Does MGUS always precede myeloma?

A while ago, I asked my dear Sherlock (grazie!) to send me the study on this very topic, published in the January 29 2009 and also the May 28 issues of “Blood”: (Update: after writing and publishing this post, I discovered that the full study is available for free online, just click on the tinyurl link, then on “full text”; please note that there is also a related Spanish article titled “Are all myelomas preceded by MGUS?”…you will find the link almost at the bottom of the page).


12 researchers from different cancer institutions examined the cases of 77,469 individuals who had participated in the nationwide population-based prospective 1992-2001 “Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial” or PLCO. They identified 71 patients who developed MM during the course of the study. A series of tests determined that almost all had passed through a prolonged pre-malignant stage (8+ years before diagnosis). I would like to point out that, at the beginning of the study, all the trial participants were healthy.


A few details concerning the 71 myeloma patients: 71.4 % were males, and the average age was 70. Important note: 8+ years before their MM diagnosis, 82.4% of these patients had MGUS. But 2 years before their MM diagnosis, 100% of them had MGUS. Therefore, In the present study, an asymptomatic MGUS stage preceded the diagnosis of MM in all cases. “In all cases.” Wow. Anyway, you can read a few more details and numbers in the abstract.


The full study begins with the usual dire statistics…skip skip skip. Then we find the crucial question: is myeloma always preceded by asymptomatic MGUS or SMM? If so, the researchers say, then we need to focus on identifying risk factors for MGUS and to improve our knowledge on underlying mechanisms of transformation from MGUS to MM, with the aim to define better predictive markers of progression and to develop chemopreventive approaches. Good idea!


And then: how can a preceding MGUS stage be ascertained in folks who are diagnosed with myeloma? If there are no blood samples from previous years, that would be impossible. And in fact the researchers write that Thus far, it has been impossible to determine if a protracted premalignant phase (MGUS) precedes MM in all patients.


“Thus far.” But the above-mentioned Screening Trial gave these researchers the golden opportunity to test blood samples taken from patients 8 years plus before their myeloma diagnosis. All that blood was tested via serum protein electrophoresis, immunofixation and FLC assays.


Interesting titbit. MGUS and SMM were lumped together, because for the purposes of this study our interest was to determine whether a premalignant asymptomatic stage preceded all cases of MM, regardless of whether that stage met the clinical diagnosis of MGUS or smoldering MM. So when we read MGUS in this study, it also means SMM (my current stage). Good to know.


A few more details: the researchers discovered that about 50% of the MM cases remained fairly stable…whereas the rest had a yearly M-protein increase. In the end, though, all of these patients—the fairly stable ones and the, er, more unstable ones—progressed to active myeloma (well duh, this is hardly surprising, since the researchers examined patients who ended up being diagnosed with myeloma…not those who remained MGUS or SMM).


In the Discussion, the researchers write that virtually all MM cases are preceded by MGUS. They then add: At the same time, however, one has to keep in mind that the vast majority of MGUS cases will never develop MM. It depends, they say, on the status of risk factors such as a high serum M-protein level, non-IgG MGUS and so on. In the absence of risk factors, the likelihood of progressing to active myeloma is itsy bitsy teeny tiny.


The researchers point out that it would be important to identify, via molecular markers and whatnot, the subsets of MGUS cases at high versus low risk of developing MM. Our finding that MM is universally preceded by a prolonged premalignant stage with up to 75% of MM patients having detectable M-protein 8 or more years prior to diagnosis of the malignancy fills a key gap in the present literature on myeloma-genesis.


They then add that even those who have had MGUS (or SMM) for 25-30 years may progress eventually to active disease. So our risk of developing myeloma diminishes with every “stable” year that passes but never vanishes, so we have to resign ourselves to be monitored for the rest of our lives. Well, no surprises there…


I came across an interesting hypothesis concerning those who progress from MGUS to active myeloma. In these particular cases, the researchers suggest that MGUS might not be a benign condition at all, but rather a slow-growing form of myeloma. They write that Although it remains to be confirmed, we have speculated that “evolving MGUS” potentially could be a reflection of an “early” myeloma with a slow rate of progression. Well, well…


There were a few drawbacks in this study, such as the lack of a younger-than-55 population: the population-based PLCO cancer screening study enrolled healthy individuals who were 55-74 years at baseline […]. And let’s not forget that the average age of the 71 myeloma patients was 70. Quite a big drawback, especially for younger folks like yours truly. Oh well. 

The study ends with the following statement: Thus, regardless of the terminology used (MGUS or otherwise), we can confidently say that the presence of an M-protein in 93% of patients with MM seven years prior to diagnosis of MM as seen in this study strongly confirms that a protracted premalignant stage (biologic MGUS) precedes all cases of MM. […] Future studies are needed to provide new insights on the pathogenesis of MGUS and better predictors for development of MM in order to take early actions to prevent or delay MGUS progression.

I would have been curious to know how many of the PLCO participants remained MGUS or SMM. Too bad that data couldn’t have been included here. Oh well…can’t have everything!

For my sister

img_0233I am sending you a huge birthday hug! I wish you and niecie could beam yourselves over the ocean at least for today, so we could all be together. Well, at the very least I hope that you-know-who lets you win a Scrabble game or two today! (wink!)

I love you!!! Have a super birthday, bellona!

2008 contractor awards

First, just a quick note to say that my parents arrived safe and sound from the U.S. on Tuesday afternoon. As you can imagine, we have been catching up (I haven’t seen my parents since October 2008), so I haven’t done any research…well, until this morning, when I actually read a study and drafted a post, which, however, is not quite ready yet. Tomorrow, tomorrow…


In the past few days, however, I have found a bit of time to read and respond to private e-mails and contacts from my blog. I also received some welcome news: a few new curcumin-takers were kind enough to let me know that their previously (before curcumin, i.e.) increasing myeloma markers have finally stabilized. YAY!


As for the many readers who send me “thank-you-for-your-blog” messages, I want you to know that, while I cannot reply to any of them (or I’d be doing nothing else jy091), I deeply appreciate your extremely kind comments, I really really really do, thank you so very much! I instead do reply, or try to reply!, to anyone asking specific questions…which reminds me: if you have asked me a question and have not received an answer, that means that either I missed your message in the first place or the “Mailer Daemon” prevented me from communicating with you (Barry is one such case). So please write to me again. Thanks. 


And now for a bit of fun, which is always good for the immune system. A blog reader (merci !) sent me a very funny message today: the 2008 contractor awards…I laughed out loud at some of the images, which I later found (most of ’em, plus a few more) on YouTube: Which one do you think should have won? Hehe.

Venaria Reale

img_0163I have to admit that I was a bit disappointed in the ancient Egyptian exhibition hosted at Reggia Venaria…yes, there were some magnificent colossal statues, and the one in the last room was splendid…but I had expected to be absolutely floored by the reproduction of the underwater environment…and…well, that just didn’t happen. The “underwater” part of the exhibit consisted mainly of a series of darkened rooms…one in particular was a dark narrow hallway displaying artefacts behind small glass “portholes” positioned at various heights. Under normal circumstances, bending over to peer inside a “porthole” would not have been a problem…but on Saturday afternoon the place was crowded with hot and tired tourists wandering around aimlessly in the very stuffy darkness. I had to be careful about not bumping into them. That was a rather unpleasant experience, yes, especially whenever I heard someone cough nearby (YIKES!). I don’t suffer from claustrophobia, but if I did…well, I’d have scampered out of there like a rabbit fleeing from hungry lions!


