IMV 2015: Activated pathways leading to high-risk myeloma: Professor Gareth Morgan, UAMS Myeloma Institute, Arkansas, USA discusses how our understanding of the biological pathways in MM has progressed recently.

Gene expression profiling (GEP) is currently the best approach for defining risk in multiple myeloma (MM). Mutation detection may be used for improving risk stratification and providing additional targets for therapy. Professor Gareth Morgan from the Institute of Cancer Research, who recently moved to the US to take up a post at the University of Arkansas for Medical Sciences, highlighted the importance of understanding the mutational spectrum in MM for refining risk stratification and designing targeted treatment strategies to overcome high-risk status.

MM is characterised by hyperdiploid and non-hyperdiploid genetic events that include mutations, methylations and copy number and structural abnormalities. Key genetic targets that are activated in MM include the MYC, RAS, MMSET, nuclear factor-κB, PI3K/Akt, MAF, and CCND pathways. Professor Morgan stressed that a given cytogenetic lesion cannot be described as ‘high-risk’ in itself, but certain lesions such as the t(4;14) translocation which is common in MM have a greater chance of becoming high risk as the disease progresses. The number of lesions is an important risk factor and GEP remains the prognostic tool of choice.

There is no single mutation associated with MM, but rather a spectrum of mutations and the clinical relevance of each mutation is not fully known. Professor Morgan’s group recently published data from 463 MM patients who were enrolled in the National Cancer Research Institute Myeloma XI trial, which showed that the mutational spectrum in MM is dominated by RAS (43%) and NFκB (17%) pathway mutations.¹ These mutations had a neutral effect on the clinical prognosis; in contrast, mutations in cell cycle (MYC, Amp1q and CCND1 mutations) and apoptosis (TP53, ATM, ATR, and ZNFHX4 mutations) pathways had a negative impact on survival whilst mutations in IRF4 and EGR1 were associated with overall favourable survival rates.¹

As a clinician it is important not to lose sight of the need to treat primary translocations and hyperdiploidy in MM – or as Professor Morgan put it, “target the tree trunk rather than the branches.” However, identifying clinically relevant mutations means specific interventions can be used to target, for example, RAS pathway mutations (using BRAF/MEK inhibitors), secondary translocations (using MYC inhibitors) or epigenetic modifications (using UTX inhibitors). A number of agents are currently in phase 2 and 3 clinical trials in MM, including MEK inhibitor trametinib and BRAF inhibitor vemurafenib. Apoptosis constitutes a common pathway for resistance in MM and could potentially be targeted in subgroups of patients. Professor Morgan concluded that treating high-risk MM remains a major clinical challenge and new potential targets and strategies should be explored with a view to refining prognosis and therapy in the near future.

References

1.  Walker BA, Boyle EM, Wardell CP, et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol 2015.