Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)

Abstract

Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.

Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy

“…In contrast, CTPC might not only reflect tumor load but, particularly, the ability of persisting tumor cells to disseminate the disease and support tumor growth and progression at (multiple) distant sites in BM and other tissues, as previously suggested 16 based on their more immature and prominent stem cell-like PC features compared with (paired) BM-derived tumor-plasma cells (TPC). 3 Despite all of this, every CTPC 1 case in our cohort was BM MRD 1 , suggesting that the presence of blood CTPC after therapy might be a surrogate marker of persistent BM MRD in guiding (eg, avoiding) subsequent (more invasive) BM aspiration procedures, particularly among sCR/CR patients. In contrast, a significant fraction of our CTPC 2 cases were BM MRD 1 and/or sIF 1 , supporting the notion that MM is a BM disease with greater levels of infiltration by (usually) functional PC in BM vs PB.…”

“…Recent large-scale genome-sequencing studies using bone marrow samples have demonstrated that most cases of MDS and other related neoplasms, such as acute myeloid leukemia and myelodysplastic/myeloproliferative neoplasm overlap syndromes, harbor pathogenic somatic mutations in diverse myeloid cancer driver genes. [2][3][4][5][6] Moreover, some or all of these mutations can be detected in PB granulocytes in most patients with MDS and related neoplasms (Phillip D. Michaels, Dahai Wang, A.S.K., manuscript in preparation). 7,8 Despite these advances and the widespread use of NGS testing, there are limited data on the clinical use of NGS testing in the early evaluation of patients with cytopenia(s).…”

“…1,2 This is mainly because of (1) the minimally invasive nature of blood vs bone marrow (BM) analyses, (2) the possibility for more precise quantification of absolute numbers of CTPC than BM minimal residual disease (MRD) resulting from absence of potential hemodilution, and (3) the (nonlinear) correlation observed between CTPC numbers and BM disease burden at diagnosis. 1,3 Recently, we have shown by high-sensitivity next-generation flow (NGF) that CTPC are systematically present in blood of MM at diagnosis, with an adverse prognostic impact for higher counts. 3 These results highlight the relevance of greater levels of disease dissemination via blood in conferring a malignant behavior to MM, suggesting the presence of blood CTPC might be required for subsequent disease progression of treated MM patients.…”

“…1,3 Recently, we have shown by high-sensitivity next-generation flow (NGF) that CTPC are systematically present in blood of MM at diagnosis, with an adverse prognostic impact for higher counts. 3 These results highlight the relevance of greater levels of disease dissemination via blood in conferring a malignant behavior to MM, suggesting the presence of blood CTPC might be required for subsequent disease progression of treated MM patients.…”

Enhancing the R‐ISS classification of newly diagnosed multiple myeloma by quantifying circulating clonal plasma cells

“…The prognostic significance of cPCs when measured by MFC has been well established across the spectrum of plasma cell disorders, such as MGUS, smoldering myeloma, MM and AL amyloidosis, at the time of diagnosis. It has also been established as a prognostic marker in MM patients undergoing ASCT by predicting for early relapse .…”