentrations, with greater response rates in patients with lower sBCMA concentrations and with the 200 mg dose. sBCMA concentrations rapidly decreased upon linvoseltamab treatment and normalized as patients achieved a deeper response, consistent with sBCMA being a marker of disease burden in MM, with greater reductions observed in responders vs non-responders.