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Paradigm Shift: MGUS, Smoldering Myeloma, And Multiple Myeloma Are All One Disease

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Published: Nov 12, 2010 5:41 pm

Until 2009, it was generally accepted that monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, and multiple myeloma were three distinctly separate diseases.

If MGUS was accidentally discovered during a patient’s routine medical testing, the patient was often advised to ignore the abnormal test results for the foreseeable future. Most clinical settings encouraged only infrequent routine monitoring, since both MGUS and smoldering myeloma conditions were considered distinct diseases with a small probability of the patient developing multiple myeloma. Often the patient’s personal primary care physician provided any follow-up periodic monitoring.

2009 Study Finds MGUS Phase Present In All Multiple Myeloma Patients

In May 2009, a just completed prospective study, “Monoclonal Gammopathy of Undetermined Significance (MGUS) Consistently Precedes Multiple Myeloma,” published in the prestigious journal, Blood, changed the myeloma landscape forever, and for the better for all pre-myeloma patients. A group of researchers including lead researcher Dr. Ola Landgren of the National Institutes of Health determined that MGUS consistently precedes multiple myeloma.

These three conditions are not separate diseases but one disease on a continuum; all multiple myeloma cases are preceded by an MGUS/smoldering myeloma phase, whether it is identified or not.

[MGUS is clinically defined as having less than 10 percent plasma cells in the bone marrow and less than 30 g/l monoclonal protein (M-spike) in the serum; smoldering multiple myeloma has greater than 10 percent plasma cells in the bone marrow and greater than 30g/l M-spike in the serum; multiple myeloma adds CRAB (increased Calcium, Renal function abnormalities, Anemia, and Bone involvement) findings to the increased plasma cell and M-spike numbers.]

This study discovered that, “Multiple myeloma is universally preceded by a prolonged premalignant stage with up to 75 percent of multiple myeloma patients having detectable M-protein eight or more years prior to diagnosis of the malignancy.” The study’s authors further discovered that the, “well-documented 1 percent annual average risk of multiple myeloma progression among MGUS patients is highly heterogeneous and emphasize the fact that the risk of developing multiple myeloma varies greatly among patients diagnosed with MGUS.”

This landmark study recommended further research to examine the molecular pathways of disease leading from MGUS to smoldering myeloma to multiple myeloma. With these proposed additional studies, it is hypothesized that myelomagenesis pathways will be identified, which would then make possible the identification of steps, or development of compounds, to prevent or delay progression of one of these two earlier phases.

New 2010 Study To Identify Risk Factors Leading To Multiple Myeloma

Just one year later, the National Institutes of Health (NIH) has initiated a recommended follow up study, “Natural History Study of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM).” This study is designed to follow either MGUS or smoldering myeloma patients for up to five years or to the time of progression to multiple myeloma if that occurs during the study period. The objective of the study is to identify risk factors that may cause MGUS and smoldering myeloma to progress to multiple myeloma.

There are currently 26 patients enrolled with an additional 14 anticipated by October. The full study cohort will be 356 people, comprised of 256 MGUS patients and 100 smoldering multiple myeloma patients. Patients enroll at the NIH in Bethesda, Maryland, a northwest suburb of Washington, D.C., easily reached by thousands of individuals.

The first day of the initial visit to enroll in the study includes routine blood and urine tests, a skeletal survey series of x-rays, and a meeting with the research staff for an intake interview to collect medical history data. The second day includes a bone marrow biopsy performed by an expert physician’s assistant. These tests are necessary to confirm either an MGUS or smoldering myeloma state in order that the study’s conclusions will be deemed valid by the scientific community.

During a second one-day trip to the NIH six months later, only blood and urine will be collected. After that second six month visit, a study participant returns annually for up to five years total depending on whether there is progression. At either of those endpoints, five years or progression, the second and final bone marrow biopsy is performed.

NIH Study Results Are Critical To Future Disease Prevention Strategies

This newest study is the logical progression to the earlier 2009 study mentioned in this article. It is a critically important study for all MGUS or smoldering myeloma patients because it is the first attempt to identify the molecular pathways from an earlier phase of disease to multiple myeloma. Only armed with that information can we hope to develop steps to prevent or delay progression in appropriate patients such as high-risk MGUS or smoldering myeloma.

I urge any MGUS or smoldering multiple myeloma patient who can travel to the NIH to enroll in this study as soon as possible. Our individual participation in studies and trials is the key to finally conquering myeloma. Each precious year brings us closer to that goal.

Please contact the research nurse, Mary Ann Yancey, at 301-435-9227 or for additional study information or to discuss enrolling. You may contact me directly at for additional information about my personal experience at the NIH.

Carole S. Giampalmi is a smoldering myeloma patient who entered the NIH study in July.

