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MCRT Webcast: MGUS and Smoldering Myeloma (SMM)
Posted: Nov 03, 2020
MCRT Webcast: MGUS and Smoldering Myeloma (SMM) image

Precursor conditions of myeloma may or may not progress to active myeloma, but they must be monitored regularly to determine if they are progressing.  Monoclonal gammopathy of undetermined significance (MGUS) is an abnormal protein—the M protein—in the blood that increases in an aging population.  While not all people with MGUS will develop myeloma, all myeloma patients have once had MGUS.  MGUS can progress to smoldering myeloma (SMM), which progresses at different rates in different people, but has traditionally not been treated.  Now patients who are identified as having high-risk SMM are being treated in clinical trial settings.  There is an ongoing debate among myeloma specialists if the SMM classification is still relevant.

Drs. Irene Ghobrial and Shaji Kumar explain what MGUS and smoldering myeloma are and what patients should know about progression and treatment:


Shaji Kumar, MD, Mayo Clinic, Rochester, MN: MGUS and Smoldering Multiple Myeloma (SMM)

  • Plasma cells are mature white blood cells of the B-cell family
    • They have important function of making antibodies or immunoglobulins (Ig) to help fight infections
    • Abnormal plasma cells can lead to many disorders
    • The focus of this talk is the malignant proliferation that is uncontrolled (monoclonal gammopaties)
  • They are made of two larger molecules (heavy chains) and two smaller ones (light chains)
    • Heavy chains can be five different types: IgG and IgA are most common; IgM, IgE and IgD are less common
    • Light chains are either kappa or lambda
    • They are bound together to create an immunoglobulin
  • Monoclonal gammopathies are characterized by abnormal plasma cells (clonal) and typically secrete light chains in blood or urine
    • At least 90% of monoclonal gammopathies are MGUS (monoclonal gammopathies of undetermined significance)
    • Smoldering myeloma (SMM) is less common
    • Both are considered to be precursor conditions
  • MGUS and SMM are typically found in bone marrow
    • Also present as plasmacytomas, swellings of soft tissue caused by monoclonal gammopathies
    • Can also be found in the blood stream using more sensitive testing
  • Light chains can be detected through a electrophoresis test, seen in M-spike
    • Immunofixation is a test used to identify type of heavy and light chains in the M-spike
    • A serum free light chain assay will differentiate between a kappa or lambda light chain and measure amounts
    • Taken together, these tests help determine what the monoclonal gammopathy is doing
  • It is unclear why some people develop monoclonal gammopathies, but there are subgroups in the population who are at higher risk of diagnosis
  • Increasing amounts of monoclonal proteins and plasma cells characterize progression from MGUS to SMM to multiple myeloma
    • Myeloma causes end-organ damage, but smoldering myeloma does not
  • Research is increasing to determine if SMM can be prevented from become active
    • The risk of MGUS progressing to active myeloma increased at a rate of about one percent per year, which is why patients should be monitored regularly
    • Approximately half of SMM patients progress to multiple myeloma in the first five years of diagnosis, 16 percent over the next five years, and then plus one percent per year after ten years
    • The key indicator researchers are trying to determine which patients are at greatest risk of progressing (high-risk SMM and high-risk MGUS)
  • Revised risk stratification (20/20/20)
    • Combined assessment of plasma cells in marrow, M spike, and free light ratio


Irene Ghobrial, MD, Dana Farber Cancer Institute, Boston, MA: Understanding MGUS and Smoldering Myeloma Progression

  • We should be “upset” about being told to watch and wait because in no other cancer do we wait for the disease to become active before treating
    • But over-treating has pitfalls; many with precursor conditions will not develop myeloma, so it does not make sense to treat them
  • How and when should a patient know when it is time to do something, how do we predict the risk of progression?
    • Dr. Ghobrial started the PCROWD study to engage MGUS and SMM patients to get blood and marrow samples and clinical information to study this
  • Prediction methods must become more precise, genetic information indicates three areas of interest in DNA: MYC alterations, MAP kinase mutations, DNA repair mutations
    • Having one of these features means one is at risk of progression to myeloma, not having one may mean one is not, but this must be made more accurate
    • The microenvironment—the immune cells that surround the cancer cells—is also important
    • Having MGUS or SMM means the immune system is not completely healthy; the cancer cells are changing the immune cells and changing their behavior
  • Predicting progression takes all these factors into account
    • Precision (personalized) medicine utilizes the immune system to inhibit progression
  • What else can we do?
    • Familial incidence studies indicate certain people are at risk for myeloma (see Dr. Kumar’s comments above)
    • Age is an important factor, the older we get, the greater the likelihood of developing MGUS
  • Screening for incidence and progression is the PROMISE Study
    • Answer three questions to determine if you or your family members are eligible
    • Submit blood sample to determine the presence of MGUS
    • Mass spectrometry being used to study samples
  • Another study is expected to open soon: the IMPACT study
    • Participation in PCROWD or PROMISE is prerequisite
    • Will try to determine if MGUS and SMM patients are more at risk for COVID-19
    • Will efficacy of vaccines be compromised?
    • Samples of immune cells will be sequenced to determine how they respond to vaccines


