Pathway-Directed Therapy in Multiple Myeloma

SIMPLE SUMMARY: Multiple Myeloma is a cancer of plasma cells in the bone marrow. While effective treatments are available and many patients can now live years with the disease, most patients ultimately run out of treatment options. Pathway-directed therapy looks at genetic aberrations in the tumor cells and tries to blockade the tumor’s Achilles heel. Since myeloma cells show changes in several pathways, which can vary between different patients, agents targeting these pathways often only show activity in few patients. Pathway-directed therapy in myeloma is therefore often combined with personalized medicine, which aims to identify drugs that might interfere with the most important pathways in a particular patient. There are several pathways that can be targeted in myeloma, and, in combination with personalized medicine, some have shown promising results. However, there is still a challenge in identifying suitable patients and preventing resistance to single drugs, most likely caused by other pathways assuming the function of the blockaded one. Further research is therefore required to improve pathway-directed therapy. ABSTRACT: Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM.