Risk of progressing from smoldering to active myeloma

A recent exchange with a blog reader/myeloma patient list member made me rush to re-read and re-post about a 2007 Mayo Clinic study titled “Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma” (the full study is now available: http://tinyurl.com/c9f8lb).


It is based on a review of Mayo Clinic smoldering myeloma patients whose risk of progression to active myeloma was calculated at 10% per year for the first 5 years, 3% for the next 5 years and 1% for the last 10 years (“last”? Hmmm…). But read this: the cumulative probability of progression was 73% at 15 years.


I knew about this study, I even posted about it after it was published, but, I confess!, back then, for some inexplicable reason, I completely missed what I now consider to be one of the main points: the cumulation business. Okay, I am hardly a math genius…never was, never will be. But I must also have been in denial at the time, because the study spells it out…very clearly…as we will see.


First, another admission: I probably would have paid more attention to this study if it had focused on my own age group, give or take a few years, in a similar state of, uhm, good health. I have always been very very (very!) wary of statistical studies…there is so much missing information, blablabla. I find these studies interesting, but that’s where it ends.


Anyway, point is, what I remembered about the study’s percentages was totally wrong. I thought that after 5 years spent in a smoldering state, the risk of progression to active myeloma went down to 3%. Well, sure, technically that is what happens, according to the Mayo study, but it’s not that simple.


It’s not as though you begin each smoldering year from scratch. With every year that passes, in fact, you have to add the risk percentage that you accumulated in previous years. My blog reader set me straight on this point: the progression risk is cumulative. That means that after, say, six smoldering years, your risk of progression is as follows: 10 x 5 = 50 + 3 = 53%. Oh boy, there is quite a difference between 53 and 3%!


Let’s see, based on this study’s group classification, I would be in group 1. So, now that I am in my fourth smoldering year (as far as I know), my present risk of progression to active myeloma would be about 40%. Not too staggering. But what shocked me for a split second is this: even if my overall risk percentage drops from 10% to 3% next year, my cumulative risk percentage could reach 90% in 2020. 90%??? A question popped into my head as I read that: has anybody gone beyond the 100% threshold? Okay, that’s my goal now…to pass that threshold…!


Another thing caught my eye: The median time to progression was 2 years in group 1. Well, I am way past the median point…I have been in group 1 (in fact, a couple of times I even jumped into group 2, a “better” group in terms of progression risk) for 3.5 years, now, so I have beaten the median time, at least.


You can read the study on your own and, if you are smoldering, figure out what your risk of progression might be. Or…not. You see, I am not at all sure that I am better off knowing about this cumulative business. I think I might have preferred to have lived the rest of my life in blissful ignorance of the…dangers of progression.


But statistics are just numbers, after all…and numbers can be beaten. And, as my case shows, median times can certainly be beaten!

In conclusion, based on conventional medical statistics, my progression percentage seems to be much higher than I thought (er, if I even thought about it at all…!). So, the question is: am I worried about progressing to active myeloma? Uhm, let’s see now, I will have to get back to you on that one in the year 2029…or 2039…or…

Somewhat pale, but present…

A blogging friend (thanks!) sent me this list of medical funnies, which I will add to the ones I already have on one of my Funny Pages (scroll down my blog on the right until you reach “Laughter and MM”…there is a whole bunch of funny stuff there…and, incidentally, don’t forget to laugh until your belly aches at least once a day!). I should state that I have no idea if any of the following are TRUE sentences, but, no matter, whatever makes us smile or laugh is good!


These are sentences actually typed by Medical Secretaries in NHS Greater Glasgow:


·        The patient has no previous history of suicides.

·        Patient’s medical history has been remarkably insignificant with only a 40 pound weight gain in the past three days.

·        While in ER, she was examined, x-rated and sent home.

·        The skin was moist and dry.

·        Occasional, constant infrequent headaches.

·        Patient was alert and unresponsive.

·        Rectal examination revealed a normal size thyroid.

·        She stated that she had been constipated for most of her life until she got a divorce.

·        Both breasts are equal and reactive to light and accommodation.

