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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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Assessment of Multiple Myeloma Cells and Normal Plasma cells in representative patients with Multiple Myeloma before and after high dose melphalanUsing 7 color-multiparameter flow cytometry, multiple myeloma cells (MMCs) and normal plasma cells (N-PCs) were assessed in bone marrow or peripheral blood samples of patients after induction treatment (1 day before high dose melphalan, HDM), 7 days after HDM and autologous hematopoietic stem cell transplantation (ASCT), 3 months after HDM. MMCs and N-PCs were also measured in the thawed stem cell leukapheresis product grafted to the patients. (A) MMC and N-PC evaluation in a representative patient with positive residual disease after induction treatment (MRD+). MMCs were identified on the basis of aberrant CD56 expression and monoclonal lambda light chain expression. Data are the dotplots of CD56 and Lambda light chain expressions. MMCs were undetectable 7 days and 3 months after HDM+ASCT in the peripheral blood. (B) Bone marrow cells from one representative MRD+ patient out of 3 were harvested 7 days after HDM+ASCT and cultured for 6 days with 2 ng/mL of IL-6. Before culture, bone marrow cells contained CD38high CD56+ MMCs (70% of CD38high cells) and CD38highCD56− N-PCs. After a 6-day, the CD38high CD56+ MMCs were viable, being Annexin V− 7AAD−. (C) N-PC evaluation and lack of MMCs in a representative patient with negative residual disease after induction treatment. MMCs of this patient aberrantly expressed CD56 and CD200 at diagnosis. After induction treatment, only N-PCs could be detected in the bone marrow, peripheral blood and leukapheresis product.
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Figure 2: Assessment of Multiple Myeloma Cells and Normal Plasma cells in representative patients with Multiple Myeloma before and after high dose melphalanUsing 7 color-multiparameter flow cytometry, multiple myeloma cells (MMCs) and normal plasma cells (N-PCs) were assessed in bone marrow or peripheral blood samples of patients after induction treatment (1 day before high dose melphalan, HDM), 7 days after HDM and autologous hematopoietic stem cell transplantation (ASCT), 3 months after HDM. MMCs and N-PCs were also measured in the thawed stem cell leukapheresis product grafted to the patients. (A) MMC and N-PC evaluation in a representative patient with positive residual disease after induction treatment (MRD+). MMCs were identified on the basis of aberrant CD56 expression and monoclonal lambda light chain expression. Data are the dotplots of CD56 and Lambda light chain expressions. MMCs were undetectable 7 days and 3 months after HDM+ASCT in the peripheral blood. (B) Bone marrow cells from one representative MRD+ patient out of 3 were harvested 7 days after HDM+ASCT and cultured for 6 days with 2 ng/mL of IL-6. Before culture, bone marrow cells contained CD38high CD56+ MMCs (70% of CD38high cells) and CD38highCD56− N-PCs. After a 6-day, the CD38high CD56+ MMCs were viable, being Annexin V− 7AAD−. (C) N-PC evaluation and lack of MMCs in a representative patient with negative residual disease after induction treatment. MMCs of this patient aberrantly expressed CD56 and CD200 at diagnosis. After induction treatment, only N-PCs could be detected in the bone marrow, peripheral blood and leukapheresis product.

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).


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)

Assessment of Multiple Myeloma Cells and Normal Plasma cells in representative patients with Multiple Myeloma before and after high dose melphalanUsing 7 color-multiparameter flow cytometry, multiple myeloma cells (MMCs) and normal plasma cells (N-PCs) were assessed in bone marrow or peripheral blood samples of patients after induction treatment (1 day before high dose melphalan, HDM), 7 days after HDM and autologous hematopoietic stem cell transplantation (ASCT), 3 months after HDM. MMCs and N-PCs were also measured in the thawed stem cell leukapheresis product grafted to the patients. (A) MMC and N-PC evaluation in a representative patient with positive residual disease after induction treatment (MRD+). MMCs were identified on the basis of aberrant CD56 expression and monoclonal lambda light chain expression. Data are the dotplots of CD56 and Lambda light chain expressions. MMCs were undetectable 7 days and 3 months after HDM+ASCT in the peripheral blood. (B) Bone marrow cells from one representative MRD+ patient out of 3 were harvested 7 days after HDM+ASCT and cultured for 6 days with 2 ng/mL of IL-6. Before culture, bone marrow cells contained CD38high CD56+ MMCs (70% of CD38high cells) and CD38highCD56− N-PCs. After a 6-day, the CD38high CD56+ MMCs were viable, being Annexin V− 7AAD−. (C) N-PC evaluation and lack of MMCs in a representative patient with negative residual disease after induction treatment. MMCs of this patient aberrantly expressed CD56 and CD200 at diagnosis. After induction treatment, only N-PCs could be detected in the bone marrow, peripheral blood and leukapheresis product.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Assessment of Multiple Myeloma Cells and Normal Plasma cells in representative patients with Multiple Myeloma before and after high dose melphalanUsing 7 color-multiparameter flow cytometry, multiple myeloma cells (MMCs) and normal plasma cells (N-PCs) were assessed in bone marrow or peripheral blood samples of patients after induction treatment (1 day before high dose melphalan, HDM), 7 days after HDM and autologous hematopoietic stem cell transplantation (ASCT), 3 months after HDM. MMCs and N-PCs were also measured in the thawed stem cell leukapheresis product grafted to the patients. (A) MMC and N-PC evaluation in a representative patient with positive residual disease after induction treatment (MRD+). MMCs were identified on the basis of aberrant CD56 expression and monoclonal lambda light chain expression. Data are the dotplots of CD56 and Lambda light chain expressions. MMCs were undetectable 7 days and 3 months after HDM+ASCT in the peripheral blood. (B) Bone marrow cells from one representative MRD+ patient out of 3 were harvested 7 days after HDM+ASCT and cultured for 6 days with 2 ng/mL of IL-6. Before culture, bone marrow cells contained CD38high CD56+ MMCs (70% of CD38high cells) and CD38highCD56− N-PCs. After a 6-day, the CD38high CD56+ MMCs were viable, being Annexin V− 7AAD−. (C) N-PC evaluation and lack of MMCs in a representative patient with negative residual disease after induction treatment. MMCs of this patient aberrantly expressed CD56 and CD200 at diagnosis. After induction treatment, only N-PCs could be detected in the bone marrow, peripheral blood and leukapheresis product.
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).

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