Audience Questions & Answers

  • 0:55 - How common is it to have clonal evolution in SMM prior to treatment and what implications does this have on severity?  And can someone with SMM bank their stem cells for use if they develop active myeloma?  Clonal evolution in MGUS?
  • 4:40 - When should patients think about collecting T Cells?
  • 7:31 - If one has high-risk SMM, what are the criteria when and if to start treatment?  [Dr. Kumar references the need to have more accurate imaging techniques in his answer.  More about this can be found in the Myeloma Crowd Round Table Interactive Webcast on Myeloma Imaging.]
  • 12:22 - Is it better to treat SMM as if it were myeloma or will this develop resistance to possible future treatments?
  • 14:25 - For patients with biclonal SMM, how does it differ from monoclonal?  Is it better in the long run?
  • 18:55 - Are there links to Gaucher’s Disease and other autoimmune disorders in the MGUS stage?
  • 22:46 - Does high blood ferritin (iron in the blood) have a correlation of progression from MGUS to myeloma?
  • 23:41 - What are the differing clinical trial approaches in progression and myeloma that patients should consider?
  • 28:45 - Why is it said there are no symptoms with MGUS?  How often should testing be done?  If bone marrow biopsies show lesions, is that active myeloma?  And what about other conditions like kidney disease?
  • 31:22 - How often should one have biopsies done and how often should one do MRIs and more sensitive imaging?  [More about imaging can be found in the Myeloma Crowd Round Table Interactive Webcast on Myeloma Imaging.]
  • 32:24 - Are corneal deposits related to SMM disease activity and will they respond to treatment?  Would the presence of eye edema change a patient’s diagnosis from SMM to high-risk SMM?  Do eye issues have anything to do with MGUS, SMM or progression?
  • 35:07 - Is ITP (immune thrombocytopenia purpura) related to MGUS?
  • 36:08 - Does higher incidence in African-Americans include those who are biracial?  And can biracial patients join the PROMISE Study?
  • 36:56 - How do participants return samples to the PCROWD and PROMISE studies and notified what their results are?
  • 38:57 - Are there other treatment studies, not observational, for MGUS?
  • 40:07 - What can patients do outside of studies to slow or eliminate progression?
  • 41:56 - Is MGUS just cancer held in check, slow-growing, or pre-cancerous?  If the latter, what is the difference at the cell level?
  • 44:22 - What causes bone pain in these precursor conditions if there are no bone lesions present?  What should one do?
  • 45:20 - What do you do with SMM patients who have the gain1q genetic feature?
  • 46:53 - For a patient who was diagnosed with SMM a year after being diagnosed with MGUS and not eligible for clinical trials, what is recommended for dealing with the mental stress and challenges?
  • 48:36 - If myeloma is treated and goes into remission, does it become MGUS again?
  • 50:52 - What is known about MGUS and peripheral neuropathy?  Why does it occur?
  • 53:16 - Is there a difference in the type of clinical trial available and possible treatment based on age—old or young?
  • 55:08 - Should MGUS or SMM patients have DNA testing done?
  • 57:56 - How is early detection of precursor conditions being affected by the realities of the COVID pandemic?


Questions Answered by Dr. Kumar in Chat Forum

General Topics

  1. These are very high level questions.  I am newly diagnosed and confused.

Answer:  I would recommend that you talk to your physician and also interact with other patients on patient support groups.

  1. Are there any studies on why myeloma occurs?

Answer:  Many investigators are trying to identify factors that increases the risk of developing myeloma.  At this time we do not have any definitive data.

  1. Is there a way to tell how long one has had MGUS?

Answer: Unfortunately, no.

  1. If monocolonal proteins are cancer cells why are they not considered to be cancer?

Answer:  The monoclonal protein is secreted by plasma cells that are called clonal. However this in itself does not qualify it as a malignancy or cancer but is typically considered as a precancerous state with an ability to progress to the cancerous phase.

  1. What is the FISH test?

Answer:  It is a way of looking at the chromosomes in the myeloma cell.  [To learn more about this, please go the Myeloma Crowd Round Table on Myeloma Genetics.]

  1. Can you explain double hit, triple hit? 1q gain and 13 deletion?

Answer:  These typically refer to the number of high risk abnormalities that can be present simultaneously, 13 deletion is not considered as one of these high risk abnormalities.  [To learn more about this, please go the Myeloma Crowd Round Table on Myeloma Genetics.]

  1. How worried should a SMM patient be about being immunocompromised during COVID pandemic?

Answer:  I would do the common precautions to avoid the risk of infection.

Familial Incidence

  1. Is SMM hereditary?

Answer:  We do not think about myeloma or the precursor conditions as being hereditary in the true sense.  There is an increased risk amongst first degree relatives with multiple myeloma which is approximately two- to threefold as compared to the general population.  However, given the low prevalence of these conditions in the general population, even that two- to threefold increase does not really translate to a high number.  But it does highlight that there is a genetic component to the development of these plasma cell disorders.

  1. I was incidentally  diagnosed with lambda MGUS at the age of 39 and progressed  to myeloma at 47, have had it for 14 yrs.  I have three daughters in their 20s.  Should they be tested for MGUS?

Answer:  No.  We do not recommend testing first degree relatives for MGUS on a routine basis.

  1. I have a first cousin with a rare type of lymphoma.  Does this have anything to do with my diagnosis?

Answer:  I would not think that this would have any implication to your diagnosis.

