The myeloma tap: part II

Day before yesterday, in part one, we saw that the only myeloma cells capable of cloning themselves are the ones that do not express CD138. The following excerpt from the Johns Hopkins study says it well: “multiple myeloma cell lines and primary bone marrow contain small populations of clonotypic B cells that do not express the characteristic plasma cell surface antigen CD138 and are capable of clonogenic growth and differentiation into multiple myeloma plasma cells in vitro and in vivo.”

Myeloma stem cells, therefore, don’t have CD138 sticking to their surfaces. Herein lies a big difference between regular myeloma cells and myeloma STEM cells: the former have CD138, the latter don’t. Enough said on CD138. Let’s look at other findings now.

I mentioned in my January 12th post that the capable-of-cloning-themselves myeloma cells are resistant to chemotherapy AND look like normal memory B cells AND also display "cellular properties characteristic of normal stem cells, suggesting cancer and normal stem cells share multiple mechanisms that promote drug resistance.” In fact, according to the 2008 stem cell study, both myeloma and normal stem cells have “intracellular detoxifying enzymes,” enzymes that, as I understand it, shoo away the chemo toxins, thus protecting the stem cell from apoptosis. This would provide a good explanation for why myeloma eventually becomes resistant to chemotherapy agents.

So, in sum, what does all this mean? In the researchers’ words, “Because cancer stem cells are a relatively low frequency population in most tumor types, the true inhibition of these cells is likely to be difficult to assess early after treatment, and a prolongation of disease remission would be required to establish such activity.” Well, that doesn’t sound very encouraging, does it?

Back in the middle of November, in a private exchange, a blog reader compared myeloma to a tank of water with a tap and a drain, an analogy he took from the film "Lorenzo’s oil," (those interested can go read a 2007 update on the real ALD story: Anyway, the blasted paraprotein shoots out of the "tap," and the drain hole (our kidneys) gets rid of it. Myeloma cells, he was told by his haematologist, have a half-life of 5-6 weeks (I have been trying to find an online reference to this, but so far, on the UK freelite website, I found only that the “the serum half-life of intact immunoglobulin IgG is 20-25” days, so I will ask my haematologist about this in February). In other words, the cells stay in the body for that time and are then expelled via the kidneys.

Point is, are stem cells our "tap"? If so, how can we turn it off? I sure would like an answer to those questions! I would like to add that during yesterday’s meeting, Dr. Benelli suggested another "tap" theory to me, which I will be looking into in the next few days. Interesting times.

Concluding remarks. In the short term, yes, this stem cell research is exciting news but that’s what it remains: news. It has little relevance to us patients. For now. It holds promise for the future, though, indeed let’s hope the very near future. A finding that may prove to be useful is that “the developmental signaling pathway Hedgehog is up-regulated in multiple myeloma stem cells and regulates cell fate decisions.” So we meet again, Mr. Hedgehog! Back in early August, on August 2 and 3 to be precise, I wrote about cyclopamine, a poison contained in corn lilies that was found to be a Hedgehog pathway inhibitor (see my page on cyclopamine).

A couple of days ago, in a private exchange, an MMA list member asked me if the stem cell study had changed my supplement plans for the future. I answered yes, it has, in the sense that I hadn’t really thought seriously about taking parthenolide until I read about myeloma stem cells and how parthenolide and DMAPT (water-soluble form of PTL) annihilate leukaemic stem cells in vitro. So parthenolide shot right to the top of my supplements-to-try list. I am now planning to test parthenolide in March, after the Biocurcumax experiment has ended.

Summary of the main points made in the stem cell study, from my point of view:

  1. clonogenic myeloma stem cells do not express the characteristic CD138 antigen.
  2. myeloma stem cells constitute less than 2% of the myeloma "population."
  3. myeloma stem cells look like memory B cells.
  4. myeloma stem cells display normal stem cell characteristics that protect them "from toxic injury."
  5. like normal stem cells, nearly all myeloma stem cells (>98%) studied were in the quiescent (dormant, inactive) state, which is possibly another "major mechanism of drug resistance."
  6. conventional chemotherapy doesn’t affect myeloma stem cells.

The myeloma tap: part I

This post was way too long so I decided to cut it in half. I will post the second part tomorrow. Only then will today’s title make complete sense.

