SMM-MM risk of progression

(Oldest post first…please scroll down for updates…)

 

April 16 2009 post. 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…

July 24 2009 post. IMPORTANT UPDATE! Premise: in my blog, my intention has always been to report on my own experience concerning both health issues and life in general, with some funny stuff thrown in here and there. I have always intended to do this in a straightforward and humorous manner…that’s how I am in real life, after all! And if I make a mistake, or base a post on incorrect information that I found on my own or that I received from someone else, I try to set things right as soon as possible. Well, I made a mistake in my April 16 2009 post. I meant to write a “correction” post earlier, but other things (life!) got in the way…then a blog reader reminded me of my duty just this morning. OOPS!

I owe a huge debt of thanks to that same blog reader who wrote me a message back in early May (!) concerning my above-mentioned post, the one about the risk of progression from SMM to MM. After reading it, in fact, he wrote directly to one of the authors of the NEJM study. He then sent me their exchange, which I, without naming names for reasons of privacy, will post about today, with his prior permission, of course. Since numbers, as those of you who know me well, are not at all my forte, sigh, I will simply post the examples that my blog reader and the expert used:

Blog reader: I have a friend who currently has Smoldering Multiple Myeloma and has had that diagnosis for 10 years. She has been advised that according to your graph – “Figure 2. Probability of Progression to Active Multiple Myeloma…” she has a 66%  probability of developing MM sometime in the future. Further, that as time passes, since the cumulative probabilities are increasing, if she makes it to 15 years, she will then have a 73% probability of progressing to MM and eventually she will have a virtually 100% chance of progression.

I see the data as retrospective rather than prospective. That is, on average, 66% of people with smoldering MM already have progressed to MM after 10 years. As for those who have not progressed at 10 years (about 34% of the original group), an additional 7% in absolute terms or about 21% in relative terms (21% of 34% = 7%)  will progress  – thus arriving at the 73% cumulative probability at 15 years.

I realize the 21% is a theoretical and imperfect estimate since it does not take into consideration many factors such as death from unrelated causes etc. However, would you say that the 66% value in your graph refers to the proportion of people who have progressed to MM at 10 years and is not an estimate of the proportion of people who will progress after 10 years?

The expert: You are correct in your assumption that the 66% value refers to the proportion of people who have progressed to MM or AL amyloidosis at 10 years and is not an estimate of the proportion of patients who will progress after 10 years.  As a matter of fact, the risk of progression after 10 years is approximately 1% to 2% per year.

Our data indicates that the patient is at greatest risk during the first five years and then the risk decreases.  As you pointed out, we are all at risk of succumbing to something as times goes on.

So, the rather dismal statistics in the NEJM study refer only to those who HAVE PROGRESSED from a smoldering state to active myeloma after 10 years. It does not take into consideration those who HAVE NOT PROGRESSED. Indeed, if you have NOT progressed, your risk factor decreases with each passing year, which, by the way, coincides with my original interpretation of the study. In the study author’s own words, As a matter of fact, the risk of progression after 10 years is approximately 1% to 2% per year. Hah.

By the way, another myeloma list member recently left a comment on my April 16 post. Here is her take on the study (my emphasis): 

“The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years.” What this means is that in year 1, 10% of the group of smolderers progressed to full MM, same in each of years 2-5. Then, after that, of those who were left in the group, in each of years 6-10, 3% of the group progressed. Next, again out of those who were left, only 1% of them progressed each year thereafter. So basically, the rule is “the longer you have been smoldering, the more successful you will be at staying in the smoldering state”, statistically speaking and in layman’s terms. You don’t accumulate [ ie. add ] the percentages as you go along. For example, if you make it as far as year 6, then your chances of progressing during year 7 are 3%.

Okay, so, having SMM does not mean that some day you will inevitably progress to active myeloma. Some of us will, some of us won’t.

I hope this is reassuring to those of you who, like me, have been in a stable smoldering state for a while (2010 will be my fifth year as a…smolderer). And, once again, I deeply apologize for having waited so long to post about all this…ah, what can I say in my defence? I must be super allergic to numbers…in fact, here it comes…ahhh…ahhh…atchooooo! (etciù! in Italian…)

November 22 2010 post. A blog reader/Facebook friend (thanks!) notified me about a new progression-from-MGUS-to-MM study, which I asked another friend (more thanks!) to retrieve for me. Click here to read the abstract: http://goo.gl/MWpRY A key excerpt: …it currently is not possible to accurately determine individual risk of progression. Well, in addition, sigh, to containing a split infinitive that makes my skin crawl, that statement doesn’t really sound too promising, does it? Well, let’s have a look at the full study now…

In the Introduction we find a discussion of “racial disparity patterns.” MGUS and MM are 2-3 times more common in African-Americans than in Caucasians, and Asians have a lower prevalence of MGUS than Caucasians. Why is that, I wondered? Diet? Genetic makeup? Luck? What?

