Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Leukemia ; 33(7): 1713-1722, 2019 07.
Article in English | MEDLINE | ID: mdl-30573775

ABSTRACT

The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.


Subject(s)
Diffusion Magnetic Resonance Imaging/methods , Flow Cytometry/methods , Hematopoietic Stem Cell Transplantation/adverse effects , Multiple Myeloma/therapy , Neoplasm, Residual/diagnosis , Positron-Emission Tomography/methods , Biomarkers, Tumor/genetics , Follow-Up Studies , Humans , Multiple Myeloma/pathology , Neoplasm, Residual/diagnostic imaging , Neoplasm, Residual/etiology , Prognosis , Remission Induction , Survival Rate , Transplantation, Autologous , Exome Sequencing
2.
Nat Commun ; 8(1): 268, 2017 08 16.
Article in English | MEDLINE | ID: mdl-28814763

ABSTRACT

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.


Subject(s)
Bone Marrow/pathology , Multiple Myeloma/genetics , Plasma Cells/metabolism , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Aged , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p18/genetics , Disease Progression , Female , Fibroblast Growth Factors/genetics , Humans , Male , Middle Aged , Mitogen-Activated Protein Kinases/genetics , Multiple Myeloma/pathology , Mutation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , STAT3 Transcription Factor/genetics , Sequence Analysis, DNA , Tumor Suppressor Protein p53/genetics
3.
Blood Cancer J ; 7(2): e535, 2017 02 24.
Article in English | MEDLINE | ID: mdl-28234347

ABSTRACT

The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.


Subject(s)
Multiple Myeloma/genetics , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Humans , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Prognosis , Retinoblastoma Protein/genetics
5.
Blood Cancer J ; 6(7): e453, 2016 07 29.
Article in English | MEDLINE | ID: mdl-27471869

ABSTRACT

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.


Subject(s)
Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Multiple Myeloma/drug therapy , Neoplasm Proteins/biosynthesis , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bortezomib/administration & dosage , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Lenalidomide , Male , Melphalan/administration & dosage , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Neoplasm Proteins/genetics , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives
6.
Leukemia ; 30(2): 423-30, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26526987

ABSTRACT

Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.


Subject(s)
Gene Expression Profiling , Multiple Myeloma/genetics , Disease-Free Survival , Humans , Multiple Myeloma/classification , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Recurrence
7.
Oncology ; 80(5-6): 330-2, 2011.
Article in English | MEDLINE | ID: mdl-21791942

ABSTRACT

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Astrocytoma/drug therapy , Brain Neoplasms/drug therapy , Glioma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Astrocytoma/secondary , Brain Neoplasms/pathology , Carboplatin/administration & dosage , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Drug Administration Schedule , Etoposide/administration & dosage , Female , Glioma/secondary , Humans , Ifosfamide/administration & dosage , Male , Middle Aged , Recurrence , Retrospective Studies , Temozolomide , Treatment Failure
8.
Leuk Res Treatment ; 2011: 329572, 2011.
Article in English | MEDLINE | ID: mdl-23213540

ABSTRACT

It has been revealed that the Wnt/ß-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/ß-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.

9.
Leuk Res Treatment ; 2011: 428960, 2011.
Article in English | MEDLINE | ID: mdl-23213543

ABSTRACT

Recent studies have shown genetic and epigenetic aberrations resulting in aberrant activation of the Wingless-Int (Wnt) pathway, thus influencing the initiation and progression of acute myeloid leukemia (AML). Of major importance, these findings may lead to novel treatment strategies exploiting targeted modulation of Wnt signaling. This paper comprises the latest status of knowledge concerning the role of Wnt pathway alteration in AML and outlines future lines of research and their clinical perspectives.

SELECTION OF CITATIONS
SEARCH DETAIL
...