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

Abstract

Our prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R-ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009 to 2017. Those patients that had ≥5 cPCs/μL and either R-ISS stage I or stage II disease were re-classified as R-ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥5 cPCs/μL at diagnosis was as follows: R-ISS I (N = 110) -40 months and not reached; R-ISS II (N = 69) -30 and 72 months; R-ISS IIB (N = 96) -21 and 45 months and R-ISS III (N = 281) -20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R-ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.

Detection of Circulating Tumor Plasma Cells in Monoclonal Gammopathies: Methods, Pathogenic Role, and Clinical Implications

“…During recent decades, different methods have been developed and used for the detection of CTPC (Graphical abstract [ 19 , 21 , 22 , 23 , 30 , 35 ] and Figure 2 ). Conventional cytology was first used (in combination with complete blood counts obtained in an automated hematology analyzer) for the identification of circulating PC in blood smears of patients diagnosed with monoclonal gammopathy.…”

“…The latter technique allowed for (more specific) assessment of greater numbers of clonal PC in the blood of MM and MGUS patients based on restricted light chain expression by tumor PC [ 19 , 23 ]. In order to further increase the sensitivity and specificity of the above techniques, several different conventional flow cytometry [ 20 , 22 , 31 ] and next generation flow cytometry (NGF) procedures [ 21 , 35 ], together with polymerase chain reaction (PCR)-based, e.g., allele-specific oligonucleotide (ASO) quantitative PCR (qPCR) [ 19 , 113 ] and next generation sequencing (NGS) [ 114 ] techniques, were subsequently developed and tested. In addition to differences in the sensitivity reported for the above flow vs. molecular techniques, the results obtained so far are also influenced by the type of material analyzed (e.g., inclusion of nucleic acid from non-viable cells in molecular techniques) and/or the way patients were selected for analysis (e.g., inclusion of patients that reached no response or partial response together with complete response cases).…”

“…Flow cytometry has long been recognized as a well-suited methodology for the enumeration of CTPC in blood of plasma cell neoplasms patients [ 20 , 22 , 122 ]. This technique is an easy, fast (<4 h), affordable and worldwide available approach which has been extensively used to identify, characterize and count CTPC in the blood of patients with plasma cell neoplasms.…”

“…However, the lack of standardized protocols (i.e., very heterogeneous antibody panels have been used and variable numbers of cells analyzed per sample), the highly variable sensitivity levels reached for detection of CTPC (which translate into variable frequencies of CTPC-positive patients), together with the need for fresh (<24–48 h) samples, have limited the reproducibility of results, and thereby, its broader use and applicability ( Table 2 ). Despite these limitations, flow cytometry has shown that the presence and number of CTPC in blood (both at diagnosis and after therapy) has important clinical implications in MM, and to a lesser extent, also in MGUS, and SMM patients [ 20 , 22 , 124 ].…”

“…Circulating tumor plasma cells (CTPC) have long been detected in the blood of PCL patients [ 16 , 17 , 18 ], as well as in a significant fraction of MM [ 19 , 20 , 21 , 22 ], and to a lesser extent in MGUS cases [ 21 , 23 ]. From a clinical point of view, the presence and number of CTPC has been proven to have both diagnostic and prognostic implications in MGUS [ 21 , 23 ], SMM [ 24 , 25 , 26 ] and in symptomatic MM [ 20 , 21 , 27 , 28 , 29 , 30 , 31 ] patients.…”