And there is also a certain degree of familial clustering…that is, if someone in your family has MM, then you apparently have a higher risk, perhaps two-fold, of developing it. The researchers therefore conclude that there seem to be susceptibility genes in the causation of MGUS and MM. No cases of multiple myeloma in my own family, incidentally. I am the first…and, I hope, the last!

Ah, here is an interesting bit of news: Although MGUS is commonly referred to as a single entity in the literature, indeed there are two kinds of MGUS: lymphoid (or lymphoplasmacytoid) MGUS, and plasma cell MGUS. Let’s take a closer look:

1. Between 15 and 20% of MGUS folks belong to the former group: they secrete IgM and can progress to Waldenström macroglobulinemia, lymphoma, or other malignant lymphoproliferative disorders.

2. Most MGUS folks instead have a plasma cell phenotype, characterized by a serum M-protein concentration of less than 3 g/dL, fewer than 10% of plasma cells in the bone marrow, and with no end organ damage.

The two types of MGUS are completely different, on a biological level. This study focuses on the second group…

Reading on and skipping a few bits. Ah, here we go. The authors discuss the two major models for risk stratification: 1. the Mayo Clinic model and 2. the Spanish study model. Concerning the latter, do you remember the fuming post I wrote about the SMM “high-risk” Spanish study? Ooooh, whenever I am reminded of that study, my blood begins boiling…For a reminder, see: http://margaret.healthblogs.org/life-with-myeloma/what-is-multiple-myeloma/myeloma-supplements-and-il-1-beta/a-high-risk-smoldering-myeloma-study-ridikkulous/. Oh well…

Let’s look first at the Mayo Clinic model, which focuses on serum protein abnormalities. The following features are considered as adverse risk factors: non-IgG isotype, M-protein concentration 41.5 g/dL, and an abnormal serum free light chain (FLC) ratio (normal reference 0.26–1.65). In the Mayo Clinic model, at 20 years of follow-up, patients with MGUS with all three risk factors on average have an absolute risk of MM progression of 58%; for MGUS patients with two, one, and none of these risk factors, the corresponding absolute risk is 37%, 21%, and 5%, respectively.

This model also gives SMM risk factors: serum M-protein concentration >3 g/dL, bone marrow plasma cells >10%, and an abnormal free light chain ratio. The cumulative risk of progression at 10 years with one, two, and three of the risk factors was 50%, 65%, and 84%, respectively. Based on this model, by the way, I am in the group with an 84% risk of progression. Well, no surprise. I can interpret my own numbers by now. So far, they haven’t scared me… Besides, statistics are just…numbers… 

I would really really really like to skip the Spanish SMM study altogether, for the above-mentioned reasons…but no, I won’t. For the sake of fairness. The Spanish model uses BMBs (=bone marrow biopsies) to determine the ratio of phenotypically aberrant plasma cells (aPCs) to total bone marrow plasma cells (BMPCs) at diagnosis. The patients with at least 95% aPCs/BMPCs at diagnosis had a significantly higher risk of MM progression. Other factors, such as immunoparesis (=the reduction of one or two immunoglobulins, in a nutshell) and DNA aneuploidy (=DNA abnormalities, again, in a nutshell), are also considered.

More specifically, for patients with MGUS with no, one, or two risk factors (>95% aPCs/BMPCs and DNA aneuploidy), the risk of progression at 5 years was 2%, 10%, and 46%, respectively. For patients with SMM (risk factors: >95% aPCs/ BMPCs and immunoparesis), the corresponding numbers were 4%, 46%, and 72%, respectively. Okay, I think I have devoted enough attention to the Spanish model…

Our study authors reach the conclusion that the risk of MM progression varies greatly among individuals diagnosed with MM precursor disease. Clearly, we need better markers to define high-risk (versus low-risk) MGUS/SMM and to better predict individual risk of MM progression.

Subsequent sections deal with:

1. MicroRNAs. Remember my miRNA post (=October 28)? If not, here is the link: http://margaret.healthblogs.org/?s=microRNA At any rate, the study authors tell us that It is now known that miRNAs can act as tumor suppressors or proto-oncogenes, and that they are misregulated in most human cancers. So these thingies could perhaps be used as markers of malignant disease in a wide variety of cancers. I will skip the technical bits, i.e., the detailed descriptions of miR-93 versus miR-106b…uff uff uff. Bottom line: some miRNAs were up-regulated in MM but not in MGUS…

2. Gene promoter methylation. Oh no, no way…not getting into that…skipskipskip…

3. Molecular imaging. Yes, let’s have a quick look at this topic. Here we learn that in the future it may be easier to detect bone lesions using molecular imaging techniques equipped with novel MM-specific tracers. That sounds helpful. In particular, they discuss the use of a Fluorodeoxyglucose (FDG)-PET/CT, which can detect bone marrow/myelomatous involvement with a quite high sensitivity and specificity. The radiation exposure, we are told, is about 1.6 REM.

I looked up the amount of radiation that we get from a chest X-ray = 0.01 REM…So 1.6 sounds like quite a bit…! The authors tell us that, as far as they know, this new technology hasn’t been used to identify early skeletal lesions in patients with MGUS…Too much radiation, I wonder?

They then discuss the “angiogenic switch” hypothesis, which is an attempt to explain the progression from a pre-malignant to a malignant stage. This switch would result from cumulative genetic damage leading to an imbalance of pro- and anti-angiogenic factors, creating an adequate microenvironment for a tumor to grow. I don’t want to go over the process of angiogenesis again, since I have written quite a lot about it here…

An important excerpt: In MM, increased angiogenesis results in changes of microcirculation in bone marrow. Interestingly, MGUS patients have a low-intensity pattern of microcirculation compared to MM patients. But, the researchers add, more studies are needed in order to determine whether a particular type of contrast-enhanced MRI, called DCE-MRI, can be used to predict progression to MM…

Wait a second. Contrast liquid? Could it be gadolinium? I checked on PubMed, and yes, gadolinium is indeed used in these types of MRIs… Do you remember my post on gadolinium, by any chance? If not, see: http://margaret.healthblogs.org/life-with-myeloma/what-is-multiple-myeloma/mris-and-gadolinium/ Incidentally, the reason WHY I began wondering about gadolinium is when I read that a patient with MGUS/SMM with a pathologic DCE-MRI pattern developed a progression to MM 6 months after the DCE-MRI. Hmmm and double-hmmm. Progressing to active myeloma just six months after having a DCE-MRI… Fate or pure coincidence? Or…something else?

Nope, I don’t think that I would ever have one of those MRIs…

November 23 2010 post. And now, finally, we get to the Conclusion. The researchers state that, from a clinical standpoint, it is essential to identify which of us are going to progress to MM, in order for our doctors to be able to keep a closer eye on those in a high-risk category and be able to use some or all of these markers to determine the choice of therapy and response to therapy in patients with full-blown MM.

From a research standpoint, they say, the development of better biologic and molecular markers will improve our understanding of the molecular pathways involved in disease progression in patients with MGUS/MM. This, in turn, will help identify newer therapeutic targets and novel treatments

More or less, that is the study’s conclusion. But I still have a few comments to make on what I read in the middle of the study…at the end of the discussion concerning genetic abnormalities, hyperdiploidy, trisomies, RAS mutations and MYC up-regulations:

Taken together, although many of the above-mentioned markers have been identified in patients with MGUS, and the prevalence of some markers has been reported to differ between MGUS and MM, currently it is unknown whether any markers are associated with an excess risk of progressing from MGUS to MM. Importantly, at this time no systematic study using serial samples (from the same patient over time) has been conducted to formally address the role of these genetic markers in predicting disease progression in patients with MGUS/SMM.

What this section says to me…quite loudly, in fact…is that all the MGUS/SMM progression studies are little more than a long series of words and sentences surrounded by elaborate graphs and Tables. To be blunt, these studies are essentially useless to us (=the patients). The bottom line, in fact,  is that not even one of them can predict who will progress to active myeloma and who will remain at the MGUS or SMM stages…

At this point, though, I asked myself the following question: do I really need or even want to know if I am going to progress to active myeloma some day? Heck. No. I. Definitely. Do. Not.

Knowing what might or might not lie ahead for me two, four or ten years from now wouldn’t have an impact on my life… Oh wait a second. That is not entirely true. It would almost certainly have an impact: stress, to some degree. And stress, as we know, makes MM cells proliferate (http://margaret.healthblogs.org/life-with-myeloma/what-is-multiple-myeloma/multiple-myeloma-and-stress/).

So why would I willingly choose to add a “timer” to my daily life? Indeed, why would I choose to add to Stefano’s burden of worry and stress (…even though he never shows it, I know it’s there…)? Or to my family’s worries? Why? Why? Why? Wouldn’t it be better just to enjoy my life, husband and cats, have fun with my friends, take curcumin and other promising anti-myeloma, non-toxic, backed-by-science substances and so on?

Sometimes, just sometimes, perhaps it is best not to know: “Where ignorance is bliss, ‘tis folly to be wise…”

Now, don’t get me wrong, eh. Blissful ignorance doesn’t mean that I never think about the possibility that one day I might progress to full-blown myeloma. Hah. Believe me, I do…perhaps not every single day…but I do… And, when I find out that a myeloma friend, especially one close to my heart, is dying, the emotional pain is a bit hard to bear…Susie, many hugs to you…

No, blissful ignorance doesn’t mean that I will stop doing all the things I do to slow down or even, wowsie!, halt my progression… Besides, all of these activities really help me deal with my fear of (and anger toward!) the nasty beastie that is currently slumbering inside my bone marrow…

And my research and ramblings might be of help to others, too. That is a great comfort to me…

December 13 2011 post. A friend (thank you!) sent me a case study last week. You can view the abstract here: http://goo.gl/baWTd It actually turns out to be quite a bit more than a case study, as we will see…

Without further ado, let’s hop right into the full study. The central character, in this first part, is a healthy 72-year-old white man with smoldering myeloma diagnosed 6 months ago, a man who had an 11-year history of MGUS. Coincidentally, his MGUS was diagnosed in 1999, which is the year of my own MGUS diagnosis…

In 2009, he had a bone marrow biopsy (=BMB) that revealed 40 % plasma cells, and his free light chains ratio was 2.44. He also had a test called fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), which showed a mild FDG uptake in the sacrum. The result, however, was: no bone lesions.

Two months later, during a follow-up visit, his M-protein had increased from 4.4 g/dL to 4.9. Since he complained of lower back pain located in the sacrum and left iliac bone areas, he had a second FDG PET/CT. This time, focal lesions were found in those two areas…

Now, okay, I know that I have a suspicious nature, but doesn’t it seem a bit too coincidental that this patient had TWO of these tests in what seems to me to be an amazingly short period (TWO months)…and the second FDG PET/CT revealed focal lesions? These, by the way, can be benign, I read. Well, forget it, let’s keep going…

You can read some details about FDG PET/CTs here: http://goo.gl/gEkdM Scroll down to “Operation,” where you can read that a short-lived radioactive tracer isotope mixed with FDG, which is an analogue of glucose (hmmm and double-hmmm) is injected into the patient’s bloodstream…After about an hour, this tracer finds its way into the tissues of interest

Now scroll down to the “Safety” paragraph. Yikes! Now, I don’t have a whole lot of time to do research on the FDG PET/CT topic today, but I just read that it is essential to avoid unnecessary and repetitive imaging or excessive re-staging in patients who may have already been imaged previously at the same or other locations (see: http://goo.gl/hIctB).

Food for thought. Or not…

At any rate, getting back to our case study, the patient was diagnosed with multiple myeloma and began treatment with lenalidomide/dexamethasone with partial response after 3 cycles. The authors don’t mention him again…

The rest of the study is an interesting analysis of previous “progression” studies, beginning with those showing how active myeloma is preceded by MGUS and SMM. We have already discussed this topic, so there is no need for me to summarize this part.

Here is something for us to chew on: the change from MGUS to active myeloma is not sudden, the authors say. Rather, several overlapping oncogenic events within plasma cells and the marrow microenvironment accumulate from normal plasma cells through precursor disease to advanced multiple myeloma. These cellular changes can be seen in almost all MGUS patients, and from MGUS onward, and include hyperdiploidy and primary immunoglobulin translocations at the 14q32 locus. Cyclin D dysregulation is also mentioned as a very common early event.

Next, we get into a rather long overview of risk criteria (skipskipskip)…notably, the Mayo Clinic criteria and that grrrrr! outrageous Spanish SMM chemo study. Interestingly, the authors prefer the Mayo Clinic system, which is more readily available and allows the clinician to spare patients with low-risk MGUS from undergoing a bone marrow biopsy. Couldn’t agree more!

Then we get to the “Imaging” part: In current practice, imaging in MGUS and smoldering myeloma fulfills 2 roles: ruling out progression and monitoring for early complications.

The authors point out that the skeletal survey is relatively insensitive and nonspecific for detecting myeloma-related bone disease (=the lesions have to be quite evident to be picked up by an x-ray)…but it also only requires a relatively small dose of radiation to perform on the whole body.

They then describe the Whole-body low-dose multidetector row CT, which can detect lesions smaller than 5 mm. This test has negative consequences, though = heaps of radiation. Okay, neeeext!

Whole-body MRIs are more effective than skeletal surveys, they say. That reminds me–I have had a few MRIs (only of my spine), but without any contrast liquid…Let’s never forget that gadolinium, frequently used as a contrast agent, makes MM cells proliferate…!!!

Now for the “Clinical Management” part. MGUS patients apparently have a higher risk than healthy folks of developing thrombosis and fractures. I have read about those studies, but have actually not…read them (to my recollection). Concerning thrombosis, the study to read is: http://goo.gl/Be0SC. For fractures, see http://goo.gl/0qRKP The full texts are available online…for free, which is helpful. (You might have to click on “manual download.”)

Going on…ah, here is an interesting statement: Treatment trials for MGUS are problematic, as patients are relatively healthy and most patients have a low lifetime risk of progression, especially when other causes of death are taken into account. Thus, an ideal treatment would be nontoxic and directed toward patients with high risk of progression. “Nontoxic,” huh? Hmmm, I just might have a few ideas…! Hehe.

The subsequent paragraph is not as upbeat. It concerns my own condition, smoldering myeloma: Early treatment strategies for smoldering myeloma are particularly attractive as the rate of progression to multiple myeloma is quite high. Okay, while these strategies might appear “attractive,” the authors add that all the SMM chemo clinical trials have failed so far. Indeed, if anything, the smoldering patients in these studies were worse off than when they started…

I was rather surprised to read the authors’ words of caution concerning that SMM Spanish study: […] it is unknown whether treating patients with smoldering myeloma improves overall survival or quality of life, as such data are not yet available. Well, you already know what I think about that infamous study…about all the toxicities that these poor patients are enduring…Talk about unnecessary…to say the least…! Uffa! Okay, Margaret, enough…

The authors conclude that Aimed at preventing progression, smoldering myeloma could be treated as a chronic disease, with relatively benign maintenance therapy used to control the malignant clone. Alternately, highly active therapy could be used with the goal of cure, although this may prove challenging in the context of current treatment options. However, to responsibly perform any such trial, well-designed correlative studies should be performed to assess the theoretical possibility of unexpected long-term adverse events or selecting for more aggressive disease. Well, I like the bit about “benign maintenance therapy”…In Margaret’s world, curcumin and a few other things fall into that category…

The study ends with a few notes on “future directions.” And read this: even smoldering patients at the highest risk for progression, with detectable disease on advanced imaging will likely become candidates for early treatment strategies, likely with agents not currently available in the clinic. “With agents not currently available…” Well, you don’t have to read between the lines: that sentence rules out the Spanish SMM study…

And hey!, I didn’t say it…Two researchers from the Center for Cancer Research at the National Cancer Institute did…so there.

The above-quoted paragraph continues (and this is how the study ends): However, such trials should be cautiously designed to assess progression-free and overall survival, as high response rates may not correlate with survival and prolonged stable disease may provide key benefit to patients.

PRECISELY. ESATTAMENTE. Let’s focus on prolonged stable disease…

It appears clear (to me, anyway) that asymptomatic smoldering patients should NOT undergo any conventional treatment, even if they are in a high-risk category. Yes, of course that is just my opinion. However, based on the Mayo Clinic criteria, I am in the highest-risk-for-progression group. So this evening I am taking a stance, once and for all: I would rather go bungee jumping (yikessss!) every single day than have chemo at this point. It’s too bloody risky…

Paraphrasing my hero, Prof. Aggarwal (I don’t recall the exact quote, sorry, and have to go prepare dinner now…), it’s not really such a good idea to go and poke a sleeping tiger…

January 20 2011 post. Here is the link to a study I learned about from a Facebook friend (thanks!): http://goo.gl/rI9fq Yes, yet another MGUS-SMM progression to MM study. Hmmm, they seem to be popping up like dandelions these days, don’t they? That is good, of course! The more we learn, the better off we are. And this study is also a relatively easy read. If you don’t have time to read the whole shebang, though, just jump to the Summary at the end.

