A New Treatment Option for Relapsed Myeloma Targeting MAPK Signaling

A new treatment option for relapsed myeloma may be available via the MAPK signaling pathway. 

Multiple myeloma patients learn all sorts of fancy new (and long) words for the variety of treatments that we live/have lived with. And so, we learn and have learned about immunomodulators (e.g., Revlimid), proteasome inhibitors (e.g., Velcade), CD38 inhibitors (e.g., Darzalex), stem cell transplants, alkylating agents (e.g., cyclophosphamide), nuclear protein export inhibitors (e.g., selenixor), anthracyclines (e.g., doxorubicin) and steroids (e.g., dexamethasone). Many of us will still relapse despite the availability of all these options and combinations of options. Nobody needs to convince us that there is a need for additional treatment tools.

The latest issue of the journal Case Reports in Hematology presents an interesting paper summarizing a case report of a myeloma patient who continued to relapse soon each time after a different regimen was tried and who went through a series of regimens that many of us are familiar with. Unfortunately, all to no avail. 

There is a molecular signaling pathway (the way that instructions are given to cells relative to cell growth and survival) abbreviated as MAPK. Abnormal MAPK signaling may lead to uncontrolled cell proliferation, resistance to programmed cell death and resistance to chemotherapy and/or radiation therapy. You can click on this link if you are interested in learning more about MAPK signaling.

MAPK dysregulation, through a variety of mutations, has been implicated in a variety of cancers. One such mutation, labeled BRAFV600-E, is a therapeutic target of melanoma, colon cancer, thyroid cancer, lung cancer as well as one of the leukemia variants. There is a school of thought that this particular mutation leads to resistance to proteasome inhibitors (such as Velcade, Ninlaro, Kyprolis). Molecular analysis of multiple myeloma has shown that about 4-10% of myeloma patients harbor BRAF mutations, but there is no BRAF targeted therapy currently approved to treat multiple myeloma. And this brings us back to the patient mentioned in the previous paragraph. With treatment failure after treatment failure, that patient’s medical team tried a combination of BRAF and MEK (a separate protein activated downstream from BRAF) directed compounds. The patient’s myeloma achieved a rapid response in 5 weeks and continued progression free for 8.5 month. True, this is a single case report, but it suggests that BRAF/MEK inhibition may be an additional therapeutic option in treating relapsed/refractory myeloma.

The authors of the study further state:

‘Two clinical trials to assess the effectiveness of BRAF/MEK inhibition in relapsed/refractory multiple myeloma, NCT02834364 and NCT03091257, are currently recruiting. The results of these trials should provide further insight into the targeting of the MAPK pathway in treatment of multiple myeloma.’

Those who are interested in these two studies can click on the above links to learn where the studies are being conducted, whom to contact, etc.