Gene Discovery May Present a Future Option for Treating High Risk Multiple Myeloma

BY PAUL KLEUTGHEN It is becoming increasingly hard to keep up with the many advances in the treatment of blood cancers. In the case of multiple myeloma, we have seen the advent of several new FDA-approved treatment alternatives and several more are at various stages of clinical effort. It seems that the field of drugs used is gradually shifting to monoclonal antibodies (Mab) so it was interesting to see a recently published article in the Blood Cancer Journal that not only provides a new gene treatment target of our disease but also provides encouraging, pre-clinical results of two potentially ‘small molecule’ drugs. ‘Small molecule’ drugs that we may be familiar with are Velcade or Revlimid. The article gets right to the point from the start :

‘Outcomes for many myeloma patients have improved over the past two decades with the introduction of proteasome inhibitors, immunomodulatory drugs and, more recently, monoclonal antibodies. However, high-risk disease, characterised by ⩾1 adverse cytogenetic features (t(4;14), t(14;16), t(14;20), 1q+, 17p−) or distinct gene expression profiles (for example, UAMS GEP70 score) remains therapeutically intractable, with little evidence that currently available therapies have improved patient outcomes. New treatment strategies are therefore urgently required.’

The authors identified that overexpression of the EZH2 gene has a negative effect on outcomes of MM patients. The authors collected peripheral blood samples of over 1,500 MM patients who were enrolled in late stage clinical studies and were able to conclude the following :

• ‘High expression of EZH2 is associated with poor patient outcomes and features of high-risk and proliferative disease.’
• ‘ … this effect is independent of therapy and persists even with immunomodulatory drug/proteasome inhibitor combination treatment used …’
• ‘For the first time, we have identified an association between EZH2 expression and survival in myeloma that is robust across different data sets, persists regardless of therapy used and is independent of other factors known to influence myeloma patient survival.’

And now for the good news: the authors tried two recently discovered potent and selective EZH2-inhibitors that are currently used in early Phase I clinical studies across different types. The article indicates that :

• ‘The inhibitors used in this present study, EPZ005687 and UNC1999, have been well characterised in previous studies and have been shown to be specific for EZH2 with few off-target effects.’
• ‘… we demonstrate the in vitro efficacy of EZH2 inhibition in both myeloma cell lines and in primary patient samples …’
• ‘Many of the cell lines and the patient samples had features of high risk disease—suggesting that EZH2 inhibition is active even in this setting. This is particularly promising given the lack of effective therapeutic options for these patients.’
• We present evidence that EZH2 is an important therapeutic target in myeloma and suggest that clinical trials of EZH2 inhibitors enrolling myeloma patients should be considered.

The fact that the two compounds mentioned above are already in clinical trials is positive news in that safety and dose ranging evaluations will have already progressed which will help expedite the development timeline of either or both these compounds to give us another treatment target and treatment option in the, not too distant, future. Of specific interest is also the in-vitro response seen in cell/cell linings of high-risk myeloma.