Here is a particularly interesting titbit, which you can find in the paragraph titled “From ‘Multiple Myeloma Without a Progressive Course’ to Smoldering Multiple Myeloma”: basically, before 2003, there was a bit of confusion on how to define asymptomatic myeloma. Some studies, e.g., made a distinction between SMM and IMM (or indolent myeloma). This lack of consensus means that, Due to these varying definitions, one has to be cautious when assessing results across different studies. In fact, it is very problematic to compare SMM data collected prior to 2003, the year that the International Myeloma Working Group (IMWG) released a consensus on the specific diagnostic criteria for the known monoclonal gammopathies. By the way, IMM has now been lumped in with MM, whereas SMM is defined as ”asymptomatic myeloma.” I must say, I found the news about how difficult it is to judge SMM data before 2003 a bit troubling. Too bad!

If you have SMM, please make sure to read the paragraph titled ”Current Clinical Recommendations.” I was interested in what Dr. Langren had to say about the use of conventional chemotherapy in SMM: Using standard chemotherapy in SMM, early treatment has not been found to delay progression to active disease and overall survival. There you go…

She then spends a few words on that simply outrageous (hmmm, I really must find a synonym for “outrageous”…), still ongoing Spanish SMM-chemo trial. She comments that it is still impossible to determine if early treatment improves overall survival. Until we know the answer to this important question, we can only speculate whether early treatment has the potential to cure SMM, or if SMM should be classified as a chronic, asymptomatic disease state requiring maintenance therapy. Well, “speculation” is not good enough for me…no siree!

Then I read something that made the hairs on the back on my neck stand up (and freeeeeeze!). My emphasis: At the same time, we do not know if early treatment may facilitate selection of aggressive clones that are more capable of competing in the treatment-altered microenvironment (Figure 1). Because none of these scenarios has been proven true, it is very important to conduct well-designed correlative studies in clinical trials aimed at treating SMM patients.

Very important??? Why, that is possibly the biggest understatement I have read so far this year. I don’t know how you feel…but I would most certainly NOT care to anger my myeloma cells to the point where they would/might become more aggressive…Forget it, not happening…

This study does nothing but confirm my cautious approach to SMM: do NOT poke the tiger! By the way, I am not suggesting that those of us who are in the high-risk-for-progression group should simply sit back and wait. No, I very strongly believe that we can be proactive in many ways–diet, supplementation, laughing like a drain (I just learned that expression, hehe), etc… But we should avoid chemotherapy at this stage…No, not even in a clinical trial setting, especially if any of the researchers have a connection to the big drug companies that are funding the trial (as in the case of that confounded Spanish trial). As I have said over and over again (and will probably say it again!), early treatment in asymptomatic myeloma is too bloody risky. Case closed. 

January 24 2011 post. I have written so much about risk factors for MGUS and SMM progression to active MM that sometimes I forget if I have posted about such and such a study/article/whatever. I always do a search of my own blog before addressing what is clearly a familiar topic…but I still cannot be 100% sure. This is one of those cases…that is, I don’t think I have posted about this particular study, but I may have…and, if so, well, pazienza, as we say in Italian…

It was published in “Leukemia” in April 2010. See: http://goo.gl/l0DQH As usual, a friend (thank you!) sent me the full text. Now, for the umpteenth time (but it never hurts to refresh our memories…), let’s go over the definition of MGUS and SMM, which is nothing new, by the way (see: http://goo.gl/HtSZv).

  1. MGUS: serum M protein < 30g/L, < 10% clonal plasma cells in the bone marrow, no end-organ damage. That is, no CRAB symptoms: C=hypercalcemia, R=renal insufficiency, A=anemia or B=bone lesions.
  2. SMM = > 30 g/L serum M protein, > 10% clonal protein in the bone marrow but still no end-organ damage. The difference, as you can see, are the higher numbers for SMM, which mean higher risk of progression (but not necessarily…).

This 2010 study focused on the residents of a county in Minnesota, 50 years of age or older. More specifically, 241 residents with MGUS were followed for up to 39 years (13.7 years, on average). Of these, 27% developed full-blown multiple myeloma, Waldenstrom’s macroglobulinemia, primary amyloidosis or a lympho-proliferative disorder. The time to progression ranged from 1 to 32 years (average: 10.4 years). The overall risk of progression was 1.5% per year. I decided to skip some of the well-known bits of info, for instance, that there probably is a genetic component in MGUS blablabla. Okay, now we will go over the various sections of the study…

Predictors for progression. The size of the M protein, the type of M protein, the percentage of cancer cells in the bone marrow and the free light chain ratio can help identify those at higher risk of progression. Interesting and important: the physician should be aware that the presence of anemia, renal insufficiency or hypercalcemia may be unrelated to the presence of the M protein.

