Smoldering Myeloma: What Do The Latest Research Findings Mean? A Discussion With Dr. Ola Landgren
Published: Jan 13, 2012 12:57 pm
As The Beacon previously reported, Spanish researchers recently presented clinical trial results showing that active treatment may be beneficial for some smoldering multiple myeloma patients.
Specifically, the results of the study showed that high-risk smoldering multiple myeloma patients who received Revlimid plus dexamethasone followed by Revlimid maintenance had a longer time to disease progression and better overall survival than patients who did not receive treatment (see related Beacon news).
To help Beacon readers put these results into perspective and better understand their implications, The Beacon asked myeloma specialist Dr. Ola Landgren for his feedback and thoughts on the study.
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The resulting discussion was wide-ranging and touched on issues of interest to all multiple myeloma patients -- not just those with smoldering myeloma.
Dr. Ola Landgren, who was not involved with the Spanish study, is a Senior Investigator at the National Institutes of Health (NIH) and Chief of the Multiple Myeloma Section at the National Cancer Institute (NCI). He is regarded as an expert on monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma, and he is involved in a number of important studies into potential new treatment regimens for multiple myeloma.
The Myeloma Beacon: How significant are the findings of the Spanish research team, led by Dr. María-Victoria Mateos?
Dr. Landgren: I find the results by Mateos et al. of major importance. Their data show that treatment of high-risk smoldering multiple myeloma translates into both progression-free and overall survival benefits. These are novel insights. In my opinion, they set the stage for the development of new treatment studies for high-risk smoldering multiple myeloma, aiming to delay and/or prevent progression to multiple myeloma.
Are the findings sufficient to recommend any change in current practice in regard to the treatment of high-risk smoldering myeloma patients?
No, I don't think so. This study is based on approximately 60 treated and 60 non-treated high-risk smoldering multiple myeloma patients. The main reason why I don't think it is time to change clinical care is that I think we need to see the results replicated in other independent studies. This view is in full accord with that of the investigators of the Spanish study; they emphasize the need for validation.
Another reason is that, until we have better biological markers easily available to define an individual's risk of progression to symptomatic multiple myeloma, there is a risk of over- and under-treatment of patients diagnosed with smoldering multiple myeloma.
Let me also say that, based on our completed and ongoing research, I personally do not think that smoldering myeloma truly exists as a disease entity.
I think there are patients in the so called “smoldering multiple myeloma” category that are more like patients with MGUS, while others are what I would call “early myeloma.”
This is not a perspective, however, that you will find in the textbooks (yet).
In our clinic at the NIH, we have assessed a large number of patients diagnosed as smoldering multiple myeloma, with a wide range of tools, including flow cytometry, biomarkers, microRNAs, genetic profiling, molecular / functional imaging, marrow vascularity, early bone changes, and so on. And we have learned that there is tremendous heterogeneity in terms of biology and the risk of developing symptomatic multiple myeloma.
More importantly, what we have seen is that the biological markers in so-called “high-risk smoldering myeloma” patients are very similar to those seen in patients with symptomatic multiple myeloma. This is why I would rather call high-risk smoldering myeloma “early myeloma.” The main difference is that the early myeloma patients have not (yet) developed kidney failure, bone fractures, or other symptoms.
[For more information about Dr. Landgren’s studies of precursor diseases and how they progress to active myeloma, see a related Beacon opinion article.]
What caveats do you feel are important to mention in regard to the Spanish research?
In addition to the above mentioned need for validation of the results in other studies, I think a caveat is that the study focused mainly on clinical markers. For example, additional molecular markers and functional imaging would allow a much more detailed investigation into why and how the treatment works in some patients and not in others. That would be a translational / biological approach. I am in favor of translational / biological treatment studies to maximize the possibilities to advance the field.
Of course, I realize that it boils down to resources, and I know it is very expensive to do those types of things. Also it takes a lot of advanced infrastructure. Hopefully, future studies will provide more translational / biological insights.
If you believe the Spanish research argues in favor of early treatment of high-risk smoldering myeloma patients, do you feel that the treatment regimen used in the Spanish trial is the best treatment option, or is there evidence that treatment with other agents might be as effective – or even more effective?
The brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions. Until we have clear answers, we can only speculate based on available knowledge.
