• 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