“Unrelated,” eh? Now, that is something that I have thought about and pointed out now and again. That is, if you are borderline anemic, that doesn’t necessarily mean that you have stepped over the line separating MGUS/SMM from active MM. Besides, one single crappy test is not enough to determine progression. You must look at trends and take into consideration your overall state of health. If your haemoglobin is low, you might be able to bring it up with a few, simple dietary changes. That is why it is so important for us to understand our type of cancer. This is just my opinion, of course!, but, after all, an informed patient is a better patient (well, usually, at least!)…and, from my viewpoint, an informed patient is also a less stressed-out patient…

Size of M protein. This paragraph tells us that the size of the M protein is the most important predictor of progression. Since my own M protein fluctuates around 30 g/L, this confirms what I already knew, that is, I am in the high-risk-for-progression group. Does that scare me? Sure it does. Sometimes. But I am such a positive cheerful type of gal that knowing that I am at high risk for progression has a minor impact on my everyday life…Luckily!

Besides…And here I want to set aside the study for a second in order to tell you a story, a true story. One of our neighbours was a healthy, strong guy (Stefano’s age) who worked out and had a very active lifestyle. He worked for the local Department of Forestry. He was more to us than just a neighbour…He was a good friend, always there when you needed him (and vice versa, of course). Such a nice guy! We were very fond of him. Anyway, one day, about six years ago, while he was pruning a tall tree somewhere out in the Tuscan countryside, his safety harness broke, and he fell to the ground. He died in the hospital a few days later. We were absolutely stunned…

Okay, my point is that we cannot predict how we are going to die. Our death might be caused by something totally unrelated to myeloma–falling out of a tree, getting run over by a car, having a heart attack or a toxic reaction to something…Comforting thoughts, eh?  Okay, perhaps not. But this story emphasizes the point that, like my neighbour, we should live life to the fullest…enjoy every moment (whenever possible)…laugh…and, er, always hold on to our panties (see previous post)…

Where was I? Ah, yes, the size of the M protein. Those patients who had an M protein of 25 g/L had a 49% risk of progression after 20 years, compared to those with 5 g/L or less whose risk was 14%. Those with 15 g/L had twice the risk of progressing than those with 5 g/L or less. Oh phooey, this is a bit TMI (= too much information). Besides, as we know, statistics are only numbers, whereas we are most definitely not numbers!

Type of immunoglobulin. In a nutshell, those with IgM or IgA are more at risk of progressing than those of us with IgG. Especially the IgA folks.

Bone marrow plasma cells. Those with more than 10% BM PCs have an increased risk of progression.

Serum FLC ratio. Those with an abnormal ratio also have a higher risk of progression: Rajkumar et al. developed a risk-stratification model for progression of MGUS. Patients with risk factors consisting of a serum M protein >15 g/l, IgA or IgM MGUS and an abnormal serum FLC ratio had a risk of progression at 20 years of 58%; compared with 37% when two risk factors were present; 21% when one risk factor was present; and only 5% when none of the risk factors were present.

I am going to skip the genetic discussion because of this statement: The gene expression profile may be of benefit in predicting the risk of progression, but no convincing data exists at present.

Patient management. This is helpful mainly for newly diagnosed patients: At first diagnosis, a complete history and physical examination should be done with emphasis on symptoms and findings that might suggest multiple myeloma or AL amyloidosis. A complete blood count, serum calcium and creatinine values and a qualitative test for urine protein should be performed. If proteinuria is found, electrophoresis and immunofixation is indicated. Serum protein electrophoresis should be repeated 3–6 months after recognition of MGUS to exclude multiple myeloma or Waldenstrom’s macroglobulinemia because the monoclonal protein is usually recognized by chance.

To these tests, I would definitely add the vitamin D test, based on the Mayo 2009 vitamin D study (see my Page “Myeloma and vitamin D”) showing that MM patients with low levels of vitamin D had worse outcomes than those with normal vitamin D levels…As you know by now, I strongly believe that this test should be mandatory!

Low-risk MGUS = M protein < 15g/L, IgG type and normal FLC. If this is your condition, then you can breathe a huge sigh of relief. Your progression risk is very low, and you don’t need a bone marrow biopsy, which is required if the patient has unexplained anemia, renal insufficiency, hypercalcemia, or bone lesions.