  1. I am a 58 year old female.  My father was diagnosed with myeloma at age 67 and died 4 months later.  I am concerned that I am at high risk for myeloma.  My white blood cell count has been trending downward for 2 years, is now at 1.5, and my neutrophils are .6.  I am anemic, very tired, and have a lot of inflammation in my body and have had some cardiac issues.  I have been doctoring with a hemotologist and the last round of tests showed an M spike in my urine and blood and I was diagnosed with IGA Kappa MGUS.  I am scheduled for a bone marrow biopsy soon.  How concerned should I be?

Answer:  We do know that there is increased risk of myeloma in first degree relatives of patients with myeloma. However , we don't have any data to suggest that the myeloma should behave any differently in this setting compared to someone who develops it without any family history.

  1. My dad died from MM, My sister is currently in remission from MM, I have MGUS. When should my two sons (40 & 35) be checked for MGUS?

Answer:  Typically, we would not recommend a screening for MGUS.  With the multiple family members involved there is certainly a higher risk for both your sons to develop MGUS.  We do not know what the best time would be to check for monoclonal protein but somewhere between 40 and 50 years would be reasonable based on what we know about the disease.  However, this should be done after a thorough discussion of the pros and cons of this approach with their internist.

Basic Information

  1. Is there likely a malignant stem cell that proliferates into abnormal plasma cells resulting in MGUS, SMM, and myeloma? If so, is anything being studied to try to eradicate the malignant stem cells?

Answer:  This is a good question.  We believe that all cancers probably have some early stage cells that is more like a stem cell from which the more mature cancer cells may evolve.  There has been quite a bit of research along these lines in multiple myeloma as well.  However, we don't know enough at this point about this stem cell that we can target that without damaging the normal cells in the process.

  1. Can the progression of MGUS to SMM to myeloma be prevented or diminished?

Answer:  There are no specific treatments or interventional approaches that can diminish the risk of progression of MGUS at this point.  However, in patients with high-risk SMM who have a high risk of progression to active disease, early therapy with lenalidomide or participation in a clinical trial could be considered.

  1. How often should someone with MGUS be checked?

Answer:  Typically, we would recommend that patients with MGUS be checked at least once a year.  However, in patients who have extremely low levels of monoclonal proteins and who have an IgG type of monoclonal protein, less frequent follow up would be reasonable.

  1. What is the definition of high-risk SMM vs. intermediate-risk?

Answer:  This is based on the level of monoclonal protein, (>2 g/dL) serum free light chain ratio (>20) and percentage of plasma cells in the bone marrow (>20%). If a person has two or more of these characteristics, then that person is considered to have high risk smoldering myeloma. If there are no risk factors, then it is considered to be low risk of progression and if there is only one of them present, then it is considered to be intermediate risk.

  1. Is there national consensus on early treatment?  Are there parallel studies ongoing nationally?

Answer:  At this time there is no uniform consensus on early treatment.  Clinical trials, at least two phase III trials, have shown benefit and that has encouraged some providers to recommend use of an early therapy period at the minimum.  Based on the results of these trials, one should strongly consider being part of a clinical trial.

  1. Has there been any further research conducted in patients with IgA Kappa and IgA biclonal (I understand outcomes in patients are said to be the same, however, would like to understand how it happens - gene switching? not sure)

Answer: Biclonal disease can happen in a small number of patients. This represents two distinct clones of plasma cells. Generally, we see this in the setting of MGUS and when patients progress to active myeloma, we typically would see one of the clones disappearing.

  1. Please explain micro vessel development in the bone marrow in the transition from MGUS to active disease.

Answer:  At this time we already know is that increase density of micro-vessels in the bone marrow of patients with MGUS usually predicts for an increase risk of progression to multiple myeloma.


  1. Would you be able to summarize the latest comprehensive predictive criteria and model for progression from standard-risk SMM to high-risk SMM requiring treatment: 20/20/20, which genetic characteristics, which other factors?

Answer:  This is based on the level of monoclonal protein, (>2 g/dL) serum free light chain ratio (>20) and percentage of plasma cells in the bone marrow (>20%).  If a person has two or more of these characteristics, then that person is considered to have high risk smoldering myeloma.  If there are no risk factors, then it is considered to be low risk of progression and if there is only one of them present, then it is considered to be intermediate risk.

  1. Why is 2/20/20 a better definition of SMM?

Answer:  This is better than what has been used before, because this accounts for the new diagnostic criteria for multiple myeloma that was developed in 2014.

Monitoring MGUS and SMM

  1. How often should be a follow up bone marrow biopsy in smoldering myeloma patients be done?

Answer:  Typically, we would not repeat bone marrow biopsies on a regular basis in someone with SMM.  However, if there is a change in other laboratory parameters that suggests that the disease is progressing, a repeat bone marrow biopsy is reasonable.

  1. I have been followed for my MGUS for four years.  It is at a low level.  Twice my results have come back "not detected."  What exactly does this mean and what is the significance?

Answer:  This likely reflects you have a very low level of monoclonal protein.  This certainly is one of the characteristics that determine the risk of progression and lower the level of monoclonal protein, lower the risk of progression is.  The fact that it was not detected on a couple of occasions just highlights that the levels are very low.

  1. What does “too low to quantify” mean for an M spike lab report?

Answer:  Usually means that the certain protein electrophoresis does not identify a very clear spike that can be measured to be confidently read out on the test.

  1. In SMM, if free light chain ratio is the only risk factor (M spike and plasma percentage stable) would it make sense to treat just based on those? They seem to fluctuate a lot, but I’ve had ratio over 100 several times.

