Remember the post I wrote back in December 2014 about myeloma subpopulations and the bone marrow microenvironment? Probably not…so here’s the link: https://margaret.healthblogs.org/good-or-bad-for-myeloma/first-do-no-harm-myeloma-subpopulations/
The main point is that not much is known about the interactions between the myeloma subpopulations living in our bone marrow, how they compete for survival and so on…
Therefore, the only conclusion, in my opinion, is that going in with conventional bombs and blasting the heck out of this microenvironment doesn’t seem to be the best strategy for those of us with MGUS and SMM…certainly not until we know a LOT more about what goes on inside this complex and, I would add, delicate setting.
Luckily, there have been more studies on this topic since my 2014 post, including this recent Dana Farber one, titled “The bone-marrow niche in MDS and MGUS: implications for AML and MM.” A blog reader sent me the link (thanks!): goo.gl/Ew3K4A
The full study isn’t available for free online, but I was able to read it thanks to a good friend. Okay, let’s have a look at it…
We know that MM is preceded by MGUS and by an intermediate stage called SMM.
Progression, that is, the “clonal evolution” of myeloma, takes place between MGUS and MM. But, the researchers add, some of the characteristics of myeloma can be found, “at lower frequencies,” at the MGUS and SMM stages. For example, the gene deletions.
Therefore, they say, it is the development of neoplastic “subclones” in the earlier stages that probably leads to the progression to myeloma.
This development wouldn’t be able to take place without the help of the bone marrow microenvironment, which therefore must be targeted in order to prevent progression as well as increase the effectiveness of conventional treatments once the stage of MM has been reached.
As I was reading this study, full of technical jargon that I could barely grasp, I began imagining the bone marrow microenvironment as a marketplace where strong nasty myeloma hooligans live and operate in coexistence with other, not-so-harmful, silly myeloma characters, as well as a bunch of normal folks, our normal cells.
Problem: myeloma clones have the ability of turning the marketplace into a toxic environment that helps them grow and proliferate.
A lot depends on how the marketplace reacts to these attempted changes. If it is weak and yields to the MM hooligans, it will become full of “weeds.” If it resists, it will be full (well, perhaps not entirely!) of crowds of happy customers, what the researchers call a “physiologically useful crop of mature blood cells,” that is, normal blood cells.
Now, a NORMAL marketplace contains all sorts of custome…I mean, all sorts of cells, including osteoclasts, macrophages, endothelial cells and, don’t you love this one?, sympathetic neurons. Lots of different cells that live happily ever after in this lovely area of the body.
Too many details here…okay, we don’t need to know this stuff…skip skip skip.
Certain cells (the above-mentioned stromal cells, e.g., after they have gone over to the dark side) become responsible for helping myeloma develop. Furthermore, whenever myeloma cells initiate a disruption, things that should be sleeping (in technical terms: in a quiescent state) wake up (remember EBV?). Not good.
Disruptions also cause tumor suppressor genes, such as Rb1, to be…suppressed. Also not good!
The end result of all the disrupting and suppressing, without any reaction from the immune system, is that the BM microenvironment becomes myeloma-friendly, and MM stem cells can begin proliferating, helped along by processes such as angiogenesis (remember all my posts on VEGF?).
As you can imagine, the study doesn’t mention anything remotely non-conventional. But some of its findings are interesting, so let’s keep reading.
Ah, another thing occurs: immunosuppressive cells arrive in the marketplace and make such a ruckus that T cells and B cells are completely overwhelmed and can’t function properly. This means, of course, that myeloma cells are no longer being sought and destroyed by our immune system.
The study therefore gives us a lesson in progression. First and foremost, as we’ve just seen, myeloma cells learn how to avoid being annihilated by the immune system. They then create what the researchers call an “immunosuppressive environment” where the immune system defenders are no longer able to function normally. Other types of important cells present in this now-toxic environment are also affected, such as stromal cells.
When MGUS progresses to SMM and then MM, immunosuppression is one of the main culprits. In fact, I recently read a study that discussed this problem, concluding that patients with SMM whose other immunoglobulins—in my case, e.g., IgA and IgM—are suppressed are more at risk of developing myeloma. *
The questions are: can we stop this process? How? And…when?
In 2014 (and before), my opinion was to “watch and wait” for as long as possible. Until CRAB symptoms appear. My opinion hasn’t changed in all these years. Indeed, it hasn’t changed today.
“Watch and wait” doesn’t mean sitting around and moping and doing nothing but watch TV series all day long. It means being proactive, doing research, enjoying life, taking something that doesn’t have any toxic side effects and that has been shown at least in vitro to be anti-myeloma, such as curcumin. And so on. There’s lots of stuff we can do in this stage…
Okay, I think this is enough for one day. After almost falling asleepzzz myself, I decided to divide this post into three parts…or perhaps only two.
So…more on this topic tomorrow! Ciao!
P.S. The study also discusses the evolution from MDS to AML, but I didn’t really look at that part, of course, since it’s not my main focus…
* P.P.S.S. While it’s true that my IgA and IgM are suppressed (barely “alive,” in fact!), it’s also true that they’ve been pretty much at the same tiny level for years now. So yes, I am in the high risk category BUT I am still here, leading a normal life, no CRAB symptoms…
Living proof that being at “high risk” doesn’t have to be as scary as it sounds…right? 🙂