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'The Seed and the Soil' in the search for the cure.

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In presenting "What is myeloma" to newly diagnosed patients, Dr. Morie Gertz uses the comparison of myeloma to "weeds" in a garden, which in this case is the bone marrow microenvironment.  A recent book, Weeds: in defense of nature's most unloved plants, by Richard Mabey, provides wonderful insights into the analogy of myeloma cells as weeds.  

So what is a weed?  The first aspect is that it is not intentionally planted- so it is not a "plant" (or flower/tree/bush) which you wanted.  Certainly, this applies to myeloma cells nobody wants them.  There are truly intruders.  Other aspects which apply are: aggressive, resilient- hard to get rid of and spreading in an unwanted fashion.  What is the driving force behind all this?  Why do weeds keep popping up?

 The answers are interesting and important.  Weeds love "disturbed ground": areas recently dug up, bulldozed, abandoned, or contaminated with toxic waste.  Classic sites for weeds were bomb sites in London during the blitz of the Second World War.  Weeds unseen for generations, suddenly grew in profusion.  The weeds started a process of environmental healing: transitioning to new urban countryside.  So weeds function in a restorative fashion.

So what is myeloma?  Local sites of myeloma in damaged tissues do occur rarely but are quite remarkable.  For example, a gentleman struck by lightning on his leg bone went on to develop myeloma at that site.  Other examples include myeloma growing in the pocket for a cardiac pacemaker which became infected and myeloma growing alongside leaking silicone breast implants.  So the point is a disturbed, activated, and damaged microenvironment can enhance myeloma growth.

Weeds also outgrow new favorable environments.  If conditions are right, weeds can overtake any garden.  Myeloma cells do the same and continue to grow when conditions favor antibody production or production of the "monoclonal spike" in an effort to combat infection.  A "positive feedback loop" can be established whereby the disturbance, activation, or damage is not corrected (for example, breast implants are leaking and are not removed) and a favorable growth environment persists.  The myeloma monoclonal protein (or antibody) cannot do its job: the local situation is not corrected.  It is amazing to see the impact of what happens when the situation is corrected   with immune modulating agents such as thalidomide, Revlimid, and Pomalidomide.  The microenvironment is stabilized: growth slows or stops.  There is an opportunity for abnormal cells to be eliminated.  But, like weeds, myeloma cells are remarkably resilient.  We need ways to wipe out every last cell and/or keep the microenvironment hostile for new growth.

In nature, mature forests teach us many lessons.  Trees and shrubs dominate some weeds, those which are light dependent die off, others are not able to compete with large trees that change the soil chemistry.  So re-achieving balance is a natural strategy.  This provides hope and the expectation that correct maintenance strategies can work long term, if crafted with the aim of achieving the best immune and chemical balance. As we are learning from our fields and gardens, using stronger and stronger weed killers may not be the way to go.  So let's keep an eye on the weeds and see what more they have to teach us and help us in the search for the cure.

1 Comment

Hi,

I have heard about the weed analogy of myeloma (e.g you can remove the weed (multiple myeloma cells) but that is temporary unless you remove the root (multiple myeloma stem cell). Thus, there is an urgent need for the development of Multiple Myeloma cancer stem cell-targeted therapies. I have listed a few of them below. My question is how close any of these therapies are to completing clinical trials. Have any of these MM CSC-targeted therapies, to your knowledge, stopped myeloma from recurring in humans? If so, are any of them currently available for use?

Myeloma cancer stem cell-targeted therapies:
Rosiglitazone and all-trans retinoic acid
Dimethylaminoparthenolide (DMAPT)
anti-MMSC-1 mAb
Pretransplant targeting of multiple myeloma stem cell (MMSC) with armed activated T cells (aATC)
GRN163L (Imetelstat)
antibody C3B3
MAL3-101
Cyclopamine Rituximab
Interferon + Interleukin-6

What other MM CSC-targeted therapies are currently being developed in the pipeline?

Thanks,
A.M.

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