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Markers of progression from MGUS to MM…Part I

Posted Nov 22 2010 12:09pm

Yes yes yes, I am indeed procrastinating on my “possible viral connection” piece, which has turned into a daunting magnus opus…But at least I am procrastinating with a study that will, I hope, provide us with some juicy food for thought and, why not?, a bit of constructive debate. I have divided my long post into two parts…and will be posting Part II after I get home from work tomorrow…

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…

Written by Margaret

November 22nd, 2010 at 10:09 am

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