Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides

Abstract

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance.

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation

“…11,[36][37][38] Furthermore, recent evidence for clonal competition with alternating dominance of tumour subclones during disease progression suggests that the presence of genetic features at diagnosis may not allow conclusions to be made about their presence or absence at a later time during the disease course. [39][40][41] The database also fails to provide stringent information about treatment with novel agents. However, given that patients transplanted in the years 2004-2008 had the same outcome as patients transplanted in 1999-2003 (Supplementary Table 1), novel treatment modalities are unlikely to have had a major impact.…”

Management of older adults with multiple myeloma

“…According to a Darwinian evolutionary model, the sequence in which therapies are performed may induce different biological responses in the different clones, with the eradication of an indolent clone and the growth of a more aggressive one. 4 This will negatively affect post-relapse survival. In the future, a deeper knowledge of the biology of MM cells in the clinical setting should guide the choice of therapy to improve outcome and prevent the occurrence of refractory disease.…”

A myeloma multiplex megközelítése Magyarországon 2016-ban

“…Újon-nan diagnosztizált myeloma esetén karakterisztikusnak, de nem specifikusnak mondható a MAPK (mitogénakti-vált proteinkináz) szignálutat aktiváló mutációk jelenléte (az esetek 60%-ában kimutatható, míg primer plazmasejtes leukaemiában ritkának mondható) [9][10][11]. A RASmutációk gyakorisága/kimutathatósága az MM előreha-ladása kapcsán nő: NRAS 23-24%, KRAS 26-33%.…”