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B-cell maturation antigen (BCMA) is selectively expressed as a surface protein on plasma cells and is a validated target for multiple myeloma (MM). A soluble form of BCMA (sBCMA) is elevated in the sera of patients with MM. The bispecific antibodies teclistamab (BCMA×CD3) and talquetamab (G protein-coupled receptor family C group 5 member D [GPRC5D]×CD3) are in clinical development as therapies for MM. Using data from patients with relapsed/refractory MM (N=300) who participated in phase 1 studies of teclistamab (NCT03145181) or talquetamab (NCT03399799), baseline serum sBCMA levels were quantitatively analyzed relative to response to treatment, percentage of bone marrow plasma cells (BMPCs), and cytogenetic risk. By cycle 3 day 1 of treatment, sBCMA levels declined from baseline in 50 (88%) of 57 responders and 49 (98%) of 50 responders to teclistamab and talquetamab, respectively. Depth of response correlated with the magnitude of sBCMA reduction. In contrast, sBCMA increased in 33 (80%) of 41 patients and 24 (49%) of 49 patients who did not respond to teclistamab or talquetamab, respectively. Baseline sBCMA levels correlated with the percentage of BMPC; patients with extramedullary plasmacytomas who had low levels of BMPC (≤10%) tended to have high baseline sBCMA levels (≥400 ng/mL), based on limited data. Baseline sBCMA levels and changes in sBCMA levels at cycle 3 day 1 were similar in patients with high- and standard-risk cytogenetics treated with teclistamab or talquetamab. These results support the use of sBCMA as a potential surrogate marker of tumor burden and treatment response in MM.

Background B-cell maturation antigen (BCMA, CD269), a single transmembrane protein, can be shed as a soluble 6 kilodalton protein fragment (sBCMA) upon cleavage at the transmembrane domain by γ-secretase. Given its selective expression in the B-cell lineage, BCMA is a validated target for multiple myeloma. Teclistamab and talquetamab are CD3 bispecific antibodies developed to recruit CD3+ T cells to BCMA+ or G protein-coupled receptor family C group 5 member D (GPRC5D)+ multiple myeloma (MM) cells, respectively. Levels of sBCMA after teclistamab or talquetamab treatment were evaluated in patients with relapsed and/or refractory MM (RRMM). Methods Serum samples from patients with RRMM in teclistamab and talquetamab phase 1 studies (64007957MMY1001 and 64407564MMY1001, respectively) were collected at various timepoints between baseline and cycle 4 or end of treatment and analyzed for sBCMA by an electrochemiluminescence ligand binding assay. Quantitative analyses of sBCMA data were conducted with reference to a patient’s tumor burden and response, and to pharmacokinetic data. Results Teclistamab and talquetamab modulated levels of sBCMA in patients with high (≥50%) and low ( Conclusions Changes in the levels of sBCMA upon treatment with teclistamab and talquetamab correlated with clinical activity, supporting further clinical development. The findings support BCMA as a potential surrogate marker of myeloma tumor burden and as a valuable marker for response in patients with MM.