Here is my thinking: if you buy my arguments above about “early myeloma” – that is, that high-risk smoldering myeloma is very much like symptomatic myeloma, just with less tumor burden – then you have to ask yourself: Would you treat a younger, newly diagnosed multiple myeloma patient with a Revlimid (lenalidomide) - dexamethasone (Decadron) combination followed by Revlimid maintenance only (that is, the treatment schedule used in the Spanish study)?
My standard answer would be “No.” So, why don't we do what we typically do for symptomatic multiple myeloma with these “early myeloma patients”? Why don’t we use a three-drug combination like Revlimid, Velcade (bortezomib), and dexamethasone (Decadron), or whatever combination we believe is better?
This is why I am so excited about our newest smoldering multiple myeloma study, which will open at the NIH during the spring of 2012. It will examine a treatment regimen involving eight cycles of carfilzomib (Kyprolis), Revlimid, and low-dose dexamethasone followed by Revlimid maintenance for a minimum of one year. We are using carfilzomib instead of Velcade in order to increase the efficacy and at the same time reduce the side effects, in particular peripheral neuropathy [a condition characterized by pain and tingling in the extremities due to nerve damage].
Let me stress again, however, the need for more studies before any of these ideas start to be considered “standard of care.”
But isn’t that quite a leap? Essentially, you are advocating taking patients the medical profession today feels shouldn’t be actively treated, and treating them with one of the more aggressive drug regimens in use for active myeloma.
Again, the brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions.
To me, the whole concept of 'watch and wait' for smoldering myeloma is a consequence of multiple factors, including the fact that, until recently, we have not had access to effective drugs with reasonable or low toxicity profiles.
Also the disease monitoring methods have been, and still are, quite limited in standard day-to-day practice.
With toxic and not very effective drugs, it was not justifiable to expose any person to therapy unless there was a compelling need – specifically, clinically active multiple myeloma.
With newer, effective, and less toxic drugs, that way of thinking has to be challenged scientifically, in my opinion. That is what we are doing as we speak.
Looking at other cancers such as early breast cancer and early prostate cancer, much more work has already been done along these lines, and improved survival outcomes have followed.
Even if we assume that high-risk smoldering myeloma is really “early” active myeloma, is it a form of active myeloma that should be treated with a three-drug regimen that includes two novel agents?
Or, to put it another way, might this “early” myeloma best be considered a relatively “low risk” form of active myeloma. And, if so, wouldn’t many myeloma specialists be more comfortable using a less aggressive approach for that kind of myeloma?
First of all, I want to stress the need for better terminology and criteria. When we talk about “high risk” in various settings, I think there is a lot of confusion and inconsistency.
For example, “high-risk multiple myeloma” is commonly used as a term for (active) myeloma patients with a poorer prognosis than the average myeloma patient.
However, just to be clear, “high-risk smoldering multiple myeloma” refers to patients at high risk of transformation from smoldering myeloma (or early myeloma) to symptomatic multiple myeloma.
As I mentioned before, I think that many high-risk smoldering myeloma patients are already myeloma (that is, “early myeloma”).
Likewise, I would like to be bold and say: High-risk multiple myeloma does not truly exist as one unique biological entity with a given outcome.
Let's do an intellectual experiment. Let’s say if all multiple myeloma patients were treated only with bisphosphonates such as Zometa (zoledronic acid) or Aredia (pamidronate), then the outcome would be poor for everyone.
In such a scenario, one could call all forms of multiple myeloma “high risk.”
Instead, let's assume that a drug that cures all forms of myeloma was available. All multiple myeloma patients are treated with this drug, and all are being cured.
Now, all multiple myeloma patients are “low-risk.”
This example emphasizes the obvious. “Risk” is an interaction between biology and intervention. And intervention is a variable that changes between clinicians and institutions, and it is constantly changing over time.
To me, it suggests that there is another way of looking at multiple myeloma patients currently called “high risk.” I prefer to think of these molecular subtypes of myeloma as “myelomas we have not yet figured out how to treat.”
Again, I don’t like the term “high-risk” myeloma. It think it is misleading in that it sounds like there is one subtype of myeloma that is inherently bad, and it does not respond to therapy.
That is not true. We know there are several molecular subtypes hidden in that group and they likely require different treatments for successful outcomes. We need to figure out the biological underpinnings, identify the treatment targets, and develop the right therapies for these subtypes soon!
