7. Potential target for multiple myeloma

#### 7.1. Constraint of GEP in existing clinical practice

Important impediments still present to prevent application of this important investigation in general clinical practice. Although many specific GEP signatures have been recognized and a recent study has joint some of these signatures to create a unique signature [32] but no consensus have been accepted to date for universal use for every MM patients. GEP remains a research tool and is not yet authenticated by the FDA. For clinician point of view, the GEP data have been created generally in a setting of certain treatments that includes thalidomide, lenalidomide and bortezomib with or without auto-transplant. Since the therapeutic landscape is largely progressing in MM, re-assessments are required for each novel drug and/or combination. In particular the arrival of new therapeutic classes such as antibody drug conjugates, targeted agents (Elotuzumab, Daratumumab) and new IMiDs and proteasome inhibitors [106, 107] markedly improve the prognosis and may need different GEP studies and signatures [107, 114]. GEP has been utilized to date in few myeloma centers and mostly for investigational purposes. The development of investigators friendly and quicker methods should be considered. Simple quantitative PCR has been assessed in a group of 157 newly diagnosed patients proved good acceptable results [115]. However, a final conclusion about this test is still pending. Most importantly an integrated approach that includes gene signatures, mutational profile and microRNA expression will be requisite to allow a wider application of genomic information to direct for treatment selection as well as prognostication. Taking the current understanding of these landscape genetic assessment to the next level, it will be essential to understand the clinical influence of clonal content and advancement along with identification of sub-clonal variants and molecular alterations on disease outcome [141]. The current information about mutational load that predicts outcome will need to be re-investigated for treatment purpose. These algorithms will be amended with the arrival of immunotherapeutic strategies which may have great achievement in malignancies with high mutational load. Again, as demonstrated by Rashid NU et al. with other colleagues Mutations must be studies further as predictive markers for treatment decisions [97].

## 8. Future trend

The documentation of specific micro-RNA expression profile can also be exploited to guide therapy. Several microRNAs are being researched as treatment targets with hopes for devel-

Similarly, GEP has been employed to predict resistance to antimyeloma drugs with an interpretation that harmful agents are avoided that are not helpful. With the help of number of B-cell lines including multiple myeloma cell lines, a microarray-based GEP signature was established to predict resistance of melphalan. Although the expression profile was able to predict sensitivity vs. resistance in cell lines, its practical application needs further studies to be done [102, 103]. Interestingly, a pharmacogenomic study of global GEP of myeloma cells recovered from myeloma patients and specific time after administration of different drugs have been assessed [104, 105]. Prognostic information was acquired from GEP of refined plasma cells 2 days after providing thalidomide and dexamethasone or bortezomib to newlydiagnosed myeloma patients. An 80-gene signature was recognized following bortezomib

administration that will guide us in future for better patients' risk stratification [105].

From treatment as well as prognostic points, it is also important to consider persistent changes in genome which occurs without stimulus or as well as under the influence of microenvironment, epigenomic changes or therapy. Therefore, assessment by GEP at a single time point may not be meaningful. The advancement of GEP from diagnosis, response and relapse should be interpreted intelligently to have an answer for proper selection of the most appropriate

Important impediments still present to prevent application of this important investigation in general clinical practice. Although many specific GEP signatures have been recognized and a recent study has joint some of these signatures to create a unique signature [32] but no consensus have been accepted to date for universal use for every MM patients. GEP remains a research tool and is not yet authenticated by the FDA. For clinician point of view, the GEP data have been created generally in a setting of certain treatments that includes thalidomide, lenalidomide and bortezomib with or without auto-transplant. Since the therapeutic landscape is largely progressing in MM, re-assessments are required for each novel drug and/or combination. In particular the arrival of new therapeutic classes such as antibody drug conjugates, targeted agents (Elotuzumab, Daratumumab) and new IMiDs and proteasome inhibitors [106, 107] markedly improve the prognosis and may need different GEP studies and signatures [107, 114]. GEP has been utilized to date in few myeloma centers and mostly for investigational purposes. The development of investigators friendly and quicker methods should be considered. Simple quantitative PCR has been assessed in a group of 157 newly diagnosed patients proved good acceptable results [115]. However, a final conclusion about this test is still pending. Most importantly

opment of small molecules that target these micro-RNA function.

7. Potential target for multiple myeloma

7.1. Constraint of GEP in existing clinical practice

therapy.

52 Update on Multiple Myeloma

There is tremendous progress has reported so far, newer high-throughput technologies are being added with clinical parameters [142]. Array-based methodologies, sequencing-based method, and newer bio-informatics methodologies are in process of development. Furthermore, integrative oncogenomic work are merging new markers such as mutations, splicing events, noncoding RNA, miRs with older ones to help in better prognostication [143]. The personalized medicine depends on the assortment of a targeted therapy guided by the specific mutation or GEP signature is attractive tool treatment option. However, in future, in MM patients, treatment option selection depends on coexistence of sub-clones, dynamic evolution of the disease and triggering mutations in pathway, i.e., KRAS and BRAF for the ERK pathways [144].

To conclude, gene expression profile studies provide important knowledge regarding MM pathogenesis, and establish a powerful tool for prediction of outcome and to direct clinicians for selection of therapy [145]. The grouping of mutational profile, gene expression and splicing events with ISS and cytogenetic may become a standard of care in MM care [97].
