A recent article in the medical journal Cancer Cell documents the widespread chromosomal abnormalities present in myeloma cells. The sobering data from this study, the largest of its kind, also demonstrate why the promise of individual therapies targeted against individual genes is fading--and why the Black Swan Research Initiative approach offers a smarter plan of attack against myeloma.
We've known for several decades that myeloma cells have many chromosomal abnormalities. This is, in fact, the characteristic feature of myeloma at the molecular level. It has also been known and well documented that clonal evolution occurs and multiple subclones exist. Despite that, there has been a strong interest in developing personalized targeted therapies against individual gene mutations. (See my blog, "The Promises and Challenges of 'Personalized Medicine' for Myeloma," April 3, 2012.)
What is new and sobering, as emphasized by the authors, is the total amount of clonal heterogeneity, an amount which is even much, much greater than suspected from prior studies. Many genes are abnormal, and even within the same patient, there are multiple clones with different genetic mutations. As had been noted in the authors' earlier study of 38 patients, there are some recurring patterns of chromosomal abnormalities, including, for example, the BRAF gene. This is important because researchers have developed a cancer therapy targeting BRAF.
However, this idea of targeting individual genes is now seen to be taking us in the wrong direction. For example, not only does anti-BRAF therapy target a small fraction of a patient's myeloma cells but, more importantly, these same myeloma cells have many, many additional mutations. So while it is very interesting to identify mutations in different pathways, such as EGRI, BCL2, NFkB, and D153 and FAM46C (collectively this pair of mutations occurred in 21% of patients), the question of how to proceed in search of appropriate therapy remains unanswered. An especially important point is that an average individual patient sample has at least five subclones, each with multiple genetic mutations.
With awareness of these data, the Black Swan Research Initiative was developed in 2012.  There are several aspects to the BSRI initiative, but key points relevant to clonal heterogeneity are:
  • Best results can be expected by starting therapy before major clonal heterogeneity emerges.
  • After therapy, a much more limited number of clones remain (resistant subclones). This process is called clonal contraction (or restriction), following induction treatment. Fewer clones means many fewer mutations to deal with. 
  • Studies of these residual subclones at the molecular and drug sensitivity level are essential.
  • Using new reproducible tests for assessment of minimal residual disease (MRD), these residual clones can be detected, studied, and treated appropriately. This is the strategy for success: monitor and treat to achieve MRD-Zero.
  • It is assumed that combinations of agents and modalities and multifunctional therapies will be required to produce the best results, overcoming complex chromosomal abnormalities.
Genetic heterogeneity is a challenge, but "forewarned is forearmed." With knowledge of myeloma's widespread genetic heterogeneity, BSRI was designed to implement the best plan of attack against myeloma in 2014 and beyond.
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