Intermediate and high risk MGUS. M protein > 15g/L, IgA or IgM type, or abnormal FLC ratio. In these cases, a bone marrow biopsy (BMB) is recommended. If there is evidence of myeloma or Waldenstrom’s macroglobulinemia, then the following tests should be done: lactate dehydorgenase (LDH), Beta-2 microglobulin (B2M) and C-reactive protein. Hmmm, I wonder why the authors don’t recommend that these three tests be part of our routine testing…I mean, I have always had my LDH, B2M and CRP tested…

Smoldering (asymptomatic) myeloma. Of the 276 patients with SMM, 59% (163) progressed to MM or amyloidosis. As we already know, the overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years. Well, I have written about this before. The statistics look mighty depressing, but if you make it through the first five years, your risk percentage goes way down. And, as I have said before, numbers are only numbers…

Risk factors for progression. The size of the M protein and the percentage of crappy cells in the bone marrow are the main ones. Other factors, such as gender, haemoglobin level, type of serum heavy chain, albumin level, presence and type of urinary light chain, reduction in levels of uninvolved immunoglobulins are not significant in terms of progression…NOT significant. Well, that is very good news, especially for me, since my IgMs and IgAs are practically nonexistent…I won’t really worry about them anymore…

However, an independent additional risk factor for progression is the FLC ratio. If, in addition to a high amount of monoclonal proteins in your blood and plasma cells in your bone marrow, you also have an abnormal FLC ratio, you have a higher risk of progression than someone with a normal FLC ratio…Another risk factor are occult bone lesions. If an MRI of your spine reveals any abnormalities, that also increases your risk of progression: 1.5 years versus 5 years. Again, numbers…

Patient management. Here we can read about the tests that should be done at diagnosis and then 2-3 months after a diagnosis of SMM. In addition to a serum protein electrophoresis, CBC or complete blood count, calcium and creatinine tests, 24-hour Bence Jones urine test and immunofixation, the authors recommend a full skeletal survey, a bone marrow biopsy (BMB) and an MRI of the spine and pelvis. If your results keep showing that you are stable, then the time between tests can be lengthened to every 6-12 months after the first year. Again, there is no mention of a vitamin D test, which borders on scandalous. I recommend that all the newly diagnosed MGUS, SMM or MM patients take the 2009 Mayo Clinic vitamin D study (I link to it from my blog; see under “Myeloma and vitamin D”) to their specialists and request that their D levels be checked. Sorry to be repetitive, but this is one of my main pet peeves…

Summary. Here the authors recommend that SMM patients in the high-risk-for-progression group be considered candidates for chemoprevention trials. Candidates for WHAAATTTT??? Uffa! Uffissima!

As most of you probably know by now, I have VERY STRONG opinions on this particular issue: chemoprevention trials for SMM patients are nothing short of bloody OUTRAGEOUS…Absolute RUBBISH…Unless, of course, you are fond of skydiving without a parachute or of getting bitten by venomous snakes in the middle of a jungle, miles away from a hospital…

No. No no no. NO NO NO! Until we develop symptoms, we should steer away from any conventional treatments…away from anything that might rouse the tiger sleeping inside our bodies. Of course, we must also avoid any fishy, not-backed-by-science alternative “treatments”…We certainly don’t want to make things worse! Of course, this is JUST MY OPINION…

Another point (again, just my opinion): we shouldn’t freak out if only one test, such as haemoglobin, comes back abnormal. Even a suspected bone lesion should be fully investigated before jumping to the conclusion that it is a symptom of full-blown myeloma.

And this brings me to my final point. Based on my own personal experience, I always recommend that before beginning any sort of conventional treatment we should consult a second specialist, if not a third or fourth, which is exactly what I did in the fall of 2005, when my Italian hematologist kept insisting that I begin chemotherapy (two cycles of Velcade), then have an autologous stem cell transplant in the summer of 2006. I listened to my gut instinct and replied, “thank you, but no.” And I immediately consulted three well-known (at an international level) myeloma specialists–two in the U.S., one here in Italy.

After reviewing my test results, they all basically told me: “no CRAB symptoms, no treatment.”

And that has become my mantra…

One thought on “SMM-MM risk of progression

  1. Yolande Paine

    Dear Margaret,
    I was diagnosed with SMM three months ago. I live on the Canadian West Coast and am now actively seeking out the best medical specialists on my condition. I am particularly interested in your incredible story of living with SMM and the helpful advice you are providing all of us on various topics such as use of Curcumin etc.. Since the diagnosis my husband and I have read a lot of information but have found your site to be the most useful and provides so much hope. I live in a large urban centre but incredibly there is a lack of specialists in MM. We are prepared to go anywhere in the world for advice and wonder if you could suggest 2-3 good specialists. Thank you for sharing your knowledge and positive outlook with all of us, it makes such a difference. Best regards, Yolande

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