Page 1559 - Hematology_ Basic Principles and Practice ( PDFDrive )

1386 Part VII Hematologic Malignancies

Chromatin regulators have become an important target in under- Besides prognostication, the mutational profile is beginning to be
standing myeloma biology and as potential therapeutic targets. used to guide therapy and to develop a personalized medicine
Bromodomain-containing protein 4 (BRD4) is a widely expressed approach. The presence of NRAS mutations has been reported to be
transcriptional coactivator and has been identified as a regulatory associated with a poor response to bortezomib, whereas interferon
factor for c-Myc expression in myeloma. JQ1, an inhibitor of BRD4, regulatory factor 4 (IRF4) mutations are associated with a better
induces antiproliferative effects associated with cell-cycle arrest and outcome following immunomodulatory drug (IMiD) therapy.
cellular senescence. Although the prognostic impact of epigenomic Mitogen-activated protein kinase kinase (MEK) inhibitors for the
changes has still not been studied in detail, it has already provided MAPK pathway, BRAF inhibitor for B-RAF mutations, ATR/ATM
various therapeutic targets, including HDAC inhibitors or enhancer inhibitors, and CCND1 inhibitors are some examples of adapted
of zeste homolog 2 (EZH2) inhibitor. strategies that can now be considered in patients with specific muta-
tions. Vemurafenib was effective in a patient with myeloma with
V600E BRAF mutation. Similarly, a larger study of a MEK inhibitor,
Sequencing trametinib, in RAS-mutated/MAPK pathway–activated relapsed
refractory myeloma has shown encouraging efficacy. NGS data is also
The availability of next-generation sequencing (NGS) has revealed a being used to accurately evaluate responses to treatment targeting
complex and evolving genomic structure in myeloma. Three large minimal residual disease (MRD).
independent studies (n = 733 patients) have described the mutational
landscape in myeloma (Table 86.3). These studies failed to identify
a universal driver mutation, but they revealed recurrent lower- MICROENVIRONMENT AND SIGNALING
frequency mutations in KRAS, NRAS, FAM46C, DIS3, BRAF, and
TP53. Mutations in NRAS, KRAS, and BRAF all affect the MAPK Myeloma cells interact with BMSCs, leading to both local cytokine
pathway, with overall perturbation of this pathway occurring in production and both cytokine-mediated and adhesion-mediated
around half of the patients. Specific mutations (ataxia telangiectasia signaling changes. The adhesion of the MM cell to the BMSC is
mutated [ATM], ataxia telangiectasia and Rad3-related protein mediated by the interaction of the adhesion molecules expressed by
[ATR], TP53, CCND1), their mutational load, and copy number myeloma cells (Table 86.3) with BMSCs and extracellular matrix
abnormalities have been used as markers of prognosis in myeloma. proteins. Adhesion and associated signaling changes affect the migra-
NGS studies have confirmed that at the time of diagnosis, patients tion and localization of the myeloma cells in the bone marrow,
have a number of coexistent clones. Some mutations are in all the Moreover, proliferative/antiapoptotic signaling cascades activated
cells (clonal), whereas others are in a subset of cells (subclonal). within MM cells as a result of these interactions include phosphati-
Importantly, the clonal and subclonal content changes and evolves dylinositol 3-kinase (PI3K)/Akt, Ras/Raf/MAPK, MEK/extracellular
over time. Using sequential samples from the same patient, four signal-related kinase (ERK), Janus kinase 2 (JAK2)/STAT3, and
distinct patterns of clonal evolution have been observed (linear, NFκB. These pathways lead to MM cell growth, survival, and
10
branching, no change, and differential clonal response) (Fig. 86.3). development of drug resistance (Fig. 86.4). For example, syndecan-1,
This information can now be exploited in the clinic. Because the a cell surface transmembrane heparan sulfate proteoglycan present on
genomic characteristics continue to evolve in a patient, repeated MM cells, interacts with type I collagen and regulates the growth of
reassessment over time may be required. MM cells; it also mediates increased osteoclast (OC) activity. Elevated

TABLE Recurrent Mutated Genes in Multiple Myeloma
86.3
Prevalence in Bolli et al Prevalence in Lohr et al
Gene Function/Pathway (n = 67 Patients) (n = 203 Patients)
NRAS MAP kinase pathway 25% (17/67) 20% (40/203)
KRAS MAP kinase pathway 25% (17/67) 23% (52/203)
TP53 Tumor suppressor protein 15% (10/67) 8% (18/203)
DIS3 a Exosome endoribonuclease 1,5 % (1/67) 11% (23/203)
Recurrently mutated in NHDMM
FAM46C Unknown 12% (8/67) 11% (24/203)
Recurrently mutated in HDMM
BRAF MAP kinase pathway 15% (10/67) 6% (12/203)
V600E in 3/10
SF3B1 RNA splicing machinery 3% (2/67) 1.5% (3/203)
CYLD NFκB inhibitors 3% (2/67) 2.5 % (5/203)
TRAF3 NFκB inhibitors 3% (2/67) 5.5% (11/203)
ROBO1 Transmembrane receptor, MET signaling 7% (5/67) 2% (4/203)
EGR1 Transcription factor 6% (4/67) 3.5% (7/203)
SP140 Antigene response in mature B cells 7% (5/67) 4.4% (9/203)
LTB Lymphoid development 4.5% (3/67) 1% (2/203)
RASA2 MAP kinase pathway suppressor of RAS function 3% (2/67) 3% (6/203)
FAT3 Cadherin superfamily member 7% (5/67) 4.4% (9/203)
CCND1 Cell-cycle progression 3% (2/67) 3% (6/203)
a The differences observed in the two studies are due to a small representation of patients harboring immunoglobulin H translocation in the study of Bolli et al, with DIS3
mutations being significantly associated with NHDMM.
MAP, Mitogen-activated protein; NFκB, nuclear factor-κB.