In conclusion, I just didn’t enjoy the exhibit as much as I thought I would (my B.A. is in Social Anthropology, you see, and at one point in my life I really really wanted to be an archaeologist…archaeology remains one of my passions). To be fair, thought, there were some stunning pieces in the exhibition…so in the end it was probably worth the nine-hour round trip. I just wish we hadn’t been so oxygen-deprived in the exhibit, and that my expectations had been a bit lower.


img_0192After the exhibit, we went through the royal palace. Well, after seeing what is considered to be one of the most splendid examples of Baroque architecture (certainly in Italy), it’s clear to me that the only thing I like about that entire period is the music: Bach, Vivaldi, Handel, Purcell etc. Nope, Baroque architecture is definitely not my cup of tea…but, certainly, img_0190very grand!


The palace gardens. Ah, again, a bit of a disappointment. But it is also true that Saturday afternoon was very very hot and humid, so wandering through a garden offering very little shade certainly didn’t add to our enjoyment. I did think the rose bush garden was lovely, though. But why were all the roses white? I would have preferred to have seen rose bushes in different colours…


Oh bother, today I must seem like Mary Mary Quite Contrary…yet I am actually very happy and excited, since my parents, who are still in the U.S. img_0210right now, are arriving tomorrow afternoon in Florence. Tomorrow morning I am going to work as usual but will leave in time to meet their flight…at 2 PM. Unfortunately for them, Florence is on red alert right now…one of the hottest cities in Italy (quelle surprise!). An unusual heat wave for the month of May…luckily the heat is supposed to end a few days from now, and temperatures are supposed to go back to normal. I really hope so. I am about to melt!

Sunken treasures

Early tomorrow morning Stefano and I are going to an art exhibition just outside of Turin (region of Piemonte) titled “Egypt’s Sunken Treasures,” which includes more than 500 ancient Egyptian artefacts that were found at the bottom of the Mediterranean Sea. I am mainly intrigued by the fact that part of the exhibit reproduces this underwater environment. It sounds spectacular. More details can be viewed here:


Since Venaria Reale is a 4.5 hour drive from Florence, we will have to spend the night there (a neighbour is going to care of our kitties, as I take care of hers when she is gone…works out perfectly for both of us). On Sunday, before returning to Florence, we will also visit the Baroque royal palace that hosts this exhibit, the 17th century Venaria Reale (, and its incredible-looking gardens. Both the palace and its park are UNESCO World Heritage Sites.


And, even though I admit that Baroque is not my favourite style (I am more of a Romanesque type of gal…), I imagine that we will take our usual million and a half photos…but I will try very hard not to post all of them…hehe. Have a great weekend and…see you on Monday!

Bursting capsules

A blog reader, who is also a friend of mine in real life, recently had an autologous stem cell transplant. Now that he has recovered from the procedure, he is following my curcumin protocol.


Well, he wrote me a story that, with his permission, I thought I should post, mainly to remind us to be extra careful when handling a certain…er…item.


His wife recently bought him a nice blue and white designer shirt that he wore on only one occasion, then put in the wash. Unfortunately, though, he forgot to check his shirt pocket, which happened to contain a curcumin capsule. Most of you, certainly the curcumin-takers!, can imagine what happened next. Yep…


The capsule exploded like a “bomb” inside the washing machine, staining everything yellow…in particular the expensive designer shirt, which, even after being rewashed several times and soaked in a bit of mild bleach, still has a deep yellow stain stretching from the neck to the sleeve…


He was hoping that I might have a miracle remedy for such an occurrence, but I do not….other than using a bit o’ bleach…eh.


So, may this be a dire warning to us all…check your pockets before putting your dirty clothes in the washing machine. You can never be sure that a curcumin capsule won’t mysteriously materialize inside a pocket or a seam…mischievous stuff, curcumin!

Moringa oleifera and myeloma

Thanks to a fellow blogger, Dave (whose two-year-old son Jaymun has been battling AML since birth; the link to his website, “Jaymun’s Journey,” is on the right-hand side of this page), I learned of a new plant with amazing anticancer (etc.) powers: Moringa oleifera.


