**6. Conclusion**

**5. Other factors potentially influencing resistance to myeloma** 

Cytogenetic abnormalities in MM are broadly divided into copy number changes or translocations, most commonly involving the immunoglobulin heavy chain gene [125]. Various cytogenetic abnormalities were shown to be associated with the likelihood of durable responses to therapy but they do not directly explain mechanisms of drug resistance or disease progression [126]. High risk genetic features frequently result in the dysregulation of transcription factors or tumour suppressors and include t(4;14), t(14;16), t(16;20), del(17p) and copy number changes of chromosome 1, which are used for stratifying MM patients in clinical trials and are now becoming important in guiding therapy in routine practice [126]. For example, the EMN02/HO95 study demonstrated the benefit of double autologous stem cell transplantation in patient with high-risk genetics, essentially negating the adverse prognosis of high genetic risk MM [127]. Similarly, the addition of Bortezomib to induction regimens in patients receiving HDM/ASCT may partially overcome cytogenetically defined poor risk [128]. On the other hand, patients with trisomies may respond particularly well to lenalidomide based protocols [129]. Mutational events such as those involving p53 are associated with particularly poor PFS, however, the significant heterogeneity of point mutational events elucidated in whole exome sequencing studies means generalisations of such molecular changes are not possible [130].

The development of whole exome sequencing and copy number profiling was combined with cytogenetics in a landmark paper by a consortium of European and American groups [131]. This elegant paper demonstrated that the majority of MM patients had multiple sub-clones present at the time of diagnosis and that within sub-clones there could be differing mutational events potentially driving behaviour [131]. When serial MM samples were analysed, diverse patterns of clonal evolution were detected. In some cases, simple clonal selection could be observed following a linear pattern of clonal evolution [131]. Differential clonal responses could explain the clinical observation that a MM patient may respond to a treatment initially, lose this response, respond to another treatment and at the time of subsequent relapse respond again to the initial therapy [132]. Branching evolution was also observed in some progressing patients [131]. During disease evolution differing processes may contribute to the mutational repertoire and the relative contributions may vary over time in the same patient

resulting in mutational heterogeneity, frequently with very few recurrent genes [131].

Identification of the multiple myeloma stem cell (MMSC) has been a challenge predominantly because an agreed phenotype with MM propagating potential has not been definitively established, in part due to differences in experimental techniques and assays. The dominant view-

renewal, tumour-initiating potential and drug resistance [133, 134]. Controversy also exists

cells represent MMSCs, however, some researchers have also

plasma cells have properties of cancer stem cells such as self-

**5.1. Cytogenetics, mutation patterns and clonal evolution**

**therapies**

82 Update on Multiple Myeloma

**5.2. The myeloma stem cell**

point is that clonotypic CD138−

shown that clonotypic CD138<sup>+</sup>

Continued improvements in the efficacy and toxicity profiles of an ever-expanding number of novel MM therapies are challenging the current paradigm of high-dose therapy and autologous stem cell transplantation for newly-diagnosed MM. However, despite these advances, resistance to novel agents has been observed and will continue to be observed, requiring innovative ways to circumvent this problem. Changing therapy from one novel agent containing treatment regimen to a different one upon MM progression or relapse is reasonable, however, there is often little scientific basis for choosing the sequence of such regimens and the era of precision medicine for MM patients remains distant. Moreover, the inability to tailor treatment regimens for an individual patient based on the biology of their MM due to government mandated prescribing restrictions likely contributes to inadequate responses and drug resistance.

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In addition to those discussed, there are other potential mechanisms through which resistance to novel therapies in MM may occur, such as the role miRNAs play in promoting MM, and this list is likely to increase. However, despite the varied resistance mechanisms reported to date, the survival of patients with MM continues to improve. Whilst genetic profiling has established a so-called high-risk group of MM patients, these genetic changes do not specifically explain why resistance to a particular novel agent develops. Thus, in this Chapter, an exposition of specific biological aberrations that have been linked to drug resistance has been presented.
