Molecular Subtypes of Plasma Cell Neoplasms with Circulating Neoplastic Plasma Cells

Background:

Circulating neoplastic plasma cells (CNPCs) are frequently seen in plasma cell neoplasms (PCN). Prior studies have shown that CNPCs are usually associated with a higher tumor burden and disease progression. Additionally the percentage of CNPCs in newly diagnosed PCN as quantified by flow cytometric analysis is found to be an independent predictor of survival.

The UAMS myeloma group has established a molecular classification of PCNs based on unsupervised hierarchical clustering of gene expression profiling (GEP) data, and has identified 7 subgroups: Hyperdiploidy (HY), Cyclin D-1 (CD-1), CD-2, Low Bone (LB), Proliferation (PR), MMSET/FGFR3 (MS) and MAF (MF). This molecular subtyping in conjunction with the UAMS GEP 70 gene signature profile has been found to be clinically useful in identifying low risk group with superior event-free and overall survival from high-risk group.

The purpose of this study was to determine if a particular PCN molecular subtype was more likely to be associated with CNPCs. To the best of our knowledge, the association between the different molecular subtypes and CNPCs has not been studied before.

Design:

A retrospective review was performed to determine the number of PCN patients with CNPCs during 2015-2016. Peripheral blood immunophenotyping was performed using 8-color multi-parameter flow cytometry analysis. PCN molecular subtypes and GEP risk stratification was performed on CD138-enriched plasma cells from bone marrow aspirate based on our previously established protocol. Additional data including clinical classification, bone marrow plasma cell tumor burden and karyotype analysis were also collected.

Results:

A total of 305 patient had peripheral blood flow cytometric analysis performed during the study period; 147 patients showed presence of CNPCs (48.19%). Only 120 of the 147 cases with CNPCs had all the additional data and were included for further analysis.

Based on UAMS GEP 70 signature risk score, 86 patients (71.7%) showed low risk gene classification compared to 34 patients (28.3%) with high risk gene classification. Distribution of molecular subgroups defined by GEP data, identified that the HY group was the largest subgroup (n=29, 24.2%), followed by CD-2 (n= 24, 20%), PR (n=19, 15.8%), MF (n=15, 12.5%), MS (n=12, 10%), CD-1 (n=12, 10%) and LB (n=9, 7.5%). However, further analysis of low risk group patients identified equal distribution of HY (n=24) and CD-2 (n=23) subgroups. Further analysis of molecular subgroups based on bone marrow tumor burden is listed in Table 1.

Based on the international myeloma working group diagnostic criteria, most patients had multiple myeloma (MM) (n=112, 93.3%); smoldering myeloma (n=5, 4.2%) and MGUS (n=3, 2.5%) was less common. Of the MM group, two patients met the criteria for plasma cell leukemia and showed extensive bone marrow involvement. Bone marrow involvement in a cases ranged from <5% to 95% plasma cells; with most patients (72.5%) showing <60% cellularity replacement by plasma cells. Cytogenetic analysis revealed abnormal/complex karyotype in the majority of the patients (n=89, 73%) compared to normal karyotype (n=31, 26%).

Conclusions:

Our study indicates that CNPCs occurs more frequently in patients with low risk multiple myeloma based on UAMS GEP 70 signature classification especially CD-2 and Hyperdipoidy (HY) subtypes. This correlation is best observed in cases with <60% bone marrow tumor burden. These patients are also more likely to have abnormal/complex karyotype. Further long-term studies should be performed to determine the prognostic significance of these findings.

View largeDownload slide

View largeDownload slide

Close modal