MGUS may be linked “only” to some serious diseases…

I am slowly going through my still unopened Science Daily updates…the August 27 issue (see: contained a title that caught my interest: “Common blood disorder may not be linked to as many serious diseases.” The common blood disorder turns out to be MGUS.

In a nutshell, doctors have long been linking MGUS to more diseases than “just” multiple myeloma, amyloidosis and Waldenström macroglobulinemia. To my surprise, I discovered that there is a list of 75 other MGUS-associated diseases out there. 75! This list will almost certainly undergo some changes now…after the publication of the August 2009 Mayo Clinic Proceedings, which contain an interesting patient screening study declaring that the above-mentioned association is likely coincidental, in most cases, at least.

After reading the Science Daily summary, I went to have a look at the study (full study: Do you know that one of the MGUS-linked diseases is urticaria?! Eeek, just writing that word makes me itch all over!

Well, even though the full study is available online (above link), I thought I would take the time to go over a few points. Let’s see. The researchers confirmed that disorders of the bone, such as hip and vertebral fractures, osteoporosis, and hypercalcemia, are all significantly increased with MGUS, even in the absence of progression to multiple myeloma. We also confirmed known associations of MGUS with chronic inflammatory demyelinating neuropathy […] and autonomic neuropathy.

But they also found no significant association with MGUS in the 61 remaining disease diagnoses, an indication that most of these previously reported associations are either coincidental or clinically insignificant. So, in this patient population, 61 out of 75 diseases cannot be linked to MGUS. Interesting. Incidentally, see Table 2 ( for a complete list of diseases…you might be surprised by some of ’em…I was!

Also, have a look at Table 3 ( for a list of 20 new MGUS-associated diseases, including acute depression (!!!)…

In the Discussion part, we are also told that the frequency of osteoporosis and bone fractures is increased in patients with MGUS, independent of progression to myeloma. Eh.

Further on: The fact that we did not demonstrate a significant disease association with MGUS in such a large sample size is of major importance because it implies that these associations are likely not true associations, but rather coincidental ones. This has important therapeutic implications, because in some settings therapy has been administered to eradicate the monoclonal protein in the hopes that the associated disorder would be alleviated. Our study suggests that caution is needed.

Caution…indeed, I couldn’t agree more!

IL-1beta involved in progression from inactive to active myeloma

I found out about this wonderful little gem from a couple of myeloma list friends (thank you both so very much, D & D!). It’s an editorial (see: on a Mayo Clinic study titled “Targeting the Pathogenic Role of Interleukin 1beta in the Progression of Smoldering/Indolent Myeloma to Active Disease,” (abstract:; full study: I haven’t read the full study yet (I will read it tomorrow…it requires more attention and care than I can give it at the moment: ). Both can be found in the February 2009 Mayo Clinic Proceedings. At any rate, I am basing my post on the editorial (shorter and easier to read than the full study…).


47 patients, all at the inactive or smouldering myeloma stage (=my stage) but at high risk of progression, participated in the Mayo study, which was carried out between 2002 and 2007. The idea was to answer the fundamental question: WHAT THE HECK makes folks progress from inactive to active myeloma?


Apparently what happens is that IL-1beta, another of those beastly pro-inflammatory and pro-angiogenic cytokines, induces marrow stromal cells to produce large amounts of interleukin 6 (IL-6), thereby promoting the survival and expansion of the myeloma cells


The researchers confirmed their theory that reducing the activity of IL-1beta does, in fact, significantly increase progression-free survival (PFS) in these high-risk patients. This is extraordinary!


And now read this: blocking IL-1beta reduces IL-6 as well as the proangiogenic chemokine IL-8, therefore the use of IL-1beta-blocking strategies may result in new standards of therapy for high-risk patients with SMM/IMM. WOWIE!!!


In the study, all the smouldering myeloma patients were given anakinra, an IL-1beta inhibitor that is used for the treatment of rheumatoid arthritis and autoinflammatory diseases. I should add that 25 patients were also given a low dose of dexamethasone. Two of the them remained stable for about four years, and in fact, at the time of this writing, progression to active disease has not yet occurred […]. Since, as I mentioned, I haven’t yet read the actual study, I don’t know what happened in the other 23 cases…


Another significant excerpt from the editorial: In the study, patients with a decrease in CRP levels were more likely to have stable disease, confirming that effectively blocking IL-1beta (using CRP levels as the marker for IL-1beta activity) can halt progression to active myeloma.


Halt progression to active myeloma…aaaaah, how sweet those five little words sound…


Hmmm, but WHY am I so excited that I could skip and dance all around my study (probably will, as soon as I post this)?


