B06 HIGH LEVELS OF CIRCULATING PLASMA CELLS AT DIAGNOSIS ARE PREDICTIVE FOR WORSE PROGNOSIS IN BOTH TRANSPLANT-ELIGIBLE AND -INELIGIBLE PATIENTS WITH MULTIPLE MYELOMA

The presence of circulating tumor cells (CTCs) has long been suggested as a valuable prognostic biomarker in Multiple Myeloma (MM). Quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains challenging because of their low frequency in PB. However, evaluation of PCs in peripheral blood (PB) may outperform quantification of BM PCs. Early studies using standard flow cytometry showed that elevated numbers of CTCs predicted inferior survival. The detection of ≥0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM. The aim of the study was to define the clinical significance of CTCs and optimal cutoffs using NGF cytometry, in a large series of patients with newly diagnosed MM in a single center. At diagnosis, assessment of CTCs in PB and in BM aspirates collected in EDTA was performed using the EuroFlow NGF methodology for surface membrane and cytoplasmic staining after bulk lysis. Overall, 525 patients with newly diagnosed MM were included in this study (patients with primary plasma cell leukemia were excluded). Out of these patients, 193 were transplant eligible (36.7%) and 332 were transplant ineligible (63.2%). The median follow-up for all the pts was 42 months (range:3-66 months). CTCs were detected in 468/525 samples (89.1%) and the median CTC value was 0.014%. CTCs did not correlate with the type of response to induction therapy, but their levels were associated CTCs≥2x10-4 at baseline were associated with reduced median PFS (39 vs 60 months). Transplant eligible patients with CTCs≥2x10-4 had inferior PFS compared to patients with CTCs<2x10-4 (p=0.01). Transplant-ineligible patients with CTCs≥2x10-4 had a worse PFS compared to those with CTCs<2x10-4 (median PFS= 47 vs 23 months, p<0.001). Moreover, high CTCs levels ≥2x10-4 may identify patients with adverse prognosis within each ISS stage (median PFS 60 months vs not reached for ISS 1 p=0.1, p=0.01 for ISS 2, 39 months vs 17 months for ISS 3, p=0.04). Our large number of matched samples allowed for a phenotypic comparison between BM clonal cells and CTCs. The majority of patients with detectable CTCs (86%) showed a matched phenotypic profile of aberrant plasma cell in the two sites. However, 66 patients showed phenotypic discrepancies based on one of the following patterns: i) all phenotypic subsets were present in both BM and PB but with significantly altered ratios (≥20% of relative prevalence) for at least two concomitant subsets; ii) presence of ≥ 1 phenotypic subsets (with a minimum relative prevalence of 20% of all clonal cells) only in the BM; and iii) presence of ≥1 phenotypic subsets only in the PB. Remarkably, patients with phenotypic discrepancies had significantly higher CTC levels than those with a phenotypic agreement on the two sites (P<0.001), together with signs of a more diffuse disease pattern on imaging. The detection of CTCs is possible in 90% of NDMM patients; CTCs levels equal to or more than 0.02% is an adverse prognostic factor in patients who are treated outside of clinical trials, irrespective of their transplant status. Since the liquid biopsy is a better representative of the entire tumor load than a tissue biopsy sample, the analysis of CTCs may serve as the new hallmark for the real-time evaluation of a patient’s disease and immune status.