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

Caraux A, Vincent L, Bouhya S, Quittet P, Moreaux J, Requirand G, Veyrune JL, Olivier G, Cartron G, Rossi JF, Klein B - Oncotarget (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1040, Montpellier, France.

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.

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Cell communication proteins in bone marrow plasma before and 7 days after high dose melphalan (HDM) and autologous stem cell transplantation (ASCT)Paired bone marrow plasmas from 17 patients were collected 1 day before and 7 days after HDM+ASCT (respectively black circles and open circles) and assayed for cell communication proteins using Luminex methodology or ELISA. Data are the concentrations of IL-6, BAFF, CCL2, VEGF, IL-8, IL-15, IL-5, G-CSF, CCL3, CCL5 and IL-12 medullary plasma concentrations measured for each of the 17 patients. Horizontal bars represent the median value. The * indicates that the data before and after HDM are significantly different (P ≤ 0.05) using a paired t-test (when normality test passed) or Wilcoxon signed rank test (when normality test failed).
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Figure 3: Cell communication proteins in bone marrow plasma before and 7 days after high dose melphalan (HDM) and autologous stem cell transplantation (ASCT)Paired bone marrow plasmas from 17 patients were collected 1 day before and 7 days after HDM+ASCT (respectively black circles and open circles) and assayed for cell communication proteins using Luminex methodology or ELISA. Data are the concentrations of IL-6, BAFF, CCL2, VEGF, IL-8, IL-15, IL-5, G-CSF, CCL3, CCL5 and IL-12 medullary plasma concentrations measured for each of the 17 patients. Horizontal bars represent the median value. The * indicates that the data before and after HDM are significantly different (P ≤ 0.05) using a paired t-test (when normality test passed) or Wilcoxon signed rank test (when normality test failed).

Mentions: Twenty-three cell communication proteins could be detected (above detection limits) in the BM plasma of MM patients using Luminex or ELISA methodologies. Only BAFF concentration was significantly different (P = .003) between MRD− and MRD+ patients before HDM treatment. It was significantly 2 fold higher in MRD− patients (1753.6 pg/mL) compared to MRD+ patients (910.3 pg/mL). Cell communication proteins were also investigated in paired BM plasma of 17 patients harvested 1 day before and 7 days after HDM and ASCT. Concentrations of IL-6, VEGF, BAFF, CCL2, IL-8, IL-15, and IL-5 significantly increased respectively 4.8, 6.7, 119.4, 8.8, 9.4, 9.2 and 4.9 fold (P < .05) 7 days after HDM and ASCT (Figure 3). On the other hand, the concentrations of CCL3, IL-12, and CCL5 decreased significantly 1.2, 2.1 and 2.1 fold respectively (P < .05). The concentrations of other 13 cell communication proteins, in particular of IGF1, IL-21, and APRIL, were not affected by HDM treatment (data not shown). The rise in G-CSF concentration observed 7 days after HDM+ASCT is hardly surprising since patients received pegylated G-CSF on day 5 after autologous stem cell graft (Figure 3).


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

Caraux A, Vincent L, Bouhya S, Quittet P, Moreaux J, Requirand G, Veyrune JL, Olivier G, Cartron G, Rossi JF, Klein B - Oncotarget (2012)

Cell communication proteins in bone marrow plasma before and 7 days after high dose melphalan (HDM) and autologous stem cell transplantation (ASCT)Paired bone marrow plasmas from 17 patients were collected 1 day before and 7 days after HDM+ASCT (respectively black circles and open circles) and assayed for cell communication proteins using Luminex methodology or ELISA. Data are the concentrations of IL-6, BAFF, CCL2, VEGF, IL-8, IL-15, IL-5, G-CSF, CCL3, CCL5 and IL-12 medullary plasma concentrations measured for each of the 17 patients. Horizontal bars represent the median value. The * indicates that the data before and after HDM are significantly different (P ≤ 0.05) using a paired t-test (when normality test passed) or Wilcoxon signed rank test (when normality test failed).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539173&req=5

Figure 3: Cell communication proteins in bone marrow plasma before and 7 days after high dose melphalan (HDM) and autologous stem cell transplantation (ASCT)Paired bone marrow plasmas from 17 patients were collected 1 day before and 7 days after HDM+ASCT (respectively black circles and open circles) and assayed for cell communication proteins using Luminex methodology or ELISA. Data are the concentrations of IL-6, BAFF, CCL2, VEGF, IL-8, IL-15, IL-5, G-CSF, CCL3, CCL5 and IL-12 medullary plasma concentrations measured for each of the 17 patients. Horizontal bars represent the median value. The * indicates that the data before and after HDM are significantly different (P ≤ 0.05) using a paired t-test (when normality test passed) or Wilcoxon signed rank test (when normality test failed).
Mentions: Twenty-three cell communication proteins could be detected (above detection limits) in the BM plasma of MM patients using Luminex or ELISA methodologies. Only BAFF concentration was significantly different (P = .003) between MRD− and MRD+ patients before HDM treatment. It was significantly 2 fold higher in MRD− patients (1753.6 pg/mL) compared to MRD+ patients (910.3 pg/mL). Cell communication proteins were also investigated in paired BM plasma of 17 patients harvested 1 day before and 7 days after HDM and ASCT. Concentrations of IL-6, VEGF, BAFF, CCL2, IL-8, IL-15, and IL-5 significantly increased respectively 4.8, 6.7, 119.4, 8.8, 9.4, 9.2 and 4.9 fold (P < .05) 7 days after HDM and ASCT (Figure 3). On the other hand, the concentrations of CCL3, IL-12, and CCL5 decreased significantly 1.2, 2.1 and 2.1 fold respectively (P < .05). The concentrations of other 13 cell communication proteins, in particular of IGF1, IL-21, and APRIL, were not affected by HDM treatment (data not shown). The rise in G-CSF concentration observed 7 days after HDM+ASCT is hardly surprising since patients received pegylated G-CSF on day 5 after autologous stem cell graft (Figure 3).

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.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1040, Montpellier, France.

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.

Show MeSH
Related in: MedlinePlus