Because, drum roll!, CURCUMIN INHIBITS IL-1BETA!!! (See, e.g.: and There are heaps of studies on this topic, in fact, probably much much better than the above two that I found after a lightning search…but right now I am too elated and, well, in a bit of a hurry–it’s almost dinnertime–to see if I can find the perfect one…I just want to go ahead and post this bit of good news!


More good news: curcumin is not the only one. Here is a list of the other natural IL-1beta inhibitors that I have found thus far (ah, but my quest has only just begun, so there will probably be more…):


1.     quercetin (strongly) and

2.     omega-3

3.     genistein

4.     EGCG

5.     resveratrol

6.     ellagic acid (on my to-be-tested list)


I will stop here because I want to go give my husband a big bear hug…and do another little jig of joy around the room on the way! Yippity yippity doodle! Evvaiiiii, grandeeeee!!! 🙂

The dandelion phenomenon, part II

Picking up from where I left off yesterday, the first type of cancer to be linked to stem cells was chronic myeloid leukaemia, or CML. The Johns Hopkins researchers proceed with a lengthy discussion on a drug called imatinib, which is used in CML, but without much success in the long-term. CML patients relapse if they discontinue imatinib (which, the researchers tell us, is currently being used more than interferon-alpha or IFN), or their cancer progresses even while they are on it. There appears to be no survival advantage in taking imatinib. The explanation, the researchers suggest, may lie in the CML stem cell resistance to this drug.

They use the dandelion analogy: “This pattern of activity is analogous to cutting a dandelion off at ground level. Although this will eliminate the visible portion of the weed, the unseen root also needs to be eliminated to prevent regrowth of the weed.”

Contrary to what happens with imatinib, CML patients’ response to the above-mentioned IFN is slow and gradual, “but can be durable.” So IFN would appear to act against the CML stem cells. Then we read “Thus, treatments that selectively attack cancer stem cells will not immediately eliminate the differentiated tumor cells. In this situation, cure (elimination of the cancer stem cells) in effect precedes the clinical demonstration of complete remission (clearance of the differentiated cancer cells) and could occur without actual disease shrinkage.”

This explains why these researchers took such a strong stance against the above-mentioned theory of complete remission. Complete remission may last months or years, but the cancer will return, eventually, unless the cancer stem cells are targeted. A treatment that targets cancer stem cells, however, won’t necessarily affect the circulating non-stem cancer cells. Hence, in this scenario, cure occurs before complete remission. This is contrary to everything I have read on the myeloma patient listservs (where a lot of the focus is on complete remission, or CR as we write it) and in the official myeloma literature. There are heaps of studies on the importance of complete remission in myeloma, in fact.

The researchers go on to discuss bortezomib (marketed as Velcade), a proteasome inhibitor, and lenalidomide (marketed as Revlimid, a derivative of thalidomide) commonly used in the conventional treatment of myeloma. These two drugs “can inhibit myeloma plasma cells but appear to have little activity against myeloma stem cells in vitro,” which means that they are pruning only the visible part of the dandelion, whereas rituximab, a monoclonal antibody, targets myeloma stem cells, i.e., the dandelion’s roots, according to the Johns Hopkins team.

The danger, the researchers point out, is that “As with IFN in CML and rituximab in myeloma, therapy directed against cancer stem cells might be prematurely abandoned if clinical activity is judged solely by criteria that reflect the effects of treatment on the bulk of the cancer.” And in fact, they add,“Not surprisingly, rituximab was found to have limited activity against myeloma in a short-term clinical trial. Rituximab’s activity against myeloma stem cells probably could not have manifested as immediate clinical responses in this trial because of the persistence of the long-lived, but terminally differentiated, myeloma plasma cells.” There you go.

So when we target stem cells, we must be patient. Unfortunately, nowadays, patience is no longer a virtue. We want to see immediate results. Overnight.

The researchers suggest setting up a clinical trial using bortezomib against the bulk of the cancer cells and then rituximab against the myeloma stem cells. Almost two years and a half have passed since this study was published. I went to have a look at the clinical trials being conducted right now. There are 591 trials (!) testing rituximab. I narrowed my search to myeloma, and found that there are 18 trials using rituximab alone or in combination with other drugs, such as lenalidomide or melphalan. Only one study, at the Dana-Farber Cancer Institute, is being conducted with rituximab and bortezomib, but for patients with Waldenstrom’s macroglobulinemia.

Well, these are certainly interesting times. I am all in favour of the dandelion theory, and it is for that reason that I am monitoring the DMAPT clinical trial, which should be beginning soon. (I admit to being more interested in substances such as DMAPT than in rituximab.)

The trees that are slow to grow bear the best fruit. (Molière)

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.