Page 163 - 2019_07 resto del Mondo-web

relapse, and to improve outcomes further, strategies have been designed to eliminate the residual clonal cells that mediate relapse.8-10 In this context, an important strategy has been the use of maintenance therapy with lenalido- mide.11-13 This agent is well tolerated and has a bifunction- al mode of action directly killing the tumor cells and enhancing the immune response to the malignant plasma cells that is mediated by directing Aiolos and Ikaros to the proteasome for degradation.14-17
Understanding the features of residual cells that lead to relapse is an important challenge; however, this is technical- ly difficult, especially in patients who have achieved strin- gent complete responses. One way of understanding the characteristics of cells in remission is to study the character- istics of cells at relapse. Previous studies of the genetic fea- tures of paired presentation and relapse samples have shown that, after intensive chemotherapy, bi-allelic loss of tumor suppressor genes, in particular TP53, and the dereg- ulation of MYC by structural chromosomal changes are important features.18 In addition to mutational change, sub- clonal structure also varies at relapse and three main pat- terns have been described; branching, linear and shifting
Table 1. Previous studies assessing clonal evolution in myeloma.
patterns of clonal dominance18-23 (Table 1). Such analyses have not, however, studied uniformly treated patients for whom the depth of response or treatment information is available. To address the impact of maintenance and response depth on mutational patterns and clonal structure at relapse, we performed whole exome sequencing (WES) on paired presentation and relapse samples from 56 NDMM patients, 30 of whom had received lenalidomide maintenance and 26 who had not. All were treated at first presentation with a triple induction regimen containing an immunomodulatory agent, cyclophosphamide, and dexam- ethasone, making this the largest analysis of genetic evolu- tion in a uniformly treated series of MM patients to date.
Methods
Samples were selected from NDMM patients enrolled into the Myeloma XI trial (clinicaltrials.gov identifier: 01554852) for whom adequate DNA volumes were available.24 The study was under- taken after written informed consent from patients and ethical approval was obtained from the Oxfordshire Research Ethics
Maintenance, response status, and subclonal structure at MM relapse
Study
Keats et al. Blood 201219
Magrangeas et al. Leukaemia 201320
Bolli et al. Nat Commun 201421
Melchor et al. Leukaemia 201423 Kortum et al.
Ann Hematol 201522
Weinhold et al. Blood
201618
N. of patients
28
24
67
6
25
33
Disease status
Presentation vs. Relapse
Presentation
vs. Relapse
Presentation vs. Relapse
Presentation
vs. Relapse Presentation vs. Relapse
Presentation vs. Relapse
Technique
Array CGH
SNP array
NGS/SNP array
and cytogenetics
NGS and single
cell analysis NGS gene panel
NGS and GEP
Findings
Three major evolutionary mechanisms identified: 1. Genetically stable
2. Linear evolution
3. Heterogeneous clonal mixtures and shifting
predominant clones.
Branching evolution
outlined as a cause
for relapse in one-third of patients.
The remaining patients
displayed linear and stable
pathways to relapse.
Linear, branching, stable
and differential clonal
evolutionary responses described.
Description of kataegis and
somatic hypermutation.
Linear and branching
evolution shown at a single cell level.
Use of a targeted sequencing
panel to demonstrate gain and loss
of significantly mutated genes confirming clonal evolution.
Mutational load increases at relapse in association with enrichment of driver gene mutations and bi-allelic TSG events.
Branching evolution as the main
mechanism leading to relapse.
CGH: comparative genomic hybridization; SNP: single nucleotide polymorphism; NGS: next generation sequencing; GEP: gene expression profiling; TSG: tumor suppressor genes.
haematologica | 2019; 104(7)
1441