Regarding your last question, where you assume that “early” myeloma best be considered a relatively “low risk” form of active myeloma. I don’t think there is any data to back that up; that is a theoretical assumption.
In fact, based on our ongoing research, there seem to be “early myeloma” patients with different disease biology. Consequently, as part of a clinical treatment study, I think it is reasonable to catch low disease burden and use powerful treatment strategies.
Just to be very clear; before we have these and other related answers sorted out in clinical treatment studies, in my opinion, we should not start treating early myeloma patients in standard, day-to-day practice.
Those are great points on terminology. Can you explain a bit more, though, why you feel an aggressive approach with “early myeloma” (high-risk smoldering myeloma) may turn out to make the most sense?
If we think about “early myeloma” as a state of less tumor burden, it is theoretically possible that the less aggressive disease is curable, at least in some patients, with more effective therapy, while more aggressive disease will only be controlled (converted into chronic disease) using early therapy.
If we can cure a patient with early myeloma, that would be a huge thing for us. Of course, the pros and cons of treatment have to be balanced. We cannot accept side effects that are not in accord with the projected outcome.
In the coming years, I envision that some myeloma patients will be cured and others will have extended remission. Likely, many patients will have their disease controlled, which could be viewed as a “functional cure” -- similar, for example, to successfully treated hypertension.
Before we reach this point, a lot of work remains to be done. I think key future strategies will be (1) more rational therapies / drugs (precision medicine), (2) earlier start of therapy in many patients, and (3) better monitoring before, during, and after therapy.
Again, these are ideas and concepts based on our research. It is not meant to be implemented in any clinical standard-of-care setting at this time.
However, I am very optimistic about the future. We have many new clues and tools to advance the field. We will continue working hard for our patients. Our ultimate goal is to find a cure for myeloma. It is an exciting time to develop new strategies for myeloma and its precursor states!
Related Articles:
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Researchers Shed More Light On Risk Of MGUS In Close Relatives Of People With Multiple Myeloma
- Diet May Affect Risk Of Developing MGUS And Risk Of MGUS Progressing To Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
Excellent presentation on this study nuances. Thank you!
I agree that this was a very clearly presented conversation and the Beacon staff did an admirable job. I couldn't help but noticing a minumum of 7 times where Dr. Landgren mentioned the word "cure" or "curable," as in
"If we think about “early myeloma” as a state of less tumor burden, it is theoretically possible that the less aggressive disease is curable, at least in some patients, with more effective therapy, while more aggressive disease will only be controlled (converted into chronic disease) using early therapy."
This is clearly different from what we normally read from other articles or comments on the subject. The answer to the curability question guides many patient's choice of treatment, especially those of the younger ones. But unfortunately, just like almost any other topics on the disease, the curability issue is muddled to say the least.
Agreed Ben S. But the telling thing for me is that more and more leading researchers are daring to utter the word. Ken Andersen being another one. They are all still quite reticent when they dare to say the word, when I watch them in video presentations, but they are saying it and understand fully the ramifications. I find it quite hopeful, though I agree, it isn't right now a reality, so it can indeed get muddled up in the discussion of treatment choices.
I am a patient of Dr. Landgren's. I am in his study of the progression of myeloma from its precursor stages. I probably am a candidate for the upcoming trial due to my high risk smoldering situation. I got a lot to talk about with him in March.
(Sorry this is long ... and I hope the formatting comes out looking OK ...).
I agree, fascinating article! And I appreciate everyone's responses. Like my friend Terry, I have a direct personal interest in the subject -- and more particularly in the trial described by Dr. Landgren, for whom I, like Terry, have great respect as a researcher and physician. Like Ben S, I count seven mentions of something like 'cure', and I agree that's somewhat of a shift relative to most MM experts' interviews in past years but I also agree it doesn't at all mean the curability issue is non-muddled. Similarly, like Lori, I see the cure reference made more frequently nowadays (more than 7 years ago when I was diagnosed); but I also concur that -- with possibly very specific, infrequent, and somewhat risky exceptions -- curability is not demonstrably a reality now, and as such it can get muddled up in the discussion of treatment choices.
