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Multiple Genetic Abnormalities in Myeloma: Implications for Treatment

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.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF Hotline, call 800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.


Interestingly enough the data provided continues to talk about early treatment for MM, however the standard testing during any physical exam does not call for this M protein screen or any other specific tests to be done to try and isolate a person having this disease until bone pain is exhibited, renal failure or other symptoms of advanced disease. In today's world being fatigued is part of the day to day to an extend and while someone may show as anemic the normal treatment is to prescribe iron and dietary changes rather than look for additional markers for myeloma. This would be especially true in younger patients that don't meet the "standard" criteria for at-risk individuals

What is being done to include MM screening as part of normal CBC style testing we would have on an annual basis.

My wife was recently diagnosed with MM only after experiencing severe back pain due to a compression fracture of her T12 vert. She had just had a surgery for a hysterectomy that entails a "complete" blood work up 6 months prior which would have caught this before we are at this point.

It screams of more action early!

I find it very depressing that you say that the hope of finding specific individual genetic triggers is fading. My husband (who has a Ph.D. in biology) and I still hold out hope that this approach will lead to new drugs that can target the chromosomal (and genetic) abnormalities that lead to this disease.

Are there any other cases involving a young (37)patient with 1 lesion, 2 weeks into treatment dying from a heart attack? We recently lost a relative this way.
Thank you

Should we begin treatment as soon as possible for smoldering myeloma? What is the most reliable indicator?

this article in a way confirms Dr. Bart Barlgie approach of kitchen sink (i.e. hit them so hard!)

at any rate, it's crapshoot all over.

Could you please comment on the recent
trials from Abramson Cancer Center
HUP on genetically modifying stem cells
prior to transplant?
Thank you

Just wanted to thank you, Dr. Durie for your dedication to find a cure and inform us all about MM!!

My Mother passed away with Multiple Myeloma. Are these new studies showing that her children could be at a greater risk genetically ?

Are you referring to daratumumab and T-cell therapy clinical trials as leading us astray?

The genetics discussed here are abberations caused by myeloma, not the genes you were born with. There may be some hereditary susceptibility, but it is not implied in the genome sequencing referred to here. I think. I'm not an expert.

I encourage all who read this to support the BSRI. It is an exciting approach that could yield fantastic results. Think outside the box and help fund this project!! God Bless

Reading this article seems to imply that treatment should begin as soon as possible. What is the implication for early myeloma, I.e., what the medical profession calls smoldering?

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