Answer:  The inclusion of serum free light chain ratio of over 100 as a diagnostic feature of multiple myeloma was based on the initial assessment.  If someone has had ratio over 100 for a long period of time with no evidence of disease progression, one can safely continue to follow these patients.

  1. As a female diagnosed at 41, does this mean risk will be higher as I will have live with it longer so more opportunity for it to develop?

Answer: That is correct. Over time the longer you live with the MGUS the higher is the cumulative risk of getting myeloma. However, the risk on an annual basis remains constant at about 1%.

  1. Do you ever see the M spike increase over time and then stop before it crosses into myeloma? Or is it the case that once your M spike starts to increase it always continues into Myeloma?

Answer:  Sometimes we do see M spike that increases over a period of time and then stabilizes for long periods.

  1. With SMM and blood work monitoring every three months, when should a bone marrow biopsy be repeated?

Answer:  Bone marrow biopsy needs to be repeated only if there are concerns for disease progression

  1. I have kappa and lamda light chains, is this biclonal?

Answer:  Yes if you have both of them then this would represent a biclonal disease

  1. Why are my kappa/lambda chains counts different each time?

Answer:  The serum free light chain levels do vary a little bit from time to time.  One needs to make sure that they are being done on the same assay and are also using the same units.

  1. I have MGUS/borderline SMM and have had predictive test called a BCMA test.  It puts me in the "low risk" category for progression.  Are you familiar with that test, and is that a reliable predictor?

Answer:  This is based on some initial studies.  It needs to be studied further in the context of other risk assessment factors that have been described like the 20/2/20 system.

  1. What is the M spike number that triggers treatment?  The “ waiting for the other shoe to drop” is very difficult; asymptomatic, just crazy IgG results, etc.

Answer: I totally understand the dilemma that you are in.  Unfortunately, there is no set M spike number that triggers treatment.  In fact, the decision to initiate treatment is based on a set of characteristics that defines a diagnosis of active myeloma

  1. I have stable SMM, 10% in bone marrow, and a .9 M spike.  I’m currently being monitored by hematologist/oncologist.  When should see myeloma specialist?

Answer:  If you feel comfortable with your hematologist, that person should be able to continue to follow you. They can refer you to myeloma specialist if there are questions.

  1. What is the typical follow up for a MGUS diagnosis. Tests and timing?

Answer:  We would typically do a blood count, kidney test and calcium and the monoclonal protein in this serum and urine on an annual basis.

  1. If you treat SMM into remission do you have to go on maintenance the rest of your life?

Answer:  most of the clinical trials currently are looking at a limited duration of therapy. Hopefully that will set the stage for a limited treatment for patients with smoldering myeloma in future.

  1. I have non-secretory myeloma in stringent remission.  Is there a non-secretory kind of MGUS?

Answer: there is likely in MGUS that is known secretory, however given the fact that we don't routinely do a bone marrow it is unlikely that this would be discovered.

  1. I have a M-protein of .9 and one is .1. for a total of 1.0.  Does that mean I have a biclonal protein?

Answer: Quite likely.

  1. Is there a difference in biclonal with SMM with both IgA instead of one IgG and one IgA. I'm considering a clinical trial.

Answer:  We do not think that the outcomes are any different in these patients.  Certainly can be considered for clinical trial if you meet the enrollment criteria.

  1. How often (if at all) should a bone marrow biopsy be repeated?

Answer:  It should only be repeated if there are additional changes in the clinical or laboratory parameters that raises suspicion for disease progression.

  1. What are your thoughts regarding being hyperdiploidy p53 deletion in SMM and risk progression to myeloma?

Answer:  Presence of p53 deletion has been associated with an increased risk of progression.

  1. I had my only bone marrow biopsy in 2007 and it indicated 10 percent.  I was initially diagnosed with SMM, but had been re-diagnosed as MGUS.  Does that percentage  increase over time and should I have another biopsy done?

Answer:  These numbers can increase overtime.  However we do not routinely repeat bone marrow biopsies unless other laboratory parameters change that raises suspicion for disease progression.

  1. My myeloma (high-risk/aggressive) keeps going from smoldering to active. Is this normal?  I have not begun treatment as a result of this fluctuation.

Answer:  These kind of fluctuations can happen, especially at the borderline area.  I think it's important to watch very closely.

  1. If you have a free light chain ratio greater than 50, is multiple myeloma inevitable?

Answer: Not necessarily.

  1. My biggest concern is Free light chain ratio is above 50 and plasm cells 10-15%. What can I do to stop this progression?

Answer:  There is nothing that can be done specifically to stop the progression.  I would encourage close follow-up.

  1. The follow up for SMM was discussed but not for MGUS.  What is recommended?

Answer:  We typically do annual follow up for MGUS.

  1. What are the critical numbers newly diagnosed SMM patients need to ask for, understand, and monitor in terms of labs? Clonal Plasma Cells, and what else?  M Spike?  Free light chain ratio?

Answer:  All the about test would be important as part of the original work up

  1. Several years ago I was diagnosed with MGUS with fairly low levels.  I have gone to a specialist every year using the same lab and now am told my M spike is too low to quantify.  Do M spikes fluctuate and can they ever go away completely?

Answer:  Rarely does it go completely away, especially if you have very low levels to start with.  That is a good thing to happen.

When to Begin Treatment?

  1. If light chain polymerization prevents renal damage and excretion, then serum light chain levels would increase.  Should levels above 1500 or many thousands trigger therapy?