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  • Sean Murray said:

    Thank you Carole and The Myeloma Beacon for sharing this important news. It's just another example of the advances being made in all avenues of myeloma research and why I read the Myeloma Beacon daily.

  • Carole Giampalmi (author) said:

    Hi Sean,

    I was pleased that you read the article and realized its importance for all myeloma patients. This new NIH study offers the first real hope of possibly developing targeted drugs to stop MGUS or SMM from advancing to myeloma (MM). Let's hope the study reaches its full cohort quickly so that we can obtain the clinical data required to move forward.

    Thanks for writing.

    Carole Giampalmi

  • Lori Puente said:

    Great article Carole. Early on in our MM journey a friend told me her father was living with MM for 20 years. I didn't understand the differences and nuances at the time and the first doc we met was so pessimistic that I mentioned it. She blew it off as if this was a complete fabrication. I understand so much more now and it is exciting that it is being studied and analyzed. So far, most agree, keeping it under control in the first place or even later after it runs rampant, for as long as possible, is thus far, the best opportunity for longevity. Still not proven, but not yet disproven either.

    My mother had 5 cancers and one of them spontaneously rejected. There was evidence not only of the cancer, but that it had metastasized. Imagine. She was asked to allow NIH to follow her cancer journey extensively as they had known cases around the world of patients spontaneously rejecting cancer and trying to sort out how and why these folks did that is of great interest.

    I would also encourage folks to participate in this program. It helps us all, to do our parts for the greater good. I'll be following this activity with great interest.

  • Jim Omel said:

    What a great article Carole! Thanks for your clear definition of the categories of plasma cell dyscrasias which are obviously one and the same disease as you point out. Lets hope that your important article spurs rapid accrual to this important NIH trial so vital to the thousands of patients headed for active phase disease. Identifying patients at highest risk of progression, and developing treatments to interdict that progression are outstanding goals. Thanks for alerting us to this important trial for early phase myeloma patients. Jim Omel

  • Carole Giampalmi (author) said:

    Hi Lori,
    You had an earlier positive experience with the NIH through your Mother's cancers. That sounds like a challenging way to find out about all the wonderful work at the NIH. We are fortunate to have such a facility available here in the US. Thanks for your words of support for this program. It is one of the most important studies that I've seen in my six years with MGUS/SMM.

  • Carole Giampalmi (author) said:

    Dear Jim,
    Thanks for your words of support for accruing patients to this important study. The next phase following the conclusion of this study, development of drugs to halt progression, has the potential to give many years of disease-free life to thousands of patients.

  • Amy Hans said:

    Great article! I became part of this study and am so glad I did. I am so impressed with Dr. Landgren, Mary Ann Yancey, and the NIH! I also feel like I am doing an honorable thing...helping researcher find a way to stop MGUS and SMM dead in it's tracks!!


  • Alessandro said:

    WOW!!!! Thank you for this article! I'm sorry to live in Brazil and can't apply for the trials. MGUS leave people really worry about it. Doctors can't tell if we'll get sick or not at this point. Hope good news for us and for the Myeloma pacients.


  • Sandra Christian said:

    My best friend, who for all intents and purposes is my sister,learned today that she has smouldering multiple myeloma. I told her that "we" are not going to let this upset us; She is a very caring and knowledgeable R.N., and I that i know she will do everything she is supposed to. Her oncology doctor told her that they will watch it and check her every 3 months. I told her that I had done internet research and found out that there were 2 types: stable and unstable. Apparently the smouldering type is the same as stable.

    I hope it offers a longer life expectancy than the unstable. If one has smouldering multiple myeloma, it it for certain they will eventually develop the unstable type.

  • Carole Giampalmi (author) said:

    I just completed my second visit to NIH as part of the study mentioned in this article. The entire staff at NIH - research scientists as well as support staff - are professional, helpful, friendly, and compassionate. I really encourage anyone reading this Paradigm Shift article to strongly considering contacting Mary Ann Yancey, the research RN named near the end of the article, for information on participation. The study enrollment has reached nearly 80 enrollees, an unbelievable record of success in this short period of time. It is encouraging that so many MGUS, SMM, and MM and patients are motivated to participate in the study designed to further knowledge in the quest to help eradicate myeloma. Again, please contact me for specific information on my experiences.

  • Peter M. Parker said:

    Dear Ms. Giampalmi, do you an idea, when the results from this study will come to the bedside of patients? What the timeframe is? Seems to me, that the study is a basic research study and will come in 10 years to the bedside of patients? Am I wrong with that assumption? Best and thank you for your article, Peter Parker

  • Dorie Carolides said:


    I too am a part of the Natural History Study at NCI/NIH and agree about Dr Landgren and Mary Ann Yancey. I am also enrolled in the Imaging study for MGUS & SMM. I live in Florida and my airfare and part of the hotel expenses are covered. Of course, all of the tests and care at NIH are at no cost to the patient. I had my second visit in December. If you go to Dr Landgren's page on the NIH/NCI website there is a description of the study and his work as well as two videos where he explains his work and hope for a cure for the MGUS and SMM so that there will be no progression. The tests and information have been very comprehensive and have given my doctor a huge amount of information to better follow my condition. I also encourage others to participate in this important work that will hopefully save many lives.


