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Alert Number 303

MGUS: Not So Benign After All

Date: November 1, 2008

A couple of years ago, my husband PC had a bad fall on rough terrain (he was fooling with the dog) and bruised the side of his leg pretty extensively. Fortunately nothing was broken, and since he was wearing sturdy pants there was no broken skin either. We heaved a sigh of relief as the bruising faded over a couple of days. Then, late on a Friday evening (why do medical emergencies always happen over the weekend when it is impossible to reach anyone?) he developed sharp pain along his shin as well as bright red vertical streak running from his knee to his ankle. I knew enough to look up information on DVT, deep vein thrombosis. After getting valuable feedback from a generous expert willing to consult on the phone at an unreasonable hour, I hustled PC to the emergency room. DVT was one more bullet my husband dodged successfully over the last eight years.

For those of you who have never come across this term, venous thromboembolism is just fancy words for a blood clot that forms within the veins of your body. What makes this dangerous is that the clot can break off and travel through the veins and re-lodge in the lungs, heart or brain – causing potentially life threatening situation. Deep vein thrombosis (DVT) in the pelvic and deep veins of the legs gives rise to approximately 70% of all pulmonary embolisms, a potentially lethal complication of DVT. Here is another little bit of information: people with blood cancers are at higher risk of getting DVT. This is particularly true of people with multiple myeloma, and the risk increases when they are treated with immunomodulatory drugs such as thalidomide analogs (Revlimid).

A significant portion of CLL patients have an annoying little thing called MGUS (monoclonal gammopathy of unknown significance). Here is an excellent link if you want to know more about MGUS , and here is the short version for those of you too lazy to click on the link.

Once a mature B-cell has decided on the particular nasty pathogen it is going to fight, the single enemy that will forever define its reason for living, the B-cell transforms into a “plasma cell” whose only purpose is to turn out identical immunoglobulin molecules shaped just right to grab on to that particular bad actor. Since there are zillions of pathogens out there, our bodies have equally large zillions of plasma cells fixated on them, making exactly specific immunoglobulins to fight each and every one of them. Think of this healthy situation as a very broad repertoire of immunoglobulin molecules, each one targeting a specific bad actor, but no one type predominating more than the others. This vast diversity of immunoglobulin molecules is what makes it possible for our bodies to fight off all the nasty pathogens out there.

In multiple myeloma this happy picture breaks down. “MM” is a cancer of the plasma cells. Rather than a zillion plasma cells fixated on a zillion different pathogens, MM patients have large numbers of plasma cells that make just one kind of immunoglobulin only, a clonal horde of plasma cells all turning out the exact same immunoglobulin molecule. The clonal explosion of cancerous plasma cells causes a huge overproduction of useless copies of the same immunoglobulin molecule. Too much of the immunoglobulin protein causes the blood to become much more likely to thicken and clot – hence the risk of DVT in multiple myeloma patients. Obviously, the fact that MM patients have too many of just one kind of useless immunoglobulin molecules means MM patients are sitting ducks as far as infections are concerned.

As people get older, there is increasing chance that they have something called MGUS, and CLL patients are even more likely to have MGUS than the general population of the same age. MGUS means there are a few spikes in the immunoglobulin distribution, there are just a tad too many copies of one or more immunoglobulin molecules – more than one would expect in a healthy person. But MGUS is not MM. It may be a hint of things to come, a pre-cursor of full blown multiple myeloma. But the very name tells us we don’t really understand its significance – multiple gammopathy of unknown significance.

So, why am I writing about MGUS today? The latest issue of Blood has an important article and editorial on the subject. Abstract is attached below, let me know if you want to slog through the full text version. In a very large study using millions of people, researchers found that people with MGUS are at significantly higher risk of life threatening DVT, to the tune of more than three fold. The risk is even higher in people treated with immunomodulatory drugs such as thalidomide or its analogs. Here is the chain of my thinking:

  • Older people are more likely to have MGUS.
  • CLL patients tend to be a little longer in the tooth (forgive me, all you young guys and gals out there with CLL, life just is not fair)
  • CLL patients are more likely to have MGUS as their CLL progresses.
  • MGUS greatly increases the risk of potentially life threatening deep vein thrombosis.
  • Use of thalidomide analogs makes the risk of DVT higher.
  • Revlimid, a thalidomide analog, is increasingly being used to treat CLL.

Guess what, several months after his DVT incident, PC was tested for MGUS. He was positive for it. At that time he had not yet been treated with Revlimid. If I had known then what I know now, I would have been a bit more worried about making the decision to go ahead with the Revlimid therapy, especially given his prior episode of DVT. As it turned out, Revlimid gave him good clearance of his bulky lymph nodes ahead of his stem cell transplant, and that was a good thing. Just goes to show, there are no easy decisions when it comes to treating aggressive CLL and all of its many complications. Some times you get the bear, some times the bear gets you.

What is the take home message for CLL patients from this long winded Alert? Be sure to recognize the symptoms of a DVT, and get thee to an emergency room right away. This is especially true if you have already been found to have incipient MGUS, and you have been treated with Revlimid. DVT and its potential for pulmonary embolism can kill you a whole lot more quickly than CLL.

Be well,

Blood. 2008 Nov 1;112(9):3533. (Editorial)

MGUS: not so benign after all.

Kovacs MJ.

London Health Sciences Centre.

PMID: 18948581



Blood. 2008 Nov 1;112(9):3582-6. Epub 2008 Jun 17.

Deep vein thrombosis after monoclonal gammopathy of undetermined significance and multiple myeloma.

Kristinsson SY, Fears TR, Gridley G, Turesson I, Mellqvist UH, Björkholm M, Landgren O.

Department of Medicine, Division of Hematology, Karolinska University Hospital and Institutet, Stockholm, Sweden.

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4,196,197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.

PMID: 18559977

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