Cig-FISH-Analysis of Extramedullary Myeloma Manifestations Shows Similar Incidence of Prognostic Genetic Aberrations Compared to Bone Manifestations or Soft Tissue Involvement
Authors: Billecke Lisa , Penas Eva Maria Murga , May Annette , Engelhardt Monika , Nagler Arnon , Leiba Merav , Kröger Nicolaus , Zustin Jozef , Marx Andreas , Matschke Jakob , Tiemann Markus , Gökkurt Eray , Bokemeyer Carsten , Schilling Georgia 
Published: October 2019

Abstract
Abstract 4993

Introduction:
Extramedullary organ impairment in patients with multiple myeloma (MM) is a very rare event, mostly occurring during disease relapse after high-dose chemotherapy with autologous or allogeneic stem cell transplantation. Recent data reported by different authors suggest a very unfavorable outcome and rapid clinical course for patients with extramedullary relapses. Often the extramedullary manifestations are associated with special biological features, such as loss of CD56 expression or plasmablastic cell morphology.
In this context, only one FISH study of 9 MM patients reported that the incidence of TP53 deletions in the bone marrow of those MM patients with central nervous system (CNS) involvement was about 75% higher than in the MM patient without CNS involvement. However, there is a lack of genetic data for specific extramedullary manifestations. We herein report the first cytogenetic investigation of extramedullary organ infiltrations compared to bone lesions or consecutive soft tissue impairment of MM patients using cIg-FISH on paraffine embedded sections.

Material and method:
We investigated paraffin-embedded sections of different extramedullary organ manifestations of 13 MM patients and 11 MM patients with bone or soft tissue impairment originating from a bone lesion. Extramedullary organ involvements comprised biopsies from skin, pleura, pleural effusion, uterus, liver, CNS, subcutaneous soft tissue, lymph node, and thyroid gland, attained at different stages of the disease. The second group consisted of bone lesions or surrounding soft tissue, like muscle, which was infiltrated per continuitatem. For investigation of paraffine-embedded samples, we further developed the conditions of the well known cIg-FISH method to utilize all the advantages of this very sensitive method. We evaluated the most important prognostic chromosomal regions in MM using the following FISH-probes:
13q14 (D13S25), 17p13 (TP53), 8q24 (MYC), t(4;14) (FGFR3/MMSET;IGH).

Results:
The incidences in the group of extramedullary organ involvement vs. bone and soft tissue were as follows:
deletion of TP53: 23% vs. 18%
MYC-overrepresentation: 36% vs. 36%
deletion of 13q14: 18% vs. 36%
t(4;14) 42% vs. 30%
The incidence of TP53 deletions in organ infiltrations by malignant plasma cells was similar to bone or soft tissue involvement. Our result for MYC-overrepresentation is in line with the findings of recent analysis of bone marrow aspirates from patients with advanced multiple myeloma (32%) and showed again no difference between the two groups. Incidences of 13q14 deletion and t(4;14) varied slightly between the two groups, but are in range with other cIg-FISH-analyses on bone marrow plasma cells.

Discussion:
In this first cytogenetic investigation of extramedullary manifestations in MM patients, we showed similar frequencies of the chromosomal regions analyzed in the group of organ infiltrations by malignant plasma cells compared to bone or soft tissue involvement. All in all we could not detect differences in the incidence of the most relevant genetic aberrations of the investigated tissue probes compared to already well known bone marrow cytogenetics. Interestingly, this is in contrast to the findings of bone marrow probes in the study with patients with MM and CNS involvement, who showed a higher incidence of TP53 deletions. Concerning the group of soft tissues, originating from bone lesions this is not astonishing, maybe even expected. However, this work analyzed bone marrow of the MM patients and not the extramedullary manifestation, as we did. Further investigations or larger patient samples are needed to proof if these or other genetic aberrations are associated to the aggressive course of extramedullary manifestations of MM.

Disclosures:
No relevant conflicts of interest to declare.