A Step Toward Precision Medicine
The IMF is very pleased to have established a partnership with AbbVie to conduct the largest, most comprehensive chart-review study of myeloma patients with the t(11;14) translocation evident on FISH (fluorescence in situ hybridization) testing of bone marrow myeloma cells. This landmark retrospective analysis assesses the 16-to-24-percent of myeloma patients harboring the t(11;14) translocation. The presence or absence of other mutations is also being evaluated to determine the impact of more complex patterns of mutations. A unique aspect of the study is the ability to assess response to a variety of treatments and document lengths of remission and overall outcomes.
The t(11;14) translocation and precision medicine
The reason that t(11;14) translocation is so important is that it identifies myeloma cells with over-expression or large amounts of a protein called Bcl-2. Bcl-2 prevents apoptosis (cell death) and thus helps sustain the growth of myeloma. Blocking Bcl-2 is an effective treatment for myeloma and can be accomplished with several agents, including venetoclax, which is currently in clinical trials. This is the best example of a “precision medicine” or a targeted approach to treating myeloma. In the summary from ASH 2017, I detailed the excellent results with venetoclax used alone, as well as in combinations with bortezomib (Velcade®).
Challenges of the precision medicine approach
The new IMF t(11;14) data-gathering project will determine if other translocations or mutations are also present. This is a key point, since presence of some abnormalities, such as “trisomies” (presence of three copies of a chromosome instead of two), can improve responsiveness to treatment and outcomes, whereas co-occurrence of other abnormalities, such as 17p- or Iq+, can lead to much poorer outcomes. The challenge is that many, many genetic abnormalities are typically present. By determining what are the more common patterns, recommendations will be possible with regard to combinations of therapies likely to be most effective.
Other examples of targeted approaches
It is known that about four percent of myeloma patients have BRAF mutations. Again, targeted therapy is available. But because of the impact of many other co-existent mutations, remissions in this situation tend to be very short. Perhaps more encouraging is a recent study showing that high levels of cereblon and ikaros proteins are linked to response using IMiD therapy (immunomodulatory drugs, such as with lenalidomide Revlimid®). On the opposite side, studies are clarifying why checkpoint inhibitors (anti-PD-1/PDL-1) that had seemed like such promising targets are potentially dangerous by causing deadly heart damage (autoimmune, myocarditis). It seems that trouble comes when least expected.
The bottom line about t(11;14)
This is a very important translocation linked to better outcomes for patients with myeloma. Targeted therapy will likely to significantly contribute to improved outcomes. It is very encouraging to be making steps forward like this to refine the approach to myeloma care.
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.