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- Investigator Commentary by Dr. Albrecht Reichle
In many cancers, the homeostatic pathways between tumour and stroma cells are
dysregulated, making communicative reprogramming of these pathways (i.e.
anakoinosis) a novel therapy approach in MM. In this phase II study of
lenalidomide-resistant, heavily pretreated patients with RRMM we investigated a
unique cocktail of drugs to target homeostatic pathways between MM clones and
stromal cells. In this cocktail we included dexamethasone and pioglitazone,
which are both anti-inflammatory and angiostatic transcription modulators.
Specifically, pioglitazone targets the peroxisome proliferator-activated
receptor γ (PPARγ) (a nuclear receptor family transcription factor) and has
been reported to suppresses STAT3 activation. This regimen also included
low-dose treosulfan as metronomic chemotherapy and lenalidomide as a
pleiotropic biomodulator. As lenalidomide may upregulate PPARγ, we suspect this
drug may play a synergistic role in enhancing the activity of pioglitazone.
Indeed we see that although none of these drugs show significant activity as
monotherapy, they exert a concerted activity when combined.
A key finding in this study was that there was no difference in time to
progression between patients with high-risk and standard-risk cytogenetics,
which is not generally seen with current MM therapies. In addition to
cytogenetic risk, number of lines of therapy and refractory disease are also
associated with poorer outcomes in MM. We have shown in this study that this
population of heavily pretreated patients could achieve OS and PFS results
similar to those achieved with daratumumab monotherapy in the SIRIUS
study.32Importantly, we also showed that anakoinosis therapy, which included
lenalidomide, was able to rescue patients who were lenalidomide-refractory.
Although this is an unusual therapy, we believe that reprogramming of
myeloma-stroma homeostatic pathways through anakoinosis therapy is an effective
approach to overcome the genetic heterogeneity present in MM, particularly in
those patients with high-risk cytogenetics. In the future our aim is to
investigate how this therapy approach can be combined with other targeted
approaches in MM at different stages of therapy