Anyway, I have it, I have it! Yes, the FULL recently published Johns Hopkins myeloma stem cell study that I mentioned a couple of days ago. Okay, I confess that I have had it in my possession since last Sunday, when a very kind blog reader (thank you thank you thank you!) sent it to me, but just haven’t gotten around to writing a post about it. The study, by the way, was conducted by a team led by Dr. William Matsui and published in the January 1 2008 issue of “Cancer Research.” You can view the abstract here:

Before I go on, though, I wanted to mention that another blog reader posted an interesting New York Times article on the controversy surrounding the cancer stem cell theory and other interesting info, so if the issue of stem cells is your cup of tea, please go read Carla’s comment on my “Stem cells and myeloma” post, Jan 12th.

Back to us. I have to admit, reading this stem cell study was not exactly as fun and easy as reading one of the Harry Potter books, but I found it almost as engrossing. The study begins by providing a bit of background, including this: “Early studies examining a murine model of multiple myeloma suggested only a minority of cells were capable of clonogenic growth.” Hmmm, so only a tiny percentage of myeloma cells can clone themselves…I didn’t know that. I thought they were all capable of creating clones. Live and learn.

Myeloma stem cells are mentioned in a 1977 study (full text:, which, by the way, shows black and white photos of myeloma cells for those who might be interested. Anyway, according to the Johns Hopkins investigators, this early study showed that “the cloning efficiency of primary multiple myeloma specimens was 1 in 1,000 to 100,000 cells. To date, it has remained unclear whether these clonogenic cells are distinct from the plasma cells that constitute the majority of tumor cells.”

Then, in 2004, Dr. Matsui et al published a study (full text: in “Blood” on clonogenic myeloma cells. Clonogenic, by the way, has two meanings: 1. “giving rise to a clone of cells” and 2. “arising from or consisting of a clone.” I went through the 2004 study, which reported that “highly clonogenic cells from both human MM cell lines and primary patient samples do not express CD138, but rather markers that are characteristic of B cells.” This rather baffling sentence will, I hope, become clearer after the upcoming section on CD138 (and part II, which I will post tomorrow, should also help in that sense). The 2004 study also suggested that, like chronic myeloid leukaemia or CML, “MM is another example in which cancer stem cells are a rare cell population that is distinct from the differentiated cells that comprise the bulk of the disease.”

CD138. Now I am going to delve into some rather difficult material that has to do with this thing called CD138. Also known as syndecan-1, CD138 “is “a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells.” I know, I know…Let’s see if this will clarify matters: proteoglycans are “glycoproteins but consist of much more carbohydrate than protein; that is, they are huge clusters of carbohydrate chains often attached to a protein backbone,” according to Prof. Kimball’s Biology Pages. (Hmmm, lots of carbs plus some protein…pasta with meat sauce! )

Seriously though, it doesn’t really matter if we don’t completely grasp what CD138 is. What’s important is that we understand the following excerpt from the 2004 Johns Hopkins study. CD138 “is the most specific marker for normal and MM plasma cells. However, normal CD138+ plasma cells appear to be terminally differentiated and unable to proliferate, and there have been few studies using this marker to study the proliferative capacity of MM cells.”

Not the easiest stuff to digest, eh! Well, let’s see if I can explain what CD138 is in a few simple words (if I make any mistakes, please let me know): in sum, CD138 is a thingie (ok, a proteoglycan) sticking to the surface of regular myeloma cells—the ones, that is, that are NOT able to clone themselves. These are the CD138 "plus" myeloma cells. Patients whose myeloma cells release, or "shed," CD138 (CD138 "negative" cells) into the serum have a worse prognosis than those whose myeloma cells still have it. Hence it is a helpful prognostic marker (for more info, see this 2002 “Blood” study: CD138 levels can be measured in MGUS patients, too (see this 2006 "Neoplasma" abstract:

A September 2007 “Blood” study (see abstract: confirms that “High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis.” So again we see that if CD138 is shed into the myeloma “microenvironment,” this is bad news for us (poor prognosis etc.). Interesting aside: this is true for CLL patients as well (see this January 2008 abstract: Connections, connections.

Ok, that’s it for today! Phew.