Risk factors for progression from MGUS/SMM to full-blown myeloma…Mayo Clinic 2010 guidelines

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…


  1. Glad to learn you started the New Year with a belly laugh. I wish you many more as 2011 moves along. 🙂

    Thank you for the excellent analysis of the MGUS/SMM study.

  2. Hi Margaret

    it’s all statistics. Or is it?

    I tend to agree with you – if you don’t have bone problems, or other serious symptoms, it might be better to leave well enough alone.

    However, the level of m-protein is related to tumor burden, which is a measure of the actual number of myeloma cells you’re dealing with. Because any given cell has a certain probability of converting to the dark side, the more cells you have, the greater is the overall probability. This is reflected in the numbers given by the study.

    It would seem to me, from a simplistic standpoint, that reducing the m-spike, and therefore the number of cells, would also reduce the probability of progression.

    Provided, of course, that poking it with something like revlimid doesn’t wake the beast. If we’re dealing with something that is more like an organ, or a multicelled creature, then attacking it might trigger its survival instinct and result in it taking measures to “heal” itself, which of course means it starts growing again and is more resistant.


  3. Most informative, Margaret, and especially useful for those who are needing to make such a critical decision as doing chemo… I would never choose ‘proactive’ chemo… sounds like a snakebite in the jungle would be preferable and more survivable, if there’s a shaman around…

  4. Hi Frank, I agree with most of what you wrote, but would like to say that if you (=generic “you”) have no CRAB symptoms and your M-protein level is more or less stable, even if it is highish (as in my case, where it hovers between 25-30%, and my m-spike is more than 2 g/L…But, with ups and downs, they are both stable), I believe that it would be a big mistake to start poking the sleeping beast. If you are stable, why do it? The risks are too high, as you yourself point out in your last paragraph…
    Let me take this a step further. I have decided that, even if my m-spike should increase a bit and perhaps even quite a bit, I am not going to start poking my beast with conventional meds (or, obviously, with any iffy “alternative” stuff!). One of the most eminent hematologists in Italy doesn’t treat his asymptomatic patients even if their m-spike goes up to 5 or so. (Let me emphasize “asymptomatic.”) That seems reasonable to me. Of course, this is just my opinion, and I could be wrong!

  5. But is there research showing that patients
    with smoldering myeloma who had chemo and transplant
    had longer survival than those who opted for
    the watch and wait policy?

  6. Carla, you will find some mention of this in one of my recent posts: http://margaret.healthblogs.org/2010/12/13/why-poke-a-sleeping-tiger/
    To date, and as far as I know, all the SMM-chemo trials have failed, leaving at least some patients worse off than when they started. Not good, from my viewpoint.
    As for that awful (JMO!), ongoing Spanish SMM-chemo study, well, it is too early to tell. We cannot possibly know, or even predict, what sort of long term side effects these patients will have. But we do know about some of the short term effects. As you may recall, the side effects suffered by almost half of these patients were serious…in some cases, VERY serious. A few even had to drop out of the study.
    It just makes no sense to me. I would rather have better QOL and a shorter life than a longer life filled with illness and pain…But that is just my opinion, of course…

  7. Hi Margaret,
    I’m writing from Italy. Never heard og mgus before this afternoon when a frien of mine told me he has this disease. I know something about orthomolecular medicine and tried to find out some supplement to enhance his himmune system.
    Since now I’ve found Vid.D, Curcumin, Vit.B12.
    I’ll continue my search – also in your very informative blog. And if you would suggest something…well…sarebbe il massimo…it would be veri nice!

    Thank you in advance – un grosso saluto

  8. I am searching a lot on MGUS because my uncle,51 years old, is suffering from it and your blog has helped me know it better. Well do you have any idea if the M protein level can be controlled to normal level????

  9. Hi Margaret:

    So great to find you. I am in the scary, early period where I know I have an m-spike (IgG lambda-don’t know size) and an abnormal FLC ratio but no “CRAB” and bone density normal. Waiting for result of the 24 hour urine. Been so obsessed that I’ve basically memorized the Mayo Clinic stuff on MGUS and MM! Oncologist says he’ll await that result before recommending a BMB. Very stressful period. So thanks for some common sense and humor. Yes stats are stats, not people! Thanks.

  10. I was diagnosed with MGUS about a year ago. I am having trouble understanding the SPE interperation: mine was .57, then .53 and now .27 G/dl. Anyone know what this means or where I can find what these results mean. I recall the doc saying this was the measure to watch but have forgotten what were the norms. Thanks

  11. Hi Margaret,

    I have sarcoidosis, which I am treating with an experimental protocol ( The Marshall Protocol) which uses high dose, off label olmetec. I have been doing this for years, and despite anemia, which I believed to be the chronic disease type, and renal dysfunction due to the sarc ( which Is also in my lungs and lymph nodes), I was doing really well – working and exercising etc. Then, my doctor got concerned about my low hemaglobin and ran a SPEP test, which came back with an M protein of 1. Six months, later, the M protein is still one, , but now the gammopathy screening showed an IgG KAPPA restriction = unclear significance. I know have to do a 24 hour urine test for Bence Jones Protein and have to see a hematologist. I still feel my anemia and renal dysfunction are sarc related, but this is going to be hard to prove. Can you still have MGUS with all of this going on, too?

    Love your writing.


  12. Hi Margaret. Thanks for all of this. I see my consultant in 2 weeks and my blood tests are on Weds. I have t(4.14) and am due to go on Revlimid plus a 50/50 trial of something else. I have now to convert him to just the Revlimid plus curcumin and nigella sativa. My IgA is 19.8 and IgM and IgG are on the floor so to speak – but have only been on curcumin since late February and Nigella Sativa for about a week. Unfortunately all other blood readings are what are causing his main concern at the moment – if only we could do a home blood test as in diabetis or high cholesterol!! All the very best Anna

  13. Margaret, I recently asked my MM specialist in NYC about the IGA type being more high risk, and both he and Dr. Berenson, whom I heard speak at an engagment few days before this appt, said that it’s a very small increased risk over IGG, not some huge risk, I think the most important issue about IGA is that the m spike needs to be watched at a lower level than that of someone who is IGG, meaning, an m spike of 1.5 in an IGA patient is much more alarming than an m spike of 1.5 in an IGG patient, but the actual risk of progression of IGA over IGG is only slightly worse. Just wanted to clarify this info since it came directly from 2 myeloma specialists who told me practically the same thing, and this is current 2013 info. thanks.

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