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)
Irene Ghobrial, MD, Dana Farber Cancer Institute, Boston, MA: Understanding MGUS and Smoldering Myeloma Progression
Audience Questions & Answers
Questions Answered by Dr. Kumar in Chat Forum
General Topics
Answer: I would recommend that you talk to your physician and also interact with other patients on patient support groups.
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.
Answer: Unfortunately, no.
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.
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.]
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.]
Answer: I would do the common precautions to avoid the risk of infection.
Familial Incidence
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.
Answer: No. We do not recommend testing first degree relatives for MGUS on a routine basis.
Answer: I would not think that this would have any implication to your diagnosis.
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.
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
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.
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.
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.
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.
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.
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.
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.
20/20/20
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.
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
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.
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.
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.
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.
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%.
Answer: Sometimes we do see M spike that increases over a period of time and then stabilizes for long periods.
Answer: Bone marrow biopsy needs to be repeated only if there are concerns for disease progression
Answer: Yes if you have both of them then this would represent a biclonal disease
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.
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.
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
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.
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.
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.
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.
Answer: Quite likely.
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.
Answer: It should only be repeated if there are additional changes in the clinical or laboratory parameters that raises suspicion for disease progression.
Answer: Presence of p53 deletion has been associated with an increased risk of progression.
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.
Answer: These kind of fluctuations can happen, especially at the borderline area. I think it's important to watch very closely.
Answer: Not necessarily.
Answer: There is nothing that can be done specifically to stop the progression. I would encourage close follow-up.
Answer: We typically do annual follow up for MGUS.
Answer: All the about test would be important as part of the original work up
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?
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.
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.
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.
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.
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.
Treatment
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.
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.
Answer: Yes, the most recent phase III trial only used lenalidomide (Revlimid) and did not include dexamethasone.
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.]
Answer: There is no specific prevention program. I would encourage you to maintain a healthy lifestyle
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
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.
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.
Answer: No, they are not.
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
Answer: It seems unlikely.
Answer: It will be unlikely to be in just one arm only. There is likely another reason for the neuropathy.
Answer: Unless there is active myeloma there should not be a direct relationship.
High-Risk SMM
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.
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.
Answer: These patients should be closely watched.
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.
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.
Answer: In patients with very low levels of monoclonal protein one can defer the bone marrow biopsy.
Answer: Presence of del17p does increase the risk of progression. There are no specific treatments for this particular abnormality in SMM or myeloma.
Answer: Yes, based on the current criteria that would be considered as high-risk.
MGUS, SMM and other Diseases and Conditions
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.
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.
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.
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.
Answer: No, we have not seen this association.
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.
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.
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.
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.
Answer: Not to the best of our knowledge.
Answer: I suspect you are referring to hyperparathyroidism. I would strongly encourage you to see an endocrinologist who specializes in bone disease.
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.
Answer: I would strongly recommend using a bisphosphonate or denosumab as one would do for osteoporosis without MGUS.
Answer: I'm sorry but cannot answer this question without more details.
Answer: No, it will not.
Answer: My recommendation would be to consider a kidney biopsy.
Answer: The treatment for your autoimmune condition should not have any impact on MGUS.
Answer: Not to our knowledge.
Answer: It can happen in a very small number of patients.
Answer: No, it is not.
Answer: It can happen in a very small number of patients.
Imaging [For more information, see the Myeloma Crowd Round Table on Myeloma Imaging.]
Answer: We do not recommend routine pet scan or bone marrow biopsy in MGUS patients unless there is clinical suspicion of disease progression
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.
Answer: PET scan.
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.
Answer: No, typically we would not.
Active Myeloma
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.
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.
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
Answer: There are no large scale trials, however, individual institutions may have clinical trials.
Answer: There are some trials that will also include intermediate risks monitoring patients.
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.
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.
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.
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.
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
Answer: The trials are not specific for biclonal disease. However, this should not exclude you from being eligible for currently open clinical 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
Answer: You should discuss this with your treating physician.
Answer: Yes, there are several clinical trials ongoing. I would strongly encourage you to participate in one of them.
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.
Answer: There are a variety of different antigens that are being looked for vaccine-based therapies.
Alternative Therapies
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.
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.
Answer: There are no proven complementary or alternative medications at this time for either.
Answer: There are none with proven benefit.
Answer: There is no data to suggest that high dose vitamin C would prevent or delay progression.
Answer: No clinical data exists to support benefit of turmeric on progression.
Answer: I am sure it can help us part of a healthy lifestyle
Answer: There is no evidence to suggest this.
Answer: No, there are not.
Answer: Yes, that is OK to do.
Answer: there are some epidemiological studies that suggest this. There are no prospective trials.
Answer: There is no direct relationship
Populations
Answer: In general women constitute 40% of patients with myeloma. The ratio of men to women appears to be similar across all ethnic subgroups.
Answer: It tends to be slightly higher in farming communities.
International Issues
Answer: I am sorry I cannot answer this.
Answer: This would depend on the institution and I would recommend that you reach out to the specific clinical trial team.
Miscellaneous
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.
Answer: Insurance should cover early treatment of SMM as both are considered under the same diagnosis.
Answer: We work closely with investigators at other institutions who are working on myeloma and related disorders.
Thanks to our Round Table sponsors
.
.
.
.
.
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.
Subscribe to the weekly "HealthTree Community for Myeloma Newsletter" for Myeloma news, life with Myeloma stories, Myeloma clinical trials, Myeloma 101 articles and events with Myeloma experts.