Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular
Lourdes Farre1, Gabriela Sanz2, Neus Ruiz-Xivillé3,4
1Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
Abstract:
Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.
Insights
Extramedullary multiple myeloma (EMM) is aggressive, but a new patient-derived xenograft model allows deep study of its genetics and drug responses. This model shows promise for understanding EMM progression and testing new therapies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Extramedullary multiple myeloma (EMM) presents poor prognosis with limited understanding of its genetic drivers and effective treatments.
- Well-characterized preclinical models for studying EMM are currently lacking.
Purpose of the Study:
- To establish and characterize a patient-derived orthotopic xenograft (PDOX) model from an aggressive EMM case.
- To investigate the genetic and epigenetic alterations specific to extramedullary disease.
- To evaluate the efficacy of novel therapeutic agents in this EMM preclinical model.
Main Methods:
- Generation of a PDOX model by implanting an extramedullary cutaneous lesion from an EMM patient into NSG mice.
- Histologic and phenotypic analysis to confirm model fidelity.
- Cytogenetic studies and exome sequencing to identify genetic alterations.
- Drug sensitivity testing using lenalidomide, dexamethasone, carfilzomib, and daratumumab.
Main Results:
- The PDOX model accurately recapitulated the patient's EMM histologic and phenotypic features.
- Cytogenetic analysis revealed a hyperploid genome with significant copy number alterations and a novel translocation associated with extramedullary progression.
- Exome sequencing identified numerous variants, with only TP53 previously known as a driver in multiple myeloma.
- The PDOX model showed significant tumor reduction with standard-of-care agents and daratumumab.
Conclusions:
- The developed PDOX model provides a valuable tool for in-depth investigation of extramedullary multiple myeloma.
- This model facilitates the study of genetic and epigenetic events driving EMM progression.
- The model's response to therapy highlights its utility for preclinical drug testing in EMM.
More Related Videos
10:04Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020