·        Examination of genitalia reveals that he is circus sized.

·        The lab test indicated abnormal lover function.

·        Skin: somewhat pale, but present.

·        The pelvic exam will be done later on the floor.

·        Large brown stool ambulating in the hall.

·        Patient has two teenage children, but no other abnormalities.

·        The patient was in his usual state of good health until his airplane ran out of fuel and crashed.

·        Between you and me, we ought to be able to get this lady pregnant.

·        She slipped on the ice and apparently her legs went in separate directions in early December.

·        Patient was seen in consultation by Dr. Smith, who felt we should sit on the abdomen and I agree.

·        By the time he was admitted, his rapid heart had stopped, and he was feeling better.


Okay, these are good, but nothing, not even the rectal thyroid one, can top my all-time medical favourite: the patient was bitten by a bat as he walked down the street on his thumb. Hehe.

Little bug…

Well, I must’ve caught some sort of silly stomach bug the other day, probably when I went to renew my passport…either on the bus or in the consulate waiting room (both were very crowded and stuffy…plus I was surrounded by people coughing, sneezing and blowing their noses…). Luckily, this wasn’t such a bad bug: it lasted less than 48 hours. And, although I am still a bit weak, I am up and about and much much better today…this morning I even helped Stefano move some furniture around, then Piccolo and I watched “Baby boom,” a 1987 movie with Diane Keaton…still enjoyable…and I have seen it only about a million times…

Anyway, just thought I would post a quick note today and postpone research and writing until tomorrow. And now I think I will go watch another episode of “Middlemarch” (the BBC drama series)…ah yes, splendid idea.

Hope you all had a lovely Easter holiday…without any bugs! Ciao!

Omega 3 and hot tea

I thought I would post about two recent Science Daily articles today, as I continue to read about and research other topics.


The first (http://tinyurl.com/cu7a6x) is titled “Omega-3 Kills Cancer Cells”…intriguing, wouldn’t you say? The article discusses specifically the omega-3 acid known as DHA, or docosahexaenoic acid. It is contained in fish oil but not flaxseed oil (which instead contains alpha-linolenic acid, related to DHA but not the same thing). See this Mayo Clinic write-up: http://tinyurl.com/3c7298 A vegetarian source of DHA is seaweed, as I recall.


Well, it turns out that not only does DHA kill solid tumor cells on its own, it also enhances the killing effects of the chemo drug cisplatin, while limiting its harmful side effects. Chemopreventive, huh? Good stuff!


The Science Daily article is an interesting read, please go have a look. It reminded me that I really must look into maximum tolerated fish oil doses. As of now, I take 2 grams of fish oil (capsule form) a day. The studies I found this morning, after a quick bit of preliminary research, show that much higher doses have been tested and found to be okay. Hmmm. Does anyone here take more than 2 grams of fish oil a day?


The second article (http://tinyurl.com/d2hhuq) tells us that drinking very hot tea—70° or more, Celsius (thanks, Brad)—increases our risk of developing throat cancer. Now, I am not a tea drinker, I confess, but I am sure that a lot of you are, so I thought I would post about this study, carried out in northern Iran, which has one of the highest rates of oesophageal squamous cell carcinoma, or OSCC, in the world. Hot tea drinking is widespread in that region. While the study findings are not supposed to alarm us (or tea-selling companies, either, I guess…), they do suggest that we let our very hot food and drinks cool down a bit before swallowing. Four minutes is the minimum recommended amount of waiting time.


An excerpt from the SD article: Compared with drinking warm or lukewarm tea (65°C or less), drinking hot tea (65-69°C) was associated with twice the risk of oesophageal cancer, and drinking very hot tea (70°C or more) was associated with eight-fold increased risk. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea less than two minutes after pouring was associated with a five-fold higher risk. There was no association between the amount of tea consumed and risk of cancer.


Well, two studies that give us a bit to ponder over today.

Crocheting at 98

Yesterday more bodies were recovered from the rubble caused by the massive earthquake that struck l’Aquila and the surrounding towns. Today, too. But a few people were brought out alive and in good shape, including a fragile-looking 98-year-old woman who was pulled from the ruins of her house after spending 30 hours trapped in her bed.


