(OA-23) Circulating Tumor Cells for the Staging of Multiple Myeloma: First Results of a European Pooled Analysis of 2432 Patients with Newly Diagnosed Multiple Myeloma and Plasma Cell Leukemia

Current risk models in multiple myeloma (MM) are prognostic but insufficient for individualized treatment. Circulating tumor cells (CTCs) may offer additional prognostic value, independent of established risk factors such as cytogenetics and tumor burden. Thus, we aimed at defining the clinical significance of CTCs in a large pooled dataset including prospectively collected data from patients from clinical trials and real-world settings.



Methods: We pooled data from 2364 patients with newly diagnosed MM (NDMM) and 68 with primary plasma cell leukemia (pPCL) across five European groups (Czech Republic, Greece, Italy, HOVON, PETHEMA). All patients had CTC enumeration before treatment by flow cytometry (EuroFlow or other methods); 59% were enrolled in clinical trials (GEM-CLARIDEX, CASSIOPEIA, HOVON-143, FORTE, GEM2012MENOS65, EMN12/HOVON-129) whereas the remaining were treated in routine practice. Median age was 63 years (IQR 57–73) and 54% were transplant-eligible. Induction regimens included doublets (2.2%), triplets (88.87%), and quadruplets (9.2%).

Results: Median CTC level was 0.017% (IQR 0.01–0.114%) and was consistent across centers (p=0.2). Logarithmic CTC increments defined five subgroups with distinct median PFS (mPFS): ≤0.001% (77 months), 0.001–0.01% (51 months), 0.01–0.1% (40 months), 0.1–1% (31 months), ≥1% (16 months; p< 0.0001). Patients with NDMM with ≥1% or ≥2 % CTCs had PFS similar to those with pPCL (mPFS 16 vs 15 vs 15 months). As a continuous variable, higher CTCs correlated with inferior PFS (HR 1.17, 95% CI 1.11–1.24, p< 0.001), independent of R-ISS, 1q gain/amplification, induction regimen, and transplant eligibility. Subgroup analyses confirmed prognostic value across all clinically relevant subgroups. After determining an optimal cut-off, various CTC thresholds ranging from 0.01% to 0.1% effectively and consistently dichotomized patients based on their risk of progression in both clinical trials and real-world cohorts, regardless of transplant eligibility. CTC increased ability to stratify patients with established risk factors. For example, those having standard-risk cytogenetics with high CTCs had PFS comparable to patients having high-risk cytogenetics [t(4;14), t(14;16) and/or del17p] with low CTCs (42 vs 36 months, p=0.48). Similar results were obtained when CTC was combined with 1q gain/amplification.

Conclusions: This pooled analysis of prospectively collected data confirms CTCs as an independent prognostic factor in NDMM. Patient stratification according to logarithmic CTC levels offers the most meaningful risk stratification, identifying five subgroups with distinct outcomes, including the identification of NDMM patients having ≥1 or 2% CTCs and survival outcomes similar to those with pPCL. A cut-off in the range of 0.01–0.1% reliably distinguishes patients at different risk of progression and/or death across all clinically relevant subgroups. This study defines CTCs as an essential biomarker for the staging of NDMM patients