This morning, in fact, I read Dave’s recent report on a group of creative and dedicated Wisconsin high school students who tested a tropical plant extract on a group of mice with cancer. The mice not only survived but also appeared to have lost their tumors, whereas all the ones in the control group died. The students also administered this plant extract to healthy mice that became more active and appeared younger. More details on this fascinating story can be found here:


Moringa oleifera is a very nutritious tree…I mean, yes, you can actually EAT it. I read that its leaves contain more protein than yoghurt (!)…and also calcium, iron, vitamin Bs and so on. For a description of the Moringa oleifera tree, see: Here I read that parts of the tree are used as an antiseptic and in treating rheumatism, venomous bites (!) and other conditions. Interesting…but does it affect myeloma?


Wellwellwell, after a very quick Google search, I found a 2007 study according to which Moringa oleifera is indeed strongly cytotoxic to myeloma cells. “Oh, this is good, this is very good!,” I thought. I then checked PubMed where I found 124 studies dealing with this tree and many of its amazing properties. Today, however, I barely have enough time to take a quick look at the 2007 myeloma study. As follows.


The study (full study: tells us that Moringa oleifera is a multipurpose tree widely distributed in Asia and commonly used in Indian traditional medicine. The leaves of this tree were used in folk remedies for tumors and as a food source for humans (and, I read elsewhere, for animals, too).


Why am I not surprised to read that this tree yields substances that are antioxidant, anti-bacterial, fungicidal, hypocholesterolemic and anti-diabetic? Familiar story, eh. In any case, the researchers tested both Moringa oleifera and Vinca rosea  leaf extracts (the drugs vincristine and vinblastin derive from the latter, btw) on myeloma cells. They found that the Moringa extract had much stronger anti-myeloma effects than the Vinca one. Well, how about that?

More testing is needed, of course, but this preliminary data sounds very very good to me…enough to say that another promising substance has joined my rather…substantial, by now, list of anti-myeloma non toxic plant extracts…yay! Oh bother, my time has run out…I really must dash off now to prepare my classes for tomorrow. Ciaooo!

P.S. yes, my blog banner is a photo of Piazza del Campo, Siena. Bravi!

Phase I trial of feverfew in cancer patients

Those of you that who been following my blog in recent times know that I have been through a rather difficult period, emotionally speaking (in particular, the death of a close relative in Stefano’s family) and am only now getting my brain back on track…beginning to read studies again and so on. I have dozens of fascinating studies and Science Daily newsletters piled up on my desktop…plus interesting material and links that many of you have been sending to me. I should be finished by the year 2195…


Speaking of blog readers: Barry, I tried to send you TAB’s report, but I keep getting an “impossible-to-be-delivered” message. Sorry. I tried twice…failure both times. This happens now and again: I reply to a blog reader’s question, but my message doesn’t go through. So, if you have asked me a question and haven’t heard back from me, it may not be my fault (how’s that for a good excuse? hehe). Seriously, though, try writing to me again, using a different e-mail address if possible. Thanks!


Let’s get to today’s topic. In one of my posts on feverfew/parthenolide (PTL)/DMAPT, I mentioned en passant a 2004 Phase I feverfew trial…but I recall that I only glanced at the abstract and, back then, didn’t have access to the full study. Then I must have forgotten about it. Well, it just so happened that last week Sherlock (sei fantastica!) found and sent me a bunch of full studies on various topics, including, yippee, the 2004 feverfew trial study (abstract: Super!


Oh, before discussing the full study, I just wanted to say two more things. 1. I have planted two more feverfew plants in my front yard. The one that I planted last year barely made it through the summer and then died, much to my sorrow. It was my own bloody fault. It was a hot summer so I kept watering it…and I probably ended up drowning the poor thing. This just goes to show that too much love and attention and may not necessarily be a good thing. Anyway, this year I will do my best not to over-water the two plants that Stefano’s aunt sent to us from southern Italy. Fingers crossed. Actually, thus far they are doing fine…indeed, they are about to flower; as soon as that happens, I will post some photos.