A reporter asked her what she had done while waiting to be rescued. She answered, very matter-of-factly, “ho fatto l’uncinetto” (I crocheted), as though working with a crochet hook were the most obvious thing to do in the middle of an earthquake.


She was given food and water, but, much to everyone’s amusement, what she really wanted was a comb so she could fix her hair…. For the first time since this horrible tragedy hit the Abruzzo region, I heard a few ripples of laughter. I admit, I was amused, too. For a few seconds, anyway.


Even though right now here in Italy it’s not easy to think of anything else but the earthquake (shocks in the Abruzzo region are ongoing, by the way), I will do my best to go on to other matters. Let’s see…


This morning I went into town to renew my passport. As I was walking to my appointment at the U.S. consulate, I took a few photos, such as my new blog banner img_9934(the Ponte Vecchio is visible, sort of, in the background). Most of my photos didn’t come out too clearly (hazy morning), but I did get a  decent shot of two policemen on horseback. Right near the consulate. An unusual sight, in the middle of city traffic…


Last but not least, many thanks to François for pointing out a helpful website to me (see my Useful Links on the right): Biology questions and answers. Merci!

Replying to comments

It’s hard to watch the news. It’s hard not to watch the news. Earlier this morning I watched a live report on fire-fighters and rescue workers risking their own lives to dig a tunnel under what is left of a university student dormitory. They were trying to reach 5 students, well no…4 students. One was found dead…while I was watching the live broadcast.


I need to think about something else…


As I have mentioned, I have been very busy (I promise to stop using the word “busy” in my next ten posts…) in the past few weeks, and that situation is unlikely to change for a few weeks yet. Even when I am busy, though, I do find snippets of time to read all my blog comments and Contact form messages…I just may not have the time to answer them all. Sorry about that. If you really really (really!) want to hear from me, just send me a reminder. Sometimes messages get buried under others before I can get to them.


Anyway, today, instead of replying to individual blog readers’ public comments, I thought I would address a whole bunch in a post. Starting from the most recent.


William, see Paul’s link: http://www.alzforum.org/new/detail.asp?id=1150


Dinah, there are no clinical trials with salubrinal, I just checked. As for buying it, no, I would not recommend that. If, however, you are taking Velcade, you could ask your doctor about this new study.


Julie, I have that study, too. Haven’t read it yet. As for your patient’s myeloma type related to success with curcumin, I don’t think I can be of any help. Peter is right, the info you are seeking is not here, I’m afraid, though you could check out my Page on blog readers’ stories (I haven’t updated that page in ages, though). I don’t know if you will find the info anywhere else, unfortunately. You could try sending a message to Prof. Aggarwal. I will send you his e-mail address in a private message. Another thing: my B2M has been as high as 2.1 (right before I began taking curcumin in Jan 2006), which is still in the normal range for my lab. In November 2008 (my most recent tests) it was 1.7. I hope this bit of info is helpful.


Linda, I need more time to have a look at your links. I had my DHEA tested, by the way. Normal range.


Tom, curcumin is renoprotective, so I don’t see that it would cause problems even in the case of a transplanted kidney. If you have information that contradicts that, would you mind sending it to me? I will send you my e-mail address privately.


It wouldn’t be right for me to comment on your results. Apart from obvious issues, such as the fact that I am not a medical doctor, we have to keep in mind that lab reference ranges can be very different. They differ from lab to lab, let alone from country to country. What I do is check my results against my lab’s normal ranges to see what goes up and what goes down with every test. This gives me an overall idea of how I am doing. So you could start by doing that. If you don’t understand what a particular test means, well, here is a possibly useful suggestion: my blog links to a website called “Lab tests online,” see my Useful Links (on the right). That website might help you decipher your tests and come up with questions to ask your specialist.


Mark, you are absolutely right, I definitely do not “peddle” a product. Never have, never will. I have received freebie offers from some companies (no names) but have always turned them down. My policy is: if I can’t afford a supplement, I simply won’t try it. As for the TH2 activation thingie, I haven’t looked into that. I will try to do so…but don’t hold your breath!


