Residual malignant and normal plasma cells shortly after high dose melphalan and stem cell transplantation. Highlight of a putative therapeutic window in Multiple Myeloma?

Abstract

Multiple Myeloma (MM) is an incurable malignant plasma cell disorder. We have evaluated the counts of Multiple Myeloma Cells (MMCs) and normal plasma cells (N-PCs), seven days after high-dose melphalan (HDM) and autologous stem transplantation (ASCT). Two third of patients had detectable minimal residual disease (MRD+) (71.7 MMCs/μL) after induction treatment with dexamethasone and proteasome inhibitor. MMC counts were reduced by 92% (P ≤ .05) but not eradicated 7 days after HDM+ASCT. Post-HDM+ASCT MMCs were viable and bathed in a burst of MMC growth factors, linked with post-HDM aplasia. In one third of patients (MRD− patients), MMCs were not detectable after induction treatment and remained undetectable after HDM+ASCT. Major difference between MRD− and MRD+ patients is that N-PC counts were increased 3 fold (P < .05) by HDM+ASCT in MRD− patients, but were unaffected in MRD+ patients. Possible explanation could be that clearance of MMCs in MRD− patients makes more niches available for N-PCs. Thus, MMCs are not fully eradicated shortly after HDM, are bathed in high concentrations of MMC growth factors in an almost desert BM, are viable in short-term culture, which suggests providing additional therapies shortly after HDM to kill resistant MMCs before full repair of lesions.

DNA repair pathways in human multiple myeloma

“…In these patients, only few MMCs (5.5 MMCs/μL after 7 days) may survive in an almost empty bone marrow 9 days after melphalan treatment. 151 These few resistant MMCs likely harbor melphalan monoadducts or crosslinks, which have to be repaired to get MMC survival and tumor regrowth. Targeting DNA repair pathways with specific drugs could help killing MMCs, preventing or delaying relapse.…”

Automated and simplified identification of normal and abnormal plasma cells in Multiple Myeloma by flow cytometry

“…With the smart antibody panel, abnormal PCs were selected based on the positive and negative antibody pool signals ( Fig. 1I) (13).…”

“…We then compared our smart antibody panel with the 7-color panel routinely used for monitoring patients with MM at Montpellier University Hospital Center (France) (13). We then compared our smart antibody panel with the 7-color panel routinely used for monitoring patients with MM at Montpellier University Hospital Center (France) (13).…”

“…To improve MM diagnosis and MRD assessment, we have designed a simple 5-color antibody panel (smart antibody panel, thereafter) in a single tube and the software that allows the automatic PC detection from the flow cytometry analysis result files. We then compared our smart antibody panel with the 7-color panel routinely used for monitoring patients with MM at Montpellier University Hospital Center (France) (13). Finally, we correlated the results obtained with our new automated PC detection method with those obtained by manual detection using the FlowJo software in two different cohorts of patients with MM.…”

Targeted Therapies in Adult B-Cell Malignancies

“…Conversely, plasma cells also share CD19 and other surface markers such as CD38, CD138, CS-1, CD200, CD56, CD45, and other different markers [ 10 ] ( Figure 1 ). In addition, all markers are currently used to define normal and malignant plasma cells, thus allowing evaluation of minimal residual disease, and to establish the true complete response (CR) expressed by the return of normal plasma cells inside the bone marrow niche [ 11 ]. Targeting surface B-cell markers also leads to cell signaling, as observed with CD19, CD20, CD5, and CD22 that are B-cell receptor (BCR) coreceptors with either stimulatory or inhibitory activities.…”