Introduction: Daratumumab (DARA)-based regimens are effective and well tolerated in both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients. However, the prognosis for patients who have become refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and DARA is poor. A better understanding of determinants of response and mechanisms of resistance to DARA may lead to new rationally designed treatment strategies. We therefore characterized the effect of DARA on the immune system in MM patients treated with DARA monotherapy in part A of the DARA-ATRA study (ClinicalTrials.gov NCT02751255). Methods: In part A of this prospective multicenter phase 2 trial, 63 DARA-naïve patients were treated with DARA monotherapy (16 mg/kg; approved schedule). Median number of prior lines of treatment was 4 (range 2-11), all patients were previously exposed to lenalidomide and a PI; 89% was refractory to an IMiD, 71% to a PI and 67% to both IMiD and PI. Bone marrow (BM) aspirates obtained at baseline (BL) and at progression (PD; primary refractory, or acquired resistance after prior response) were subjected to deep immune profiling using 28 surface- and intracellular proteins measured by flow cytometry (BL n=51, PD n=47). In a subset of these patients (BL n=39, PD n=33) mass cytometry (CyTOF) was also performed profiling 39 proteins. In addition, peripheral blood (PB) samples obtained at BL (n=44) and PD (n=37) were analyzed using CyTOF. Computational analyses of flow data were performed using UMAP and FlowSOM; CyTOF data were analyzed using SPADE and Freeviz. Statistical analyses included Wilcoxon rank-sum and signed-rank tests, Generalized Linear Mixed Models and ANOVA. Results: A partial response or better was achieved in 41% of patients treated with DARA monotherapy. We compared immune profiles of responding and non-responding (primary-refractory) patients. At BL, the percentages of MM-, T-, B- and NK cells in BM were similar between both groups. However, NK cells of non-responding patients had a lower proportion of CD16 + (P=0.029), and a higher proportion of TIM-3 + (P=0.010) and HLA-DR + (P=0.043) NK cells, suggesting an exhausted phenotype. Non-responders also had a higher proportion of TIM-3 + CD4 + (P=0.022) and TIM-3 + CD8 + T-cells (P=0.004), and a higher proportion of TIM-3 + regulatory T-cells (Tregs) (P=0.042). A higher proportion of TIM-3 + -NK cells, -T-cells, or -Tregs in BM was also associated with poor progression-free and overall survival (PFS; OS). In addition, clinical characteristics associated with poor PFS such as LDH (P=0.016), extramedullary disease (P=0.001) and (R-)ISS stage III (P=0.015) were associated with an increased number of phenotypically exhausted NK- and T-cells. Similar to prior studies, DARA treatment resulted in reduced levels of CD38 on all immune cell subsets and a marked decrease in Tregs, regulatory B cells (Bregs) and NK cells in both BM and PB. Upon acquired resistance, remaining NK cells displayed higher proportions of TIM-3 + (P=0.022), HLA-DR + (P=0.0007) and LAG-3 + (P=0.011), and lower proportions of CD16 + (P=0.002) (Figure 1), compatible with an exhausted phenotype. Furthermore, disease progression was associated with an increase in CD4 + and CD8 + terminally differentiated effector memory T-cells and a decrease in CD4 + and CD8 + central memory T-cells in BM. There was no significant change in the proportion of T-cells expressing immune checkpoint molecules. CyTOF analysis of BM and PB samples confirmed flow cytometric findings. Furthermore, data-driven analysis identified immune profiles specific to progression, including a significant decrease in the fraction of Granzyme B + NK cells, and increase in the fraction of Granzyme B + Bregs at the time of progression. Based on NK cell depletion and -exhaustion observed at PD, we hypothesized that NK cell repletion may restore DARA sensitivity. Indeed, in ex vivo experiments we show that DARA-resistance can be overcome by addition of healthy donor derived NK cells to MM cells obtained from DARA-refractory patients. Conclusion: Here we show that an increased proportion of NK cells with an exhausted phenotype is associated with primary and acquired DARA-resistance, which is in line with the important role of NK cells in DARA-mediated tumor cell elimination ex vivo. Future DARA-based treatment strategies may benefit from reinvigorating NK cells and restoring their cytotoxic capacities. Figure 1 Figure 1. Disclosures Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Minnema: Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; BMS: Consultancy. Broyl: Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy. Krevvata: Janssen: Current Employment. Casneuf: Janssen: Current Employment. Abraham: Janssen: Current Employment. Verona: Janssen: Current Employment. Smets: Janssen: Current Employment. Vanhoof: Janssen: Current Employment. Cortes-Selva: Janssen: Current Employment. van Steenbergen: Biolizard working for Janssen: Current Employment. Vieyra: Janssen: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Mutis: Janssen: Honoraria; Genmab: Research Funding; Takeda: Research Funding; Novartis: Research Funding; ONK Therapeutics: Research Funding. van de Donk: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

8047 Background: B-cell maturation antigen (BCMA, CD269) is a single transmembrane protein that is selectively expressed in the B-cell lineage and is a validated target for multiple myeloma. BCMA exists as both surface protein and as a free soluble form (sBCMA). γ-secretase activity at the transmembrane domain leads to a shed BCMA protein fragment of approximately 6 kilodalton that can exist as free circulating sBCMA in blood. Teclistamab and talquetamab are CD3 bispecific antibodies that have been developed to recruit CD3+ T-cells to BCMA+ or GPRC5D+ multiple myeloma (MM) cells, respectively. The objective of this work was to evaluate sBCMA in relapsed and/or refractory MM patients in response to treatment with teclistamab or talquetamab. Methods: Serum samples from relapsed and/or refractory MM patients in teclistamab and talquetamab phase 1 studies (64007957MMY1001 and 64407564MMY1001) were collected (at various timepoints between baseline and cycle 4 or end of treatment) and analyzed for sBCMA by an electrochemiluminescence ligand binding assay. Soluble BCMA data were quantitatively analyzed in reference to patient’s tumor burden and response, as well as pharmacokinetic data. Results: Teclistamab and talquetamab modulated levels of sBCMA in patients with high ( ≥ 50%) and low ( < 50%) frequency of tumor plasma cells (TPCs), as well as in high and low risk cytogenetic groups. In cycle 3, majority of the responders had reduction in sBCMA [88% (50 out of 57) for teclistamab and 98% (49 out of 50) for talquetamab] compared to baseline. On the contrary, non-responders (progressive disease, stable disease, or minimal response) seemed to show an increase in sBCMA [80% (33 out of 41) for teclistamab and 49% (24 out of 49) for talquetamab] from baseline. Patients with deep responses tend to have higher magnitude of sBCMA reduction compared to others. Based on few patients who responded to teclistamab or talquetamab and then relapsed, sBCMA seemed to have an initial reduction followed by an increase in the levels. Soluble BCMA corelated with % bone marrow TPCs. Majority of patients with plasmacytoma (limited data) seemed to have high sBCMA; suggesting sBCMA could be a comprehensive marker for tumor burden. Teclistamab preliminary population pharmacokinetic analysis showed that sBCMA did not appear to impact teclistamab exposure, suggesting that sBCMA was not acting as a sink for teclistamab. Conclusions: Teclistamab and talquetamab induced changes in levels of sBCMA that correlated with clinical activity, further supporting clinical development of these bispecific antibodies. Lastly, the results support that sBCMA is a potential surrogate marker of myeloma tumor burden, and as a valuable marker for response in MM patients. Clinical trial information: NCT03145181 and NCT03399799.