High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma

Child, J. A.; Morgan, Gareth J.; Davies, Faith E.; Owen, Roger G.; Bell, Susan E.; Hawkins, Kim; Brown, Julia; Drayson, Mark T.; Selby, Peter J.

doi:10.1056/nejmoa022340

Cited by 1,674 publications

(1,231 citation statements)

References 22 publications

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“…ASCT improves median OS in multiple myeloma by approximately 12 months [85][86][87][88]. However, three randomized trials show that OS is similar whether ASCT is done early (immediately following four cycles of induction therapy) or delayed (at the time of relapse as salvage therapy) [89][90][91].…”

Section: Role Of Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

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Section: Role Of Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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“…Owing to the exploratory nature of the analysis, P-values were not adjusted for multiple testing. 48 TMZ and paclitaxel for malignant melanoma. 49 The IC 50 values for mono-and combination therapies of HL-60 cells with ACNU and paclitaxel are shown in Table 2.…”

Section: Discussionmentioning

confidence: 99%

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

et al. 2012

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Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMT P140K (an O 6 -benzylguanineresistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMT P140K -F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMT P140K with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency.

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“…BCNU and doxorubicin are administered as treatment of multiple myeloma, 38 ACNU and paclitaxel for non-small cell lung cancer, 39 TMZ and paclitaxel for treatment of malignant melanoma 40 and malignant brain tumors like glioma and medulloblastoma. 41 A severe problem is the development of resistance against alkylating agents by high expression of wild-type 20 In contrast with other studies examining combination gene therapy with MDR1 and MGMT expressed by a gammaretroviral vector, [27][28][29][30] we chose a third generation lentiviral self-inactivating (SIN) vector 32 .…”

Section: Discussionmentioning

confidence: 99%

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

et al. 2009

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Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O 6 -benzylguanine (O 6 -BG)-resistant mutant MGMT P140K (O 6 -methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR 0 SIN-MDR1-IRES-MGMT P140K ), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34 + ). Combination therapy with O 6 -BG/1-(2-chloroethyl)-3-(4-amino-2-methyl pyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34 + cells, monotherapy with O 6 -BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR 0 SIN-MDR1-IRES-MGMT P140K (28.3%). For combination therapy with O 6 -BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMT P140K solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR 0 SIN-MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O 6 -BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drugresistance genes, offering an opportunity to increase the cancer therapeutic index.

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High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma

Abstract: High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age.

Cited by 1,674 publications

References 22 publications

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

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