2. In November 2008, soon after taking my first feverfew pill (not the Tanacet brand used in the 2004 clinical trial, by the way, but another brand containing a slightly higher PTL percentage), I felt a surge of heat on my upper lip. I checked in the mirror, and there it was: a small but rather angry cold sore. Stefano accompanied me to a pharmacy to buy some zovirax cream that I dabbed on the spot. The following day it had vanished. Other than that minor incident, I didn’t have any particular problems with feverfew.


Okay, now for the study. The abstract, which you can go read on your own, explains what feverfew is, gives the basic info about the trial and so on. As many as 4 mg of feverfew were given to a small group of cancer patients who experienced no significant toxicity. Interestingly, the maximum tolerated dose was not reached. I had to read the entire study to find out why.


On the down side, even at the highest dose—4 mg—there was no detectable concentration in the plasma. That means that feverfew is probably poorly bioavailable, as the researchers also suggest further on in the study. But, because of my initial reaction to the feverfew pill (the cold sore, I mean), I wonder if, like curcumin, feverfew might work on different areas in the body…other than the bloodstream, that is. These are the ramblings of a non-scientific mind, of course. Okay, let’s take a look at the full study.


The first paragraph makes the point that many chemo drugs derive from plant extracts: The taxanes, paclitaxel and docetaxel, are very important anti-cancer drugs derived from the yew plant family. Then we read a list of parthenolide’s properties…the main ones are potent in vitro anticancer and antiangiogenic properties, inhibition of NF-kB, IL-6, IL-8 and drug resistance.


The purpose of this clinical trial was to see if PTL would show up in cancer patients’ blood. It was administered daily for 28 days. Subsequent 28-day cycles were administered with an intervening break. No more than 4 mg/day were given because of drug supply issues…and financial considerations. Aha, that explains why the maximum tolerated dose wasn’t reached in this trial.


The patients took feverfew capsules (brand: Tanacet) containing 500 mcg of PTL, in the morning on an empty stomach (ahhh, how I loved all these details!). They were instructed not to eat for 1 hour after ingestion. More details: In cycle 1, blood samples were drawn on day 1 and 29 in the following fashion: pretreatment, and then 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 12, and 24 hours after the ingestion of the capsules.


Patient information: Twelve patients with advanced solid tumors were treated with feverfew. The median age was 73 years (range 48 to 80). There were 11 men and 1 women enrolled. The cancers treated included eleven prostate and one breast and all patients had metastatic disease and had received prior therapy.


Problems. Even though the patients experienced no significant toxicities, the trial was stopped at the dose level of 4 mg daily once it was determined that no parthenolide was identified in the plasma of any of the patients. By the way, side effects included: fever, gastrointestinal side effects, chills, fatigue, and blurred vision. The blurred vision and fever were experienced by a diabetic patient, therefore causes other than the feverfew were considered more likely.


The ominous statement, “No patients responded to therapy,” certainly did not bode well for my own recent experiment with feverfew. You see, I took one 600 mcg PTL pill, that is, quite a bit less than the 4 mg/day dose…it seems that I should have been taking 5 or 6 pills. Well, live and learn. But the researchers had also written that, while some patients requested to leave the study and others left because of disease progression, some (no details given) had responding or stable disease, with no appearance of new lesions, and were thus allowed to stay in the study for six cycles. Furthermore, If a patient had evidence of continued response after 6 cycles, treatment was to be continued for two more cycles beyond the best response. Okay, there is no question that this part is more than a tad confusing. Perhaps I should write directly to the researchers. In any case, as far as my own experience is concerned, I have been taking feverfew since November 2008…so perhaps, uhm, the temporal effect added to my wishful thinking and positive attitude will make a difference. Realistically, though, I won’t be surprised if my next test results don’t change one whit.


Toward the end of the study, the researchers state that their efforts will now focus on purifying parthenolide and identifying causes for the inability to deliver systemic levels with low doses such as 4 mg of parthenolide per day. And, further on, The data from our trial supports the need to purify parthenolide and administer higher doses. I wish them success!