Quantification of circulating plasma cells at diagnosis can identify functional high risk multiple myeloma patients

Abstract Background: Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. About 20% of patients can be defined as functional high-risk (FHR), because of relapse within 18 months from the first line of therapy or 12 months from autologous stem cell transplantation, regardless high-risk features at diagnosis. Currently, quantification of circulating plasma cells (CPCs) is considered high-risk feature but with limited application in real-life setting. Methods: CPCs were measured in peripheral blood (PB) of 164 patients affected by newly-diagnosed MGUS (N=42), smoldering (N=31) and active MM (N=91) in real life setting. Analyses were carried out following the recently developed NGF methodology by using tube with 8-color antibody panels for monoclonal plasma cells identification :CD27, CD138, CD38, CD56, CD45, CD19, CD200, (with a median limit of detection of 0.001%). Results: CPCs were detected in 83% (35 of 42) of MGUS, 87% (27 of 31) of SMM and 100% of patients with newly diagnosed MM. We found a progressive increase from MGUS through SMM and MM, with the following median percentage and range respectively: 0.008 (0.0003-0.045), 0.01 (0.001-0.13), 0.02 (0.004-6.00), p<0.0001. No correlation was found with bone marrow plasmacells (r=0.26, p=0.06). While CD200+ CPCs were virtually absent in MGUS and SMM patients, the median percentage and range in MM was 0.005 (0-3.2). 32/91 (35%) MM patients relapsed after first line of treatment after a median follow up of 30 months, including 19 (21%) FHR patients and 3 primary refractory patients. Patients carrying a baseline CPCs count < 0.02% had a median progression free survival longer than those with more than 0.02% (respectively 28.6 vs 12.6 months, p<0.001). Median percentage of CPCs were significantly higher in FHR and not responder than in those MM patients who achieved and maintained a clinical response, respectively: 0.04 (0.008-1.6) vs 0.03 (0.007-6) vs 0.02 (0.004-1.6), p<0.001. A cutoff of 0.02% CPCs showed an independent prognostic value (HR: 2.02; 95% CI, 1.3 to 3.1; p<0.001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. While CD200 was virtually absent in MGUS and SMM, a cut-off of 0.01% of CD200+ CPCs was able to identify at baseline FHR patients (c=0.77, p=0.01). Conclusion: Evaluation of CPCs in PB improved risk stratification in newly diagnosed MM patients. In this real-life setting the detection of ≥ 0.02% CPCs (or 0.01% of CD200+CPCs) can identify at diagnosis patients with increased probability of being functional high-risk disease