P-222: Analysis of Normal Plasma Cell Distribution Across Distinct Age Cohorts Reveals Age Dependent Changes

Introduction: Plasma cells (PCs) are terminally differentiated cells that secrete large amounts of immunoglobulin (Ig). Following their generation, many PCs enter the bone marrow (BM), which provides unique niches that promote the longevity of PCs. The BM also plays a key role in the clonal PC malignancy, multiple myeloma, as well as its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). MGUS is an asymptomatic condition characterized by a clonal population of abnormal PCs that reside in the BM and has a 1% risk of progression to MM per year. The incidence of MGUS increases with age, which has important implications for MGUS pathogenesis. To begin to understand if aging results in a more permissive BM microenvironment that may predispose to the development of MGUS, we investigated if the number and spatial distribution of human BMPCs change as a function of age in healthy individuals.

Methods: Bone marrow core biopsies (BMCBs) selected for analysis in this study were determined by hematopathologists to have normocellular bone marrow, normal trilineage hematopoiesis, and no morphologic features of metastatic malignant cells. Ten BMCBs were analyzed for each of the following age ranges: 5 months-9 years; 10-19 years; 20-39 years; 40-59 years; 60-79 years; and 80-99 years. Multi-color immunofluorescence was performed to determine number and spatial localization of kappa and lambda Ig light chain expressing PCs. We also assessed expression of Ig heavy chain, TNFSF13, CXCL12, and CD271 expression in a subset of BMCBs.

Results: Quantification of PCs and clustering in BM sections across six different age groups revealed that fewer PCs and PC clusters were observed in the youngest and oldest age groups. PC clustering increased with age until the sixth decade and then began to decrease. A positive correlation between the number of PCs and PC clusters was observed across all age groups. Although our examination was limited, PC clusters were typically found to be comprised of both kappa and lambda LC-expressing cells with various combinations of heavy chain isotypes. Thus, PC clustering did not tend to involve local in situ clonal PCs in any of the age groups tested and suggests that clustering results instead from the ability of several PCs to contact supportive stromal cells that may secrete factors that promote PC survival and retention in the BM. In this regard, we observed that both single PCs and PC clusters were typically located adjacent to a CD271+ cell, a cell type that is known to also express CXCL12.

Conclusions: The current findings suggest that PCs can arrange in clusters within the BM at any age and that PC clustering is positively correlated with the number of BMPCs. PC clustering increased with age but then diminished in older adults. Further studies to understand the mechanisms responsible for PC clustering in normal BM are warranted. Studies of this nature are needed to better understand the role of the BM microenvironment in MGUS progression.