Jbehles, I would definitely not experiment with nanoparticles of any sort in my kitchen. But this info is interesting, thanks for letting us know about it.


I have to stop here. As I mentioned, if I haven’t answered a message or a comment, please send me a reminder. Thanks.


Since I have been receiving messages from concerned friends and blog readers, I thought I would post a quick note to say that Florence was not affected by the strong earthquake (http://tinyurl.com/d5me2p and http://tinyurl.com/c7db6w) that struck the city of L’Aquila, the capital of the Abruzzo region, very early this morning. L’Aquila is a 3.5 drive south of Florence, more or less.

It’s very difficult to find words in moments like these. My heart is very heavy, that’s for sure. Horrible horrible tragedy. I was struck by what a dazed survivor told a reporter: “I have lost everything. But I am alive. My family is alive. Life goes on…”

Velcade and dormant myeloma cells

Sherlock (grazie!) sent me the full study mentioned in yesterday’s post. It’s “only” 8 pages long, so I thought I would give it a whirl.


In the Introduction, we can read that the use of prolonged bortezomib therapy has lead to the development of drug resistance. The subsequent paragraphs and quite a bit of online research added a bit to my understanding of how this process occurs.


In order to retain my sanity while going through this complex study, I tried to visualize the dormancy process. For this, I needed a hibernating creature. After considering polar bears, toads and snakes, I went back to my original example: ants. If there are any ant-lovers out there, I sincerely apologize in advance for comparing them to myeloma cells.


Let’s imagine a northern European State at the beginning of a very harsh Velcade winter. As it starts getting colder, the ants aka myeloma cells get cold, too, but quite a number of them have enough forewarning and are able to escape the increasingly frigid, Velcade killer temperatures by hiding inside their underground nests. Their metabolism starts slowing down. In this inactive state, they require no food. It’s clearly a good survival mechanism.


The stubborn ones that remain above ground don’t have a chance of surviving (not in my visualization, at least). As soon as the weather starts warming up, though, the dormant ants wake up again. If I sound obsessed with ants, yes, I suppose I am. Every spring, I find myself battling fiercely with an ant colony that has established itself in my front yard. I don’t mind their being there, don’t get me wrong, but at this time of year some of them desperately and stubbornly want to march through my house, I suppose in order to reach the back yard. So right now, grrr!, I don’t feel badly about identifying them as myeloma cells. But I digress…


Now for a more, er, scientific approach.


First, though, a look at proteasomes. These are large protein complexes that are found in both normal and cancer cells. The relevant (for us) information about proteasomes is that cancer cells depend on these proteins in order to proliferate, metastasize and survive. And, in fact, increased numbers of proteasomes can be found in the blood of myeloma patients.


So one way to kill cancer cells is to inhibit the cancer-friendly activity of proteasomes. Probably the best-known proteasome inhibitor is bortezomib (marketed as Velcade). When Velcade is injected into a patient’s body, it disrupts the proteasome’s activities. As a consequence (simply put), cancer growth is inhibited, and the cancer cells die.


Now we get to our full Velcade-dormant myeloma cell study. Proteasome inhibitors provoke what is called an “ER (which, unfortunately, has nothing to do with the dashing George Clooney but stands for “endoplasmic reticulum”) stress response” in myeloma cells. This type of “stress” kills between 50 and 70 % of them, according to the study…but at the same time it sends out certain survival signals to 30-50 % of these cells that are thus able to avoid apoptosis by slipping into a deep sleep (or, more scientifically, by becoming quiescent).


They basically stop growing. And, since Velcade attacks cells that are in the process of dividing rapidly (=typical of cancer cells), this is an excellent survival strategy, which, incidentally, is used also by other types of cancer cells, such as head and neck squamous carcinoma cells.


At any rate, these quiescent cells can be annihilated, the researchers discovered, by adding to Velcade another drug called salubrinal. The actual experiment is rather neat, so I will attempt to summarize the parts that I understand in a comprehensible fashion. The researchers identified the myeloma cells that survived the Velcade attack and washed them to remove the drug. I confess, I was a bit amused by the image of myeloma cells being washed…anyway, the researchers realized that these cells had stopped growing. They were fast asleep…the little buggers. Velcade was no threat to them.


