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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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Related in: MedlinePlus

CONSORT diagram of patients with previously-untreated multiple myeloma in Montpellier University Hospital, showing number of patients, treatments delivered, and outcomeMRD, minimal residual disease; HDM, high dose melphalan; ASCT, autologous hematopoietic stem cells transplantation; MFC, multiparameter flow cytometry.
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Figure 1: CONSORT diagram of patients with previously-untreated multiple myeloma in Montpellier University Hospital, showing number of patients, treatments delivered, and outcomeMRD, minimal residual disease; HDM, high dose melphalan; ASCT, autologous hematopoietic stem cells transplantation; MFC, multiparameter flow cytometry.

Mentions: Twenty-seven consecutive MM patients from a single center (University Hospital, Montpellier, France) were included in this study (Figure 1). All patients had symptomatic untreated MM. Patients’ characteristics at diagnosis are shown in Table 1. Samples were collected after patients’ written informed consent in accordance with the Declaration of Helsinki and institutional research board approval from Montpellier University hospital (N° DC-2008-417). According to the French standard first line treatment, patients received an induction treatment of 4-6 cycles of BD followed by high-dose melphalan (HDM, 200 mg/m2) and ASCT. After the third BD cycle, patients received 10 μg/kg/day of G-CSF or 10 μg/kg/day of G-CSF plus 2 g/m2 cyclophosphamide in order to mobilize and collect HSCs. Response to therapy was assessed according to international criteria modified to include the category of near complete response (nCR: electrophoresis negative for M-protein, but immunofixation positive).[38, 39] Response assessment to BD induction (1 day before HDM) showed 48 % complete remission (CR) or nCR, 22 % of very good partial responses (VGPR) and 22 % of partial responses (PR). Three months after transplantation, 62% of patients were in CR/nCR, 21% in VGPR, and 8% in PR.


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)

CONSORT diagram of patients with previously-untreated multiple myeloma in Montpellier University Hospital, showing number of patients, treatments delivered, and outcomeMRD, minimal residual disease; HDM, high dose melphalan; ASCT, autologous hematopoietic stem cells transplantation; MFC, multiparameter flow cytometry.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: CONSORT diagram of patients with previously-untreated multiple myeloma in Montpellier University Hospital, showing number of patients, treatments delivered, and outcomeMRD, minimal residual disease; HDM, high dose melphalan; ASCT, autologous hematopoietic stem cells transplantation; MFC, multiparameter flow cytometry.
Mentions: Twenty-seven consecutive MM patients from a single center (University Hospital, Montpellier, France) were included in this study (Figure 1). All patients had symptomatic untreated MM. Patients’ characteristics at diagnosis are shown in Table 1. Samples were collected after patients’ written informed consent in accordance with the Declaration of Helsinki and institutional research board approval from Montpellier University hospital (N° DC-2008-417). According to the French standard first line treatment, patients received an induction treatment of 4-6 cycles of BD followed by high-dose melphalan (HDM, 200 mg/m2) and ASCT. After the third BD cycle, patients received 10 μg/kg/day of G-CSF or 10 μg/kg/day of G-CSF plus 2 g/m2 cyclophosphamide in order to mobilize and collect HSCs. Response to therapy was assessed according to international criteria modified to include the category of near complete response (nCR: electrophoresis negative for M-protein, but immunofixation positive).[38, 39] Response assessment to BD induction (1 day before HDM) showed 48 % complete remission (CR) or nCR, 22 % of very good partial responses (VGPR) and 22 % of partial responses (PR). Three months after transplantation, 62% of patients were in CR/nCR, 21% in VGPR, and 8% in PR.

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