Abstract
Simple SummaryB-cell regeneration during therapy has been associated with the outcome of multiple myeloma (MM) patients. However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated. Here, we show that hemodilution is present in a significant fraction of MM BM samples, leading to lower total B-cell, B-cell precursor (BCP), and normal plasma cell (nPC) counts. Among MM BM samples, decreased percentages (vs. healthy donors) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP, but not TBC/NBC, increased after induction therapy. At day+100 post-autolo-gous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens with no clear association between BM B-cell regeneration profiles and patient outcomes.B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome.
Highlights
Multiple myeloma (MM) is a hematopoietic malignancy characterized by an expansion and accumulation of clonal plasma cells in bone marrow (BM) and other tissues [1,2]
Here we focused on the relative distribution of the distinct B-cell populations in whole BM, where B-cell numbers might be influenced by the recovery of other cell populations, including the erythroid and myeloid precursors; in addition, it is important in this study that very limited numbers of paired BM samples from the same patients were analysed at diagnosis and follow-up, while in others potentially hemodiluted samples have been excluded from analysis
Interphase fluorescence in situ hybridization (i-FISH) studies were performed at diagnosis in 103/162 for detection of Ig heavy chain (IGH) gene rearrangements/translocations— t(4;14), t(14;16), t(14,20)—and for del(17/17p). iFISH studies were systematically performed on fluorescence-activated cell sorting (FACS)—purified clonal plasma cells (cPC) (FACS Aria, BD Biosciences)
Summary
Multiple myeloma (MM) is a hematopoietic malignancy characterized by an expansion and accumulation of (malignant) clonal plasma cells (cPC) in bone marrow (BM) and other tissues [1,2]. Conventional and novel treatment protocols for MM typically comprise sequential pulses of multiple drugs aimed at achieving and maintaining the highest quality of response [18] Such strategies might result in a cumulative immunosuppressive effect with an increased risk for (more pronounced) immunodeficiency and its related clinical complications [19,20,21]. Optimal B-cell and immune recovery might potentially contribute to both mitigate the clinical complications of immunoparesis and help eradicate residual tumor cells via Cancers 2021, 13, 1704 antibody mediated mechanisms and parallel T cell responses [26,27,28] In this regard, previous studies have shown that persistence of normal residual (n)PC in BM of MM at diagnosis [12] and after therapy is a strong favorable prognostic factor for patient outcome [17,22,29]. We investigated the B-cell regeneration profile in 177 BM samples from 162 MM patients treated with high-dose therapy followed by ASCT at different time points during follow-up and explored its potential association with response to therapy, the BM MRD status and patient outcome
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