B‐lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B‐cell progenitors and plasma cell precursors

Abstract

Summary. The reduced levels of normal immunoglobulin in patients with myeloma may be due to suppression of normal B-cell differentiation. However, reports on the numbers of B cells vary, with some finding decreases consistent with immunoparesis, and others reporting expansions of phenotypically aberrant cells. We have therefore assessed the phenotype and levels of B lymphocytes in patients at presentation (n ¼ 23), in plateau or complete remission (PB n ¼ 42, BM n ¼ 18), and in relapse (PB n ¼ 17, BM n ¼ 14), in comparison to normal individuals (n ¼ 10). Phenotypic analysis was performed using five-parameter flow cytometry, with CD14 used to exclude monocytes where necessary.We found no evidence of a phenotypically distinctive blood or marrow B-cell population in patients with myeloma, nor of an increase in the levels of any B-cell subset. Numbers of blood CD19 þ 38 þ normal plasma cell precursors were significantly reduced in presentation/relapse patients, but not in patients in plateau/remission. Total CD19 þ cells were significantly reduced only in patients with circulating myeloma cells, detected by IgH-PCR. In the marrow, CD19þ B cells expressing CD5, CD10, CD34, CD38, CD45 low and Syndecan-1 were significantly decreased at presentation/relapse, but not in patients in plateau/remission. The majority of these antigens are expressed by normal B-cell progenitors, indicating that myeloma also affects the early stages of B-cell development. The suppression of progenitor cells was not restricted to B-lymphoid differentiation, as total CD34 þ cells were also significantly reduced in the marrow of myeloma patients at presentation.These results indicate that, if neoplastic B cells are present in myeloma, they are low in number and have a phenotype similar to their normal counterparts. Furthermore, there is a reversible suppression of CD19 þ B lymphocytes that correlates inversely with disease stage, and specifically affects the early and late stages of normal B-cell differentiation.

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

“…Signs of severe immunosuppression, such as impairment of polyclonal B‐cell progenitors and plasma cell precursors 1 and suppression of uninvolved polyclonal immunoglobulins of a different isotype to the tumor monoclonal protein are frequently observed in patients with multiple myeloma and have been associated with adverse prognosis 2 while preserved polyclonal B cell proliferation and immunoglobulin synthesis usually is associated with favorable prognosis 3. The recently developed HLC assay allows the measurement of both pairs of a specific isotype, e.g., quantification of IgAλ and of IgAκ in a patient with IgAλ monoclonal gammopathy 4, 5.…”

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

“…[7][8][9][10] Accordingly, B-cell precursors and normal plasma cells are compromised, and immune paresis is also a consistent finding in newly-diagnosed MM patients. 11 In turn, effector cells such…”

“…immune paresis), with compromised production and BM homing of normal plasma cells, is a hallmark of symptomatic MM. 11,[34][35][36] In LTDC-MM, we observed a replenishment of early B-cell subsets in the BM (B-cell precursors), translating into increased numbers of circulating immature and naïve B-cells in PB, and a recovery of end-stage normal plasma cells in the BM. Recovery of B-cell production in the BM could be related to decreased competition between clonal plasma cells and normal plasma cells (as well as B-cell precursors), for a limited number of SDF-1-associated BM niches.…”

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…A decrease in CD19 + B cells has also been reported in MM patients [18,38,39] and B-cell levels were inversely correlated with disease stage [39]. Indeed, humoral immune deficiency with reduced levels of polyclonal immunoglobulins is a well-known phenomenon in myeloma [10,18] and is caused by both a decreased number of B cells, and by functional defects in B cells in MM, such as a reduced ability to secrete immunoglobulins and to differentiate into antibody-secreting plasma cells [38] and a reduced up-regulation of CD80 costimulatory receptor expression in response to stimulation [40].…”