Answer: This is a very good question.  There are patients in whom the free light change levels in the blood are quite high, but they do not have any of this excreted into the urine.  We believe this is likely secondary to polymerization of the light chains or other structural changes in the light change that we have not fully understood. In these patients, the implications of the high levels of light change is not the same as in other patients.  For these reasons, we would not start treatment just on the basis of a certain free light chain level in those patients with none appearing in the urine.

  1. What can be done to intervene with persons with high-risk SMM? At what point should intervention be considered?

Answer:  At this point we only have data supporting early treatment in patients with high risk smoldering multiple myeloma.  In those patients, based on phase III clinical trials, one can consider starting therapy with lenalidomide with or without dexamethasone or consider enrollment in one of the clinical trials that randomizes patients between different treatment approaches.

  1. Is there a definitive test to diagnose light chain polymerization.  Would comparison of light chains in serum vs. urine levels be useful, and how does the UPEP (urine protein electrophoresis) help (eg, low albuminuria)?

Answer: There is no specific test to look for polymerization.  However when the laboratory does the free light chain essay, they will get a sense weather this is happening.

  1. What is immune profiling, how is it done, and is there a standard?  Is immune profile testing clinically available?

Answer:  Immune profiling refers to assessment of the immune system and its functionality.  There are no universally accepted standards in terms of what defines a normal or an abnormal immune system within the context of a given cancer.  There are a variety of different technologies that are being explored and developed and hopefully this will become a part of the disease assessment in myeloma.

  1. I was diagnosed with SMM (IgG) 2 years ago.  I have done lab work every three months and the markers remain about the same.  I have not done urine lab test.  Am I missing something?

Answer:  It would be good to have a 24 hour urine test done at least one so that we have a good baseline and also to make sure there is no significant amount of protein in the urine.


  1. Can chemo treatment cause mutations of the plasma cells?  If so, could early treatment cause mutations that will be resistant to further treatment?  Also, would early treatment only leave very aggressive, resistant clones that can quickly proliferate?

Answer:  This is a theoretical concern that has not been borne out by the studies that have been done so far.  In patients with smoldering multiple myeloma who have been enrolled in clinical trials and have been treated with lenalidomide we have not seen any evidence that the myeloma becomes more difficult to control or have more genetic changes.  Having said that, treatment with some drugs like melphalan can increase the risk of developing cancers in the white cells though this is a reflection of genetic damage in those cells rather than in the plasma cells.

  1. Are there any proactive treatments for SMM outside of a clinical trial?

Answer:  On what we know from the clinical trials, in patients with high-risk SMM lenalidomide treatment is reasonable after a thorough discussion of the pros and cons.

  1. Can Revlimid be considered without dexamethasone to keep side effects as low as possible for SMM?

Answer:  Yes, the most recent phase III trial only used lenalidomide (Revlimid) and did not include dexamethasone.

  1. For someone diagnosed with SMM today, is it likely that these preventative/curative interventions will be available outside of trials?

Answer:  Yes.  In patients with high risk smoldering multiple myeloma we can certainly consider using treatment with lenalidomide as has been done in the phase three trials.  Once we have the ongoing trials demonstrate an advantage, if it does, for more intense treatment regiments, then those can be used as well.  Our projections based on emerging data is that newer/better therapies will result in higher rates of sustained MRD-negativity.  [You can learn more about MRD in this Myeloma Crowd Round Table Interactive Webcast.]

  1. I have MGUS IgGk.  Is there a prevention program I can follow?

Answer:  There is no specific prevention program.  I would encourage you to maintain a healthy lifestyle

  1. I’ve heard one of the doctors reference the notion of prevention in patients with SMM.  Can you provide any examples of what can done in the realm of prevention?

Answer:  There are clinical trials that are looking at treatment with one or more of the myeloma drugs to see if we can slow down the progression from SMM to active myeloma.

Symptoms and Side Effects

  1. I have bone pain, should I be receiving treatment?

Answer:  If the bone pain cannot be explained on the basis of bone lesions seen on X Rays or CT scan, there is no need to start treatment for myeloma.

  1. Is there anything that can be done about the fatigue associated with myeloma?

Answer:  There are no specific treatments for fatigue other than changes in lifestyle . Light exercise can help. Taking a break or a short nap in the afternoons can often help patients as well.

  1. Are blood clots a symptom of progression?

Answer:  No, they are not.

  1. Can you please clarify: are you saying that SMM treatment now can actually cause more damage, can make the condition even worse?

Answer:  No, the clinical trials in fact suggest that early treatment may be beneficial to a small subset of patients with high risk smoldering myeloma

  1. I have MGUS with major leg discomfort and nausea particularly later in the day and at night.  Could these be a symptom of myeloma?

Answer:  It seems unlikely.

  1. Does neuropathy in myeloma happen in many limbs or can it be localized in one limb e.g. right arm only

Answer:  It will be unlikely to be in just one arm only.  There is likely another reason for the neuropathy.

  1. Is fatigue a symptom of high-risk SMM?

Answer:  Unless there is active myeloma there should not be a direct relationship.

High-Risk SMM

  1. If there is high-risk SMM, is there also high-risk MGUS, especially when factoring in type, M protein level, free light chain ratio or genetic characteristics like t(4;14)?

Answer:  Yes, MGUS also can be classified on the basis of risk of progression.  It also uses similar factors as in smoldering multiple myeloma like the amount of monoclonal protein, free light chain ratio as well as presence or absence of genetic abnormalities.

