Clearance of Circulating Multiple Myeloma Cells to Assess Early Response to Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma

Introduction: Bispecific antibodies (BsAbs) targeting BCMA and GPRC5D have shown substantial efficacy in relapsed/refractory multiple myeloma (RRMM) with rapid and deep responses. Currently, two BCMA-targeting BsAbs (teclistamab and elranatamab) and one GPRC5D-targeting BsAb (talquetamab) have regulatory approval for the treatment of patients (pts) with RRMM. Conventional means of assessing response by International Myeloma Working Group criteria in pts receiving BsAbs may not reflect true response kinetics in real-time given the long half-life of monoclonal paraproteins that may persist despite bone marrow clearance of plasma cells. Early biomarkers predicting response and duration of BsAbs treatment are lacking. Circulating multiple myeloma cells (CMMCs) are malignant cells found in peripheral blood, suitable for enrichment, enumeration, and molecular characterization. This study explores CMMC kinetics in relationship to treatment response in RRMM patients receiving standard-of-care (SOC) BsAbs. Methods: This multi-center study evaluated CMMCs in pts receiving SOC BsAbs across two institutions. Peripheral blood samples were collected for CMMC enumeration using the CELLSEARCH platform at baseline, weekly for the first four weeks, and monthly thereafter until disease progression on BsAb-therapy. Blood was collected in CellRescue™ Preservative Tubes, and CMMCs were captured using anti-CD138 antibodies, stained with anti-CD38, anti-CD19/CD45 antibodies, and DAPI. CMMCs were defined as CD138+, CD38+, CD19-, CD45-, and DAPI+. Patient-, disease-, and treatment-related characteristics, including BsAb type and response, were correlated with CMMC kinetics. Results: The study to date included 31 patients with a median age of 70 years (range, 46-85). Among them, 18 (58%) were male, 9 (29%) had high-risk cytogenetics (del 17p, t(4;14), t(14;16)), and 25 (81%) were triple-class refractory. Baseline extramedullary disease (EMD) (soft-tissue only, excluding paramedullary) was present in 9 (29%) patients. The median prior lines of therapy was 5 (range, 3-16), with 18 (58%) having received prior BCMA-targeted therapy. Twenty patients received BCMA BsAb (16 teclistamab, 4 elranatamab) and 11 received talquetamab. Baseline median CMMC count was 145 cells/4 mL (range, 0-40,741). Patients with baseline CMMC <145 (N=15) had a median paraprotein of 0.2 g/dL and 6 (40%) had EMD, while those with CMMC >145 (N=15) had a median paraprotein of 1.83 g/dL and 2 (13%) had EMD. At day +30, 15 of 20 (75%) evaluable patients achieved CMMC level 0, with 11 of 15 (73%) showing clinical response (1 complete response (CR), 4 very good partial response (VGPR), 6 partial response). Among 8 patients with a D+30 response of ≥VGPR, 5 of 8 (63%) had cleared CMMCs by day +7. The overall response rate was 61% in the entire cohort. All patients achieving CR and VGPR as best response had cleared CMMCs by day +30 or at a subsequent time point. Conclusions: CMMC counts through serial peripheral blood sampling can be used to assess disease burden and early kinetics of response to BsAb therapy. Further follow-up and additional cohorts are planned to confirm performance of this assay as a biomarker in predicting response and long-term outcomes in patients receiving BsAb and other therapies, as well as interrogating mechanisms of resistance through targeted sequencing and analysis of tumor-associated antigens of enumerated cells.