Extramedullary multiple myeloma patient derived orthotopic xenograft with high disturbed genome: combined exhaustive molecular and therapeutic studies.

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 patient's tumor. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF were already observed at medullary stage and a new one, the t(10;14)(p?11-12;q32), were observed only at extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact SNV 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% vs. non-treated tumors while the anti-CD38 antibody Daratumumab showed a reduction of 46%. The generation of PDOX from small EMM biopsy allowed to go in-deep to the molecular events associated to extramedullary disease in combination with drug testing.