  • Ralph Rostock said:

    Hello, I joined this study in August 2010..I lost my medical insurance after my employer went out of business in Las Vegas NV due to severe economic depression here..I was just diagnosed with SMM at the same time and could not procure insurance no matter what the cost...After reading in this publication about the NIH study, I was accepted and able to receive much needed testing in this valuable program..I have to state that Dr.Landgren is wonderful..He has made this plight palatable to say the least, what a privilege and pleasure meeting with him..What can you say about Maryann Yancey, she is always on-the-ball so to speak, a real gracious, hardworking professional..My thanks to all. Ralph

  • John Burton said:

    A very big thankyou to fellow patients,families and carers in the USA for entry to trials and the information we gain 'downunder' from sites such as this.Having had radiation therapy early in treatment I read with interest the possible effects on stem cell production of the hyperbaric oxygen chamber.I will make further enquiries in Australia.My treatment has the added complexity of two mitral valve replacements, five weeks apart, preceding the start of chemotherapy.I've had a year of chemo including Velcade, and recently, a stem cell harvest of two four hour sessions, producing little under half that required for two possible transplants in the future.The oxygen may be a way of collecting sufficient cells with only one more attachment to the apheresis machine.Incidentally,in Australia we have an excellent health care system with various levels of cover.Our government controlled 'Medicare'has a very large private business called 'Medibank Private', but those who cannot pay still receive the same top line treatment with the same doctors in our public and teaching hospitals.The highest cover for hospital,medical,dental,optical etc for a husband and wife or a whole family irrespective of the number of children currently costs about $100 AU per week.Hopefully the US will be able to implement a wideranging health insurance scheme in the not too distant future.

    Stay Strong and take the fight to Myeloma

    John Burton (64 yo)
    Strong and fit 63yo suddenly put out of action with Multiple Myeloma
    PS I have been searching the net since diagnosed 19 months ago and
    The Myeloma Beacon is the best medicine I've found in that time.

  • Christina Lochrie said:

    I have MGUS, diagnosed in 2004 and I just found this article and the The Myeloma Beacon and read about the NIH study. Lots of great information and glad that this study is being undertaken. It will offer hope to so many. Can people from Canada join the study or is it limited to the US.

    I'll be back to read all the great articles in the Beacon regularly!

  • Carole Giampalmi (author) said:


    I apologize for not responding to your post of Jan. 13 until now. My understanding is that release of trial results is dependent on how quickly the enrollment slots are filled. I believe the study is filling much quicker than originally thought; however, remember that each patients study endpoint is the sooner of disease advancement or five years. That means that the last person to enroll must either experience advancement of disease or complete the full five year period of the study. That said, tissue samples collected from each patient during the five year period are being analyzed on an ongoing basis. Hopefully, patterns will emerge as more samples are studied. I have much faith in the NIH researchers and feel confident that positive results will arise from this study. And we all have the comfort in knowing we have made a significant contribution to one of the most important studies relating to myeloma and its precursor states. Carole Giampalmi

  • Carole Giampalmi (author) said:

    Christina, I do not know if Canadian patients can enroll in this study. I encourage you to contact Mary Ann Yancey at the number listed in the study to discuss your possible participation. Thank you for your kind words about The Beacon. Best wishes, Carole Giampalmi

  • Carole Giampalmi (author) said:

    Dear Dorie,

    I, too, was able to participate in both the ongoing myeloma study as well as the imaging studies. The NIH personnel are fantastic especially Dr. Landren and Mary Ann Yancey. We are fortunate, aren't we, if we must have this disease? I expect great results from this study. Thanks for writing. Carole Giampalmi

  • Carole Giampalmi (author) said:

    Ralph, One of the most difficult and frustrating aspects of our current health care is the devastating results when someone loses their insurance. As you point out, this study offers MGUS and SMM patients an effective path for monitoring this disease which can advance without notice or warning. I personally hope that our worst days are behind us with regard to insurance and that in the very near future, most if not all, Americans will have adequate health care insurance. Best to you. Carole Giampalmi

  • John Eldridge said:

    Carole: since MGUS can transform to WM, B-CLL, and other malignancies, as well as MM, how can it make sense to say MGUS is the same disease as MM? It makes sense that all MM is preceded by MGUS, but that doesn't mean that all MGUS is MM.