  1. How long can one watch and wait?

Answer:  Patients have been watched for decades without any evidence of progression.  So a diagnosis of a MGUS would mean that it needs to be watched closely life long.

  1. How should low-(or standard-)risk smoldering myeloma be monitored?

Answer: These patients should be closely watched.

  1. For which level of M protein would one have a bone marrow biopsy ?

Answer:  Typically, in a patient with MGUS we tend to do a bone marrow biopsy even the monoclonal protein is more than 1.5 gram/dl in a patient with IgG M-protein and at 1 gram for patients with IGA monoclonal protein.  These practices vary and no clear cut off that has been established.

  1. I received a diagnosis of MGUS after having a bone marrow biopsy in December, 2018.  Subsequently, I receive regular blood tests to watch M-protein, white blood cell count, kidney readings, etc.  My doctor tells me that they do not provide treatment for MGUS or Smoldering Myeloma, however will recommend and provide chemotherapy if/when I progress to Multiple Myeloma.  I would like to know if there are any recommendations to treat MGUS.  It is a little frustrating to hear that there is nothing to be done to help mitigate transitioning to smoldering or myeloma.

Answer: Yes, in order to determine that there are no residual lesions in another part in the body than the one where the biopsy was done to assess MRD.

  1. So should MGUS patients have a bone marrow biopsy?

Answer:  In patients with very low levels of monoclonal protein one can defer the bone marrow biopsy.

  1. Is del17p a marker the indicates high-risk SMM, and is there a treatment available?

Answer:  Presence of del17p does increase the risk of progression.  There are no specific treatments for this particular abnormality in SMM or myeloma.

  1. If I have an M-spike of 4.0 and bone marrow involvement of 30%, everything else is normal based on CRAB criteria and no lesions, is that high-risk SMM?

Answer:  Yes, based on the current criteria that would be considered as high-risk.

MGUS, SMM and other Diseases and Conditions

  1. Is there a relationship between osteoporosis and MGUS?

Answer:  Increased osteoporosis can be seen in the setting of MGUS.  The exact mechanism is unclear but is likely to be similar to what we see in myeloma.  This can result in an increase risk of fractures among patients with MGUS.  So it is important that your bone healthy is followed closely consistent with current monitoring practices.

  1. I have no organ impact for MGUS or SMM, but what should I think about complement activation resulting in monoclonal gammopathy of renal significance (MGRS)?

Answer: In this setting of MGRS , there is clearly and organ impact from the monoclonal protein.  In this setting, even though this does not meet the diagnosis of myeloma or amyloidosis, patients will need treatment to ensure that the renal function does not worsen.

  1. I have MGUS and cryoglobulinemaia.  Is this a common occurrence?

Answer:  Cryoglobulinemia is not a very common condition. However, the majority of the cryoglobulinemia that we see in association with a monoclonal protein will be in the setting of MGUS.  So this represents one of those situations where the monoclonal gammopathy is resulting in clinical consequence and hence may need treatment.

  1. Is there any link between MGUS and inflammatory disease such as sarcoidosis or immune issues like lupus?

Answer: These conditions can occur together in patients, what we call an association.  However, we do not really know if they are connected in terms of why they happen.

  1. I have SIBO (small intestine bacterial overgrowth) and my oncologist is suggesting that the MGUS might be associated with it, have you seen any evidence of this?

Answer: No, we have not seen this association.

  1. Can SMM include treatment for hypogammaglobulinemia with monthly IV Ig?  Or if the disease reaches that stage, are we really talking about active myeloma that may not have CRAB conditions?

Answer:  In patients with SMM a we do frequently see some level of hypogammaglobulinemia.  However, in the majority of the patients this does not have any clinical consequence in terms of increased risk of infections. However, if a patient does have frequent infections replacement of the immunoglobins with IV IG would be a reasonable approach.  But this also needs to be taken in the context of the bigger clinical picture and patients should be examined to see if there are other features that would suggest active myeloma.  Hypogammaglobulinemia by itself is not typically considered a reason for starting treatment along the lines of multiple myeloma.

  1. I have been diagnosed with MGUS and acquired von Willebrand Disease. My doctors believe they're related, but aren't sure. Do you have experience with that?

Answer: Yes, acquired von Willebrand disease has been associated with monoclonal gammopathy. The presence of von Willebrand disease by itself is not an indication to start treatment for myeloma. In patients with myeloma who have gone through treatment, the severity of the von Willebrand disease may improve.

  1. Are there other conditions in most patients like diabetes, high blood pressure, basically, or metabolic syndrome?

Answer: Not necessarily.  There is no clear association between monoclonal gammopathy and typical illnesses that you encounter in patients like diabetes and high blood pressure.

  1. Can you address the role of chronic inflammation (as measured by CRP and SED rate) in disease progression?

Answer: There is no proven role of chronic inflammation in disease progression. Unfortunately, CRP and sedimentation rate can be elevated by the monoclonal gammopathy itself and makes it difficult to use these as markers of inflammation.

  1. Does diabetes increase the progression of MGUS?

Answer:  Not to the best of our knowledge.

  1. I am smoldering and was told I have hyperthyroidism, doesn't know if it's primary or secondary. However, I have elevated PTH with normal calcium and normal TSH. My vitamin D is low, but when I take supplements I go into hypercalcemia. I have extreme bone pain.  Studies suggests that myeloma and hyperthyroidism correlate in some cases. Any suggestions to ask my physician?

