Residual malignant and normal plasma cells shortly after high dose melphalan and stem cell transplantation. Highlight of a putative therapeutic window in Multiple Myeloma?
Bottom Line: MMC counts were reduced by 92% (P ≤ .05) but not eradicated 7 days after HDM+ASCT.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.
Affiliation: INSERM, U1040, Montpellier, France.
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.
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Mentions: After induction treatment with 4-6 courses of BD, MMCs could be detected in BM samples of 18/27 (67%) patients the day before HDM infusion. These 18 patients are termed patients with positive MRD (MRD+). The median MMC count was 71.7 MMCs/μL (range 0.4-285.5 MMCs/μL) (Figure 2A and Table 2). For 17 of the 18 MRD+ patients, MMCs could still be detected in the BM 7 days after HDM and ASCT, however with a 92% reduction in median MMC counts (5.5 MMCs/μL versus 71.7 MMCs/μL, P ≤ .001) (Table 2). Post-HDM residual MMCs were viable cells, since they could survive for 6 days when cultured in vitro (Figure 2B). MMCs were evaluated in the grafted stem cell products of 16 of the 18 MRD+ patients. For 11 of these 16 MRD+ patients, the thawed stem cell products grafted to patients contained MMCs (Table 3). The median MMC count was 0.03 × 106 cells/kg, range 0-1.2 × 106 cells/kg, 100 fold lower than the median count of grafted CD34 stem cells (Table 3). BM could be collected 3 months after HDM for 12 of the 18 MRD+ patients. MMCs were detected in 9 of these 12 samples with a median MMC count of 2.4 cells/μL at 3 months (Table 2).