Liquid MRD Detection Using Circulating Myeloma Cells Accurately Reflects Bone Marrow Disease Status Post–CAR T and ASCT

Depth of response measured by minimal residual disease (MRD) is a critical prognostic factor in multiple myeloma (MM) and is increasingly used as a surrogate endpoint in both transplant and cellular therapy trials. Bone marrow (BM) MRD assessment using next-generation sequencing (NGS, ClonoSEQ) remains the gold standard but is limited by the invasiveness of sampling, spatial heterogeneity of disease, and the infrequency of testing—typically once per year—which can delay recognition of relapse. Circulating multiple myeloma cells (CMMCs), defined as CD138⁺CD38⁺CD19⁻CD45⁻ malignant plasma cells detectable in peripheral blood, have emerged as a minimally invasive biomarker reflecting systemic tumor burden. Data from bispecific antibody studies suggest CMMCs clear rapidly in deep responders and reappear at relapse, but their relationship to BM MRD in patients treated with CAR T-cell therapy or autologous stem cell transplant (ASCT) has not been systematically evaluated. We prospectively studied 51 MM patients undergoing CAR T-cell therapy or ASCT at Roswell Park. Paired peripheral blood and BM aspirates were collected for MRD testing. BM MRD was quantified using ClonoSEQ with a sensitivity of 10⁻⁶. Peripheral blood (4 mL) was processed using the CELLSEARCH® platform following anti-CD138 ferrofluid enrichment and fluorescent staining (CD38-PE, CD19/CD45-APC, DAPI). CMMC positivity was defined as >2 cells/4 mL. Sensitivity, specificity, and concordance between CMMC and BM MRD were calculated, and Spearman correlation assessed quantitative relationships between CMMC counts and BM MRD burden. The median patient age was 66 years (range 45–77), and 39% harbored high-risk cytogenetic abnormalities. Most patients (65%) were receiving daratumumab-based triplet or quadruplet regimens, and over half (53%) were in VGPR or better at sampling. CMMCs were detected in 28 of 51 patients (54.9%); among these, 25 were also MRD⁺ in the BM. CMMC detection achieved 89.3% sensitivity, 91.3% specificity, and 90.2% overall concordance with BM MRD (Cohen's κ = 0.79). CMMC counts correlated strongly with quantitative MRD levels (ρ = 0.72, p < 0.001). Performance was comparable between CAR T (88.2%) and ASCT (90.9%) subgroups, supporting assay robustness across therapeutic contexts. Enumeration of circulating myeloma cells using CELLSEARCH provides an accurate and reproducible liquid correlate of bone marrow MRD in patients receiving CAR T-cell therapy or ASCT. This minimally invasive approach may enable more frequent, real-time disease monitoring, facilitate early detection of MRD conversion, and inform risk-adapted strategies to optimize outcomes in the era of high-efficacy cellular therapies.