ena-STUDY-BELLVITGE BIOMEDICAL RESEARCH INSTITUTE-10-06-2021-11:54:29:092-822
Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly disturbed genome: combined exhaustive molecular and therapeutic studies
Extramedullary multiple myeloma (EMM) has an overall survivalof 6 months and occurs in 20% of multiple myeloma (MM) patients.Genetic and epigenetic mechanisms involved in EMM and thetherapeutic role of new agents for MM are not well established.Besides, well-characterized preclinical models for EMM are notavailable. Herein, a patient-derived orthotopic xenograft (PDOX)was generated from a patient with an aggressive EMM tostudy in-depth genetic and epigenetic events, and drug responsesrelated to extramedullary disease. A fresh punch of an extramedullarycutaneous lesion was orthotopically implanted in NSG mouse. The PDOX mimickedhistologic and phenotypic features of the tumor of the patient.Cytogenetic studies revealed a hyperploid genome with multiplegenetic poor-prognosis alterations. Copy number alterations (CNAs)were detected in all chromosomes. The IGH translocationt(14;16)(q32;q23)IGH/MAF was already observed at the medullarystage and a new one, t(10;14)(p?11-12;q32), was observed only withextramedullary disease and could be eventually related to EMMprogression in this case. Exome sequencing showed 24 high impactsingle nucleotide variants and 180 indels. From the genes involved,only TP53 was previously described as a driver in MM. A ratherbalanced proportion of hyper/hypomethylated sites different topreviously reported widespread hypomethylation in MM was alsoobserved. Treatment with lenalidomide, dexamethasone andcarfilzomib showed a tumor weight reduction of 90% versus nontreatedtumors, whereas treatment with the anti-CD38 antibodydaratumumab showed a reduction of 46%. The generation of PDOXfrom a small EMM biopsy allowed us to investigate in depth themolecular events associated with extramedullary disease incombination with drug testing
Extramedullary multiple myeloma (EMM) has an overall survivalof 6 months and occurs in 20% of multiple myeloma (MM) patients.Genetic and epigenetic mechanisms involved in EMM and thetherapeutic role of new agents for MM are not well established.Besides, well-characterized preclinical models for EMM are notavailable. Herein, a patient-derived orthotopic xenograft (PDOX)was generated from a patient with an aggressive EMM tostudy in-depth genetic and epigenetic events, and drug responsesrelated to extramedullary disease. A fresh punch of an extramedullarycutaneous lesion was orthotopically implanted in NSG mouse. The PDOX mimickedhistologic and phenotypic features of the tumor of the patient.Cytogenetic studies revealed a hyperploid genome with multiplegenetic poor-prognosis alterations. Copy number alterations (CNAs)were detected in all chromosomes. The IGH translocationt(14;16)(q32;q23)IGH/MAF was already observed at the medullarystage and a new one, t(10;14)(p?11-12;q32), was observed only withextramedullary disease and could be eventually related to EMMprogression in this case. Exome sequencing showed 24 high impactsingle nucleotide variants and 180 indels. From the genes involved,only TP53 was previously described as a driver in MM. A ratherbalanced proportion of hyper/hypomethylated sites different topreviously reported widespread hypomethylation in MM was alsoobserved. Treatment with lenalidomide, dexamethasone andcarfilzomib showed a tumor weight reduction of 90% versus nontreatedtumors, whereas treatment with the anti-CD38 antibodydaratumumab showed a reduction of 46%. The generation of PDOXfrom a small EMM biopsy allowed us to investigate in depth themolecular events associated with extramedullary disease incombination with drug testing