Monoclonal and polyclonal circulating plasma cells (CPCs) are linked to disease spread in multiple myeloma

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Abstract Multiple myeloma (MM) is a hematological malignancy characterized by clonal expansion of plasma cells (PC) in the bone marrow (BM), with occasional presence in peripheral blood (PB) as circulating plasma cells (CPCs). Over the past decade, patient (pt) outcomes in MM have significantly improved due to the advent of novel treatment strategies. However, the majority of pts still experience relapse. This may be associated to the ability of BM-resident PCs to escape the BM niche, leading to the emergence of CPCs clones that may drive extramedullary involvement and systemic disease dissemination. The aim of this study was to explore the correlation between CPCs and tumor dissemination, assessed by imaging characteristics using diffusion-weighted magnetic resonance imaging (DWI) and 18F-FDG/PET (PET). Additionally, the study focused on highlighting potential differences between pts presenting with aberrant monoclonal CPCs (mCPCs) and those with polyclonal CPCs (pCPCs). A total of 140 newly diagnosed (ND) MM pts were enrolled in the study. For each pt, BM aspirates and PB samples were collected and analysed at diagnosis. In addition, DWI and PET data, and baseline clinical data including the BM-PCs genomic profiles, were acquired. Multiparametric flow cytometry was used to count and characterize CPCs, with a sensitivity of at least 10-5. pCPCs were defined as PCs with a cytoplasmatic Igκ/Igʎ ratio between 0.5 and 4. CPCs were detected and characterized in 112 of 140 NDMM pts (80%), with a median frequency of 0.02% (range 0.002-17.84%). No CPCs were found in the remaining 28 pts (20%). Among the 112 pts with detectable CPCs, 83 (74%) had aberrant mCPCs with a median frequency of 0.025% (range 0.002-17.84%), while 29 pts (26%) had pCPCs with a median frequency of 0.018% (range 0.002-0.34%). Pts with detectable CPCs at diagnosis exhibited a higher genomic risk profile compared to those without CPCs, according to the new IMWG Consensus Genomic Staging (CGS) (p=0.044), and showed more unfavorable biochemical parameters, including lower hemoglobin, elevated serum calcium, reduced albumin and increased beta-2 microglobulin levels (p<0.004), suggesting that the mere presence of CPCs – whether monoclonal or polyclonal – is associated with a poorer disease profile. Moreover, pts with detectable CPCs showed a worse imaging profile: the presence of CPCs was significantly associated with diffuse BM uptake by PET (p=0.028), positive DWI (diffuse disease and/or focal lesions, p=0.01), increased occurrence of osteolytic lesions (p=0.013), and higher PET standardized uptake values (p=0.043). Specifically, pts with CPCs at diagnosis had a higher number of DWI focal lesions (4 to 10, p<0.001; >10, p=0.004), with notable involvement of the extremities (p<0.001). These findings were further supported by PET imaging, which showed focal lesions in the extremities (p=0.014). When comparing pts with mCPCs to those with pCPCs, clinical and biochemical parameters (p<0.037), DWI signals (focal lesions, p=0.027), FDG uptake (p=0.041) and high-risk CGS (p=0.032) were all significantly worse in the mCPCs group, confirming the more aggressive disease profile associated with mCPCs. Focusing on the characterization of mCPCs in 83 pts, those with higher mCPCs levels (>0.02%) had significantly higher genomic CGS risk (p=0.026), positive PET disease (p=0.025), and greater incidence of focal lesions in the extremities by DWI (p<0.0001). Additionally, lack of CD56 expression on mCPCs was significantly associated with this higher-risk group (p=0.022). Notably, the presence of pCPCs was also associated with worse clinical features compared to pts without detectable CPCs at diagnosis, as reflected by positive PET and DWI signals (p=0.035). Finally, despite the limitations of a short follow-up, the presence of CPCs, both mCPCs and pCPCs, appears to be associated with higher risk of relapse (p=0.057). To date, 23 pts have relapsed: 16 out of 83 (19%) mCPCs pts, 5 out of 29 (17%) pCPCs pts, and 2 out of 28 (7%) pts without detectable CPCs. In conclusion, the presence of CPCs significantly correlates with more widespread disease and increased skeletal involvement, suggesting the role of these cells in driving dissemination and progression in MM. Interestingly, even the presence of polyclonal CPCs was associated with a worse clinical profile compared to pts without detectable CPCs at diagnosis. Acknowledgments: AIRC19-IG22059, BolognaAIL OdV and RC2025-2797269

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