Answer: I suspect you are referring to hyperparathyroidism. I would strongly encourage you to see an endocrinologist who specializes in bone disease.

  1. I have medium-risk SMM and I am immunocompromised due to multiple sclerosis. How do the two interact and how do I treat MS without triggering active myeloma?

Answer: There is no good evidence to suggest that treatments that suppress your immune system accelerate the rate of progression of SMM to active myeloma.  Studies that have been done in patients with kidney transplant who have underlying MGUS have not shown an increase risk of progression.

  1. If a MGUS patient has severe osteoporosis what do you recommend as treatment?

Answer:   I would strongly recommend using a bisphosphonate or denosumab as one would do for osteoporosis without MGUS.

  1. With respect to protein deposits in cornea, can the treatment clear the deposits in the cornea or will corneal transplant work if interfer with vision?

Answer: I'm sorry but cannot answer this question without more details.

  1. If you have had colon cancer within last 3 years, will that make progression from MGUS/SMM faster?

Answer:  No, it will not.

  1. For someone diagnosed with MGUS with IgG kappa, what consideration should be given to worsening kidney/renal function (as indicated through creatinine levels). Are there any other tests recommended to eliminate or confirm MGRS (monoclonal gammopathy of renal significance)?

Answer:  My recommendation would be to consider a kidney biopsy.

  1. If you have a concurrent autoimmune condition with MGUS, what advice would you give to take into consideration about what effect regulating your immune system for another disease might have on your MGUS?

Answer:  The treatment for your autoimmune condition should not have any impact on MGUS.

  1. Is fibromyalgia related to MGUS and myeloma?

Answer:  Not to our knowledge.

  1. Is there growing acceptance of MGUS or SMM resulting in complement activation of conditions like renal TMA (thrombotic microangiopathy)?

Answer:  It can happen in a very small number of patients.

  1. Is hyaluraunic acid contraindicated with SMM?

Answer:  No, it is not.

  1. Is there growing acceptance of MGUS or SMM resulting in complement activation of conditions like renal TMA (thrombotic microangiopathy)?

Answer:  It can happen in a very small number of patients.

Imaging [For more information, see the Myeloma Crowd Round Table on Myeloma Imaging.]

  1. How often should MGUS patients get PET scan or bone marrow biopsy?

Answer: We do not recommend routine pet scan or bone marrow biopsy in MGUS patients unless there is clinical suspicion of disease progression

  1. How is the ASCENT trial going, which I understand is trying to see if we can find a curative effect for high-risk SMM?

Answer:  The trial continues to accrue patients.  We have accrued about 2/3 of the patients that the trial was designed to enroll.  At this point, what we have seen so far appears to be in line with what was expected with these kind of regimens based on what we have seen in multiple myeloma.  We certainly need longer follow-up before we can determine that these kind of treatments will lead to a cure.

  1. Which method to detect bone lesions is better: PET scan or MRI?

Answer:  PET scan.

  1. Should you have both MRI and PET scan once a year with SMM or just one of them?

Answer:  I would only do one and again how often this needs to be done would depend on the clinical context and your risk classification.

  1. Do you use a Pet/CT scan or MRI in a yearly checkup?

Answer: No, typically we would not.

Active Myeloma

  1. How long should a patient who is post stem cell transplant stay on acyclovir?  Are the adverse side effects from staying on this medication for greater than two years?

Answer:  Typically, we recommend that patients stay on acyclovir for a year after transplant unless they are on maintenance treatment with their drug like bortezomib or daratumumab that increases the risk of zoster reactivation. In patients who have previously had zoster, we would recommend that they stay on as the acyclovir continuously.

  1. For how long are the stem cells viable after collection?  That is, what is the longest you could wait for transplantation and still achieve a result?

Answer: We do not know if there is a clear cut off. We have used cells that has been in storage for over 15 years.

  1. Do you remove the cancer stem cells from patient after your collecting or harvesting patient's stem cells before performing auto transplant for MM patients? otherwise, it will relapse sooner or later.

Answer:  There is no good way to remove the cancer cells. Even when items have been made in the past to clean up the stem cell graft, it had no impact on the recurrence rate . This is likely related to the fact that there are remaining myeloma cells in the patient's body despite the high dose of chemotherapy which is responsible for the relapse.

Clinical Trials

  1. Are there any trials for the MGUS stage?

Answer:  There are no large scale trials, however, individual institutions may have clinical trials.

  1. Are there any clinical trials for intermediate SMM or only high-risk patients at this time?

Answer:  There are some trials that will also include intermediate risks monitoring patients.

  1. I am enrolled in the Ascent trial for SMM. While it is too early for results, the CESAR trial has been going much longer. How successful has it been?

Answer:  This is a trial is different from the ASCENT in that it uses a stem cell transplant. The data from the trial has been presented at meetings and looks quite promising and comparable to what we have seen in patients with myeloma. We really need longer term follow-up to see if you are able to cure the disease.

  1. Do trials make you sick?

Answer:  It depends on the medications that you are on.  Most of medications have some side effects and there is always a risk that one could get severe side effects from any treatment.  however, in a clinical trial you will be very carefully monitored for any side effects so that early intervention can be done to reduce or reverse these.

  1. As a SMM patient do we find our own clinical trial or does our doctor advise us of a clinical trial

Answer:  I think this would be a combination of both. You can access available clinical trials through national databases as well as through patient support groups. Your doctors also will be aware of the clinical trials and will be able to discuss them with you.