Now, there is a tremendous amount of detail in the study. I am not interested in the intricate mechanisms that show exactly how myeloma cells avoid death, mechanisms that, to be quite honest, I can barely understand, such as CHOP induction and XBP-1 splicing. So, skip skip skip.


Let’s get to the part that describes what happens once salubrinal enters the picture. After 24 hours, treatment with salubrinal of the Velcade-surviving myeloma cells resulted in a more or less a 10-fold reduction in the number of viable cells. Hey, not bad! And even after 5 days, the cells that are still dormant were highly affected by salubrinal. Ah, an important titbit: salubrinal does not affect the control population.


And now we finally (wiping our sweaty brows) reach the Discussion part where we discover that, after administration of Velcade, 30-50 % of myeloma cells escape death by becoming inactive. The researchers argue that this is more likely due to treatment adaptation than to selection of a cell population genetically predisposed to undergo quiescence. But the fact that so many myeloma cells survive treatment with Velcade is the probable and unfortunate cause of disease recurrence.


The researchers also found that survival of the residual quiescent cells hinges on the down-regulation of eIF2a phosphorylation. Phospho-whaaat? Okay, let’s not get too bogged down by the details of this phospho-thingie process. What we need to know is that the strong phosphorylation of eIF2a is associated with apoptosis. In the Velcade-surviving myeloma cells, you see, eIF2a was attenuated, so that is probably a mechanism whereby the blasted surviving cells are able to avoid apoptosis. Well, let us leave it at that…for now.


In conclusion, the solution to the Velcade-caused “dormancy” problem, as we have seen, lies in the addition of salubrinal to the mix. Salubrinal can virtually eliminate the fraction of quiescent MM cells surviving proteasome inhibition by enhancing the above-mentioned, er, eIF2a phosphorylation.


Quick note: this combination treatment will apparently benefit only myeloma patients. It doesn’t work against other forms of cancer, such as chronic myeloid leukemia.


The study’s conclusion: In summary, we report that the induction of MM tumor cell quiescence and survival can be an undesirable side effect of proteasome inhibition. We also show that, by blocking eIF2a dephosphorylation, proteasome inhibitor efficiency can be maximized during acute treatment and that residual cells can be eliminated by nontoxic doses of salubrinal as a monotherapy for MM minimal residual disease after proteasome inhibition.

Now I need a few days to digest all this stuff…

Velcade makes a lot of myeloma cells sleepy

I am still stuck in a “busyness” quagmire, but a recent post by an MMA list member caught my attention, so I took some time today to do a bit of research. Here goes. Apparently, many myeloma patients do not respond to Velcade. And those who do eventually relapse. Well, it appears that researchers may have found out why.


A study on Velcade and its effects on myeloma cells was published in “Cancer Research” in February 2009 (see abstract: http://tinyurl.com/czsn2e). Velcade by itself doesn’t kill every single myeloma cell in the body. Indeed, it apparently creates the conditions whereby quite a number of them are able to slip into a state of dormancy, just like ants that go to sleep in order to survive harsh winters in Finland, e.g. When the dormant cells resume their active state, boom!, myeloma rears its ugly head again.


But it seems that when salubrinal, a “selective inhibitor of enzymes that dephosphorylate EIF 2-alpha” (don’t ask!),  is added to Velcade, there are very few survivors. In other words, these two drugs together are able to wipe out almost all the ants in Fin…I mean, almost the entire population of dormant myeloma cells.

When I was about 2/3 of the way through the abstract, the following thought popped into my head: why not try to figure out how we can use this bit of information to kill our dormant myeloma cells via natural treatments, or at least keep them in a state of dormancy? Or…is that what we are doing right now with curcumin etc.? I began to look into this very matter earlier today but soon realized that I need a bigger chunk of free time to do a semi-decent job. Ant…I mean, and I need the full study. More to come…