High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

Haas, Rainer; Bruns, Ingmar; Kobbe, Guido; Fenk, Roland

doi:10.1007/978-3-540-85772-3_10

Cited by 2 publications

(7 citation statements)

References 159 publications

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“…Multiple myeloma (MM) is a B cell malignancy characterized by a monoclonal expansion of plasma cells in bone marrow (BM) and the secretion of paraprotein in the serum and/or urine of patients. High-dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT) has improved the clinical outcome, but eventually all patients relapse [1,2].…”

Section: Introductionmentioning

confidence: 99%

Molecular Monitoring of Minimal Residual Disease in the Peripheral Blood of Patients with Multiple Myeloma

Korthals¹,

Sehnke²,

Kronenwett³

et al. 2013

Biology of Blood and Marrow Transplantation

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The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. In bone marrow, the level of residual myeloma cells is associated with treatment outcome, but the role of clonotypic cells in the peripheral blood (PB) for the prognosis of patients is not identified yet. In this study, we retrospectively analyzed MRD by quantitative real-time IgH-PCR (IgH-qPCR) in the PB of 42 patients undergoing high-dose therapy followed by autologous PB stem cell transplantation as first-line therapy for multiple myeloma. The MRD level of PB samples was in median 40-fold lower than in bone marrow samples, collected on the same day, with a wide intra- and interindividual variation (range, .4- to 4628-fold). The presence or absence of detectable MRD levels in PB did not correlate with the serological remission status. Still, patients with negative PCR results in PB 3 months after high-dose therapy and PB stem cell transplantation had lower International Staging System stage (P = .01), lower levels of β2-microglobulin (P = .02), higher hemoglobin levels (P = .01), and a prolonged event-free (median, 15 versus 4 months; P = .004) and overall (median, 52 versus 17 months; P = .03) survival. Importantly, by sequential monitoring of clonotypic cells in PB, in 19 of 29 patients (66%) with progressive disease, an increase of the 2IgH/β-actin ratio of at least 1 log step could be detected in median 4 months (range, .8 to 13 months) before the relapse was diagnosed on the basis of the European Group for Blood and Marrow Transplantation criteria. These patients with a molecular relapse in PB before a serological relapse had a significantly shorter overall survival than other patients (median, 17 months versus median not reached, P = .02). In conclusion, IgH-qPCR is a sensitive technique for the detection of clonotypic cells in PB, which precede clinical relapse. Future studies are needed to evaluate whether these circulating tumor cells play a role in promoting disease recurrence.

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Section: Introductionmentioning

confidence: 99%

Molecular Monitoring of Minimal Residual Disease in the Peripheral Blood of Patients with Multiple Myeloma

Korthals¹,

Sehnke²,

Kronenwett³

et al. 2013

Biology of Blood and Marrow Transplantation

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“…Activin A promotes osteolysis and anemia in MM 27 and anemia in MDS. 34,35 In our gene expression assays we observed that expression of activin A in CD34 1 HSPCs was unchanged while expression of activin A receptor type IIa was diminished 1.45-fold and activin A receptor Ib was downregulated 1.54-fold after lenalidomide therapy. We assume that previously described lenalidomideinduced secretion of activin A by BM stromal cells leads to reactive downregulation of its receptor on HSPCs.…”

Section: Discussionmentioning

confidence: 75%

“…Multiple myeloma (MM) is a hematological malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow (BM) . To date, there is no cure for MM although new drugs and treatment strategies continuously improve MM patients' clinical outcome.…”

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confidence: 99%

“…Multiple myeloma (MM) is a hematological malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow (BM). 1 To date, there is no cure for MM although new drugs and treatment strategies continuously improve MM patients' clinical outcome. Current treatment strategies are based on the concept of sequential first-line induction therapy including peripheral blood stem cell (PBSC) supported high-dose chemotherapy (HDT) followed by maintenance treatment.…”

mentioning

confidence: 99%

“…In this study, we focused on the effect of six cycles of consolidation treatment during which all patients received 25 mg lenalidomide and investigated the effect of lenalidomide on MM patients' BM for toxic or mutagenic effects on CD34 1 hematopoietic stem and progenitor cells (HSPCs). We examined cell counts, proliferative capacity, gene expression profiles and the activation state of the TGF-b pathway of BM CD34 1 HSPCs before and after treatment.…”

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Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis

Wilk

Heinzler

Boquoi

et al. 2016

Intl Journal of Cancer

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New drugs for the treatment of multiple myeloma (MM) comprise immunomodulatory substances such as lenalidomide and related compounds. While lenalidomide has found its way into first-line treatment as well as into relapse therapy, little is known about lenalidomide effects on normal hematopoietic stem and progenitor cells (HSPCs). In this study, we investigated whether HSPCs are influenced by lenalidomide on a phenotypic, functional and gene expression level. For that purpose, samples from patients with MM were obtained who underwent equivalent first-line treatment including induction therapy, cytotoxic stem cell mobilization and high-dose melphalan therapy followed by autologous blood stem cell transplantation and a subsequent uniform lenalidomide consolidation treatment within a prospective clinical trial. We found that after six months of lenalidomide therapy, the number of CD34(+) HSPCs decreased. Additionally, lenalidomide affects the numerical composition of hematopoietic cells in the bone marrow while it does not affect long-term HSPC proliferation in vitro. We found a significant amplification of fetal hemoglobin (HbF) expression on a transcriptional level and can confirm a stimulated erythropoiesis on a phenotypic level. These effects were accompanied by silencing of the TGF-β signaling pathway on the gene expression and protein level that is known to be amplified in active MM. However, these pleiotropic effects gave no evidence for mutagenic potential. In conclusion, lenalidomide does not exert long-term effects on proliferation of HSPCs but instead promotes erythropoiesis by shifting hemoglobin expression toward HbF and by silencing the TGF-β signaling pathway.

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High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma

Cited by 2 publications

References 159 publications

Molecular Monitoring of Minimal Residual Disease in the Peripheral Blood of Patients with Multiple Myeloma

Molecular Monitoring of Minimal Residual Disease in the Peripheral Blood of Patients with Multiple Myeloma

Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis

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