  1. I have intermediate risk myeloma and have been asked if I wanted to join 1 of 2 clinical trials. One has the patient taking revlamid 3 weeks out of 4 for 6 months. Is this something I should even consider with intermediate risk?

Answer:  Typically, most of the clinical trials enroll patients who are at a higher risk of progression. If you fulfill the entry criteria for the clinical trials then you will need to look at the pros and cons of the particular trial.

  1. There was a trial at Mayo using annakinra, but the drug company pulled out. Is there any medication similar to annakinra available for SMM?

Answer:  there are other drugs being developed that are similar in action to anakinra. We do not have any evidence at this point to suggest that anakinra really helps delay the progression of smoldering myeloma

  1. Do you know of any trials open for biclonal IgA Kappa with IgA Lambda SMM?

Answer:  The trials are not specific for biclonal disease.  However, this should not exclude you from being eligible for currently open clinical trials.

  1. My wife is working with supposedly a myeloma specialist.  However, our feeling from her is it would be totally up to us to figure out what trial to find.   Would some specialists perhaps be more helpful in determining need for trials and help in finding trials.

Answer: I think this should be a discussion between you and your physician who can certainly help guide you. It certainly does not stop you from also searching on your own on the online databases or through patient support groups and then bring those specific questions up to your physician

  1. How do you join the observational studies just mentioned?

Answer:  You should discuss this with your treating physician.

  1. Can one join a clinical trial if one has only two of the three risks of SMM?

Answer:   Yes, there are several clinical trials ongoing.  I would strongly encourage you to participate in one of them.


  1. Is there a danger in vaccines?

Answer: There are no specific disadvantages for vaccinations in the setting of monoclonal gammopathies.  In patients with active myeloma and those getting treatment, we do not recommend live vaccinations.  Otherwise, all patients should receive the recommended vaccinations including the flu shot on an annual basis.

  1. Tell us more about vaccinations in myeloma treatment.  What antigen is being targeted?

Answer:  There are a variety of different antigens that are being looked for vaccine-based therapies.

Alternative Therapies

  1. What role do supplements play in prevention of progression?

Answer:  There is no proven role for any supplements in terms of its ability to prevent progression from MGUS or smoldering multiple myeloma to active myeloma. We would only recommend a well balanced diet and a healthy lifestyle.

  1. Instead of waiting to see what happens to MGUS patients, are there any effective benign preventive measures, such as foods, supplements, exercise, etc.?

Answer:  Unfortunately, there are no proven interventions in the form of specific diet or supplements. However, it is important to maintain a healthy lifestyle.  It is also important to ensure that there is regular follow up of the monoclonal protein.

  1. Are there any complementary or alternative therapies that have proven to be beneficial for MGUS or SMM?

Answer:  There are no proven complementary or alternative medications at this time for either.

  1. Are there alternative medicines (eg. supplements) that have evidence of slowing progression?

Answer:  There are none with proven benefit.

  1. What are your views of high dose vitamin C?  Would this be a less toxic way to help treat/prevent progression?

Answer:  There is no data to suggest that high dose vitamin C would prevent or delay progression.

  1. Is there data on the efficacy of turmeric?

Answer:  No clinical data exists to support benefit of turmeric on progression.

  1. I believe meditation and mindfullness can help.

Answer: I am sure it can help us part of a healthy lifestyle

  1. Can infrared sauna boost the T cells?  Can ozone therapy boost the immune cells in SMM free light chain-type?

Answer:  There is no evidence to suggest this.

  1. Are there supplements, exercises or other non-drug interventions that might help push out the time of progression?

Answer:  No, there are not.

  1. Can SMM patients take calcium with vitamin D?

Answer:  Yes, that is OK to do.

  1. Is there any evidence that metformin might be useful in MGUS patients without diabetes to slow the progression to MM?

Answer: there are some epidemiological studies that suggest this. There are no prospective trials.

  1. How is factor five serum related to MM?

Answer:  There is no direct relationship


  1. What percentage of myeloma patients are caucasian women?

Answer:  In general women constitute 40% of patients with myeloma.  The ratio of men to women appears to be similar across all ethnic subgroups.

  1. Are there specific areas of the U.S. where MGUS is more prevalent?

Answer:  It tends to be slightly higher in farming communities.

International Issues

  1. Does Ontario Canada have the same trials as the U.S.?

Answer:  I am sorry I cannot answer this.

  1. Are Canadians able to do trials in U.S, and do we have to pay for them?

Answer:   This would depend on the institution and I would recommend that you reach out to the specific clinical trial team.


  1. What's the average life span from diagnosis of myeloma?

Answer:  This is a moving number and can vary from 8 to 10 years currently based on large series. It continues to improve on an annual basis.

  1. What is the state of insurance covering earlier treatments?

Answer:  Insurance should cover early treatment of SMM as both are considered under the same diagnosis.

  1. What kind of awareness or cooperation do you both have with other myeloma researchers?

Answer:  We work closely with investigators at other institutions who are working on myeloma and related disorders.


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The author Greg Brozeit

about the author
Greg Brozeit

Greg Brozeit has been with the HealthTree Foundation since 2015 when he began volunteering for the Myeloma Crowd.  Prior to that he worked with Dr. Bart Barlogie and the International Myeloma Foundation, inaugurating many myeloma patient advocacy and education programs.

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