To me it's interesting for us not to read too much into researchers' interviews lest, for example, they find the need to censor themselves in the future. So with that in mind I'll go into "anal"-ytical mode. Regarding the seven mentions of 'cure', I hope anyone interested will scour the interview itself as I have (using for example a find/search command on the webpage for the partial-word "cur"), to see the context better than I'm describing here. But briefly, here's what I see for the 7 mentions:
#1. This is in context of an "intellectual experiment" where Landgren says "let's assume that a drug that cures ...". Landgren is not at all suggesting that this is reality now or even in the future, it's an intellectual experiment and I think we need to allow him or anyone else to indulge in such discussion no matter how fanciful.
#2. Same context as #1.
#3. Landgren is saying IF such and such, then there's a THEORETICAL possibility of something. Again, these are thought processes & language that researchers & others need to use in order to consider one thing or another. If they/we can't do that, at the risk of being misinterpreted, then we're hosed.
#4. This follows #3 but with an additional IF imposed.
#5. Landgren says "In the coming years, I envision that some myeloma patients will be cured ...". The timeframe is open -- it's plural, so a person might say 2 years, or a person might say 1,000 years or more. And it's a vision, not necessarily even a confident expectation. Even at that, it's for some myeloma patients, not all.
#6. This is related to #5. But it is weaker, in that it is referring to the further hypothetical POSSIBILITY of having enough future control of the disease and symptoms in some patients such that one could consider there to be "functional cure".
#7. In this concluding remark Landgren simply refers to cure as being "our ultimate goal". Sure, that's more optimistic than if he said "sorry, cure is out of the question". But I think he's just re-stating what's probably true for most of us, researcher or not.
My own hard-line view is that #5 is the most hopeful of the bunch, yet as you'll see if you re-read the passage and my comment, I don't see much to hang my hat on.
We tend to operate under a paradigm of continual improvement. Looking at trends, that's not an unreasonable view. But there's nothing in this universe that guarantees that science/humanity will be able to make ANY IMPROVEMENTS beyond where we are now (much less a cure). For all we know we MAY have reached the end of humanly possible advancements -- or if not, our cultures may lack the political/economic will or insight to continue onward. Or even if we currently have expectations that such-and-such will be an improvement, and therefore it at least warrants testing by clinical trial, we could be wrong -- we have been wrong before with various diseases etc, with disastrous consequences. As Landgren suggests, that's largely why the standard-of-care doesn't vector off every time there's something worth considering, be it carfilzomib on asymptomatic patients, or something else.
All that said, to me this IS a very hopeful interview & article, and I'm pretty excited to have read it. Landgren is making really clarifying distinctions between terms that otherwise interfere with progress & communication. He's presenting and proposing alternate views of the disease which to me seem plausible even if they need formal validation. He's describing scientific PROCESSES that are I believe our best hope for eventually finding far better treatments, yes maybe even cures, for myeloma. He's pointing out that while we do clinical trial research in an attempt to improve the standard of care, meanwhile our standard of care is far better than we've enjoyed in past years -- so if I have to deal with this disease, now is an exciting time to have it compared with 7 or 20 or 50 or 1000 years ago. And he's pointing out that although we can't have foreknowledge of our experiments, the trajectory is such that it's likely we'll see great improvements in the future. I hope to be around to see what nature and science might reveal to us in future years & decades.
Hi Dr. Landgren! Thanks for the thought provoking article. I too hope that the future of this 'treatable but not YET curable' disease lies positively in the research being done with patients with 'smoldering' myeloma. Those patients are not yet caught in a dangerous time with the awful 'CRAB' manifestations, that make myeloma so miserable.
Many of us, myself included, went right thru the 'smoldering' phase without yet being diagnosed. One question that I have is, now that treatments may be more feasible to do on 'smoldering' patients, at what age and how frequently should one be tested for the 'M' protein as part of a regular medical check up?
As part of routine, annual physical checkups over my whole adult life, I have been tested for other cancers on an annual basis (such as breast...have had mammograms since age 40). Have been tested for colon cancer, and more. Had my blood tested for all the usual things and the parameters were normal. I realize that MM is just 1% of cancer diagnoses, but wouldn't it be better for patients to know that it is developing, rather than have it hit you right out of the blue when you have some awful physical problems?
Could you please give me a considered answer to this (at what age and how frequently)... and I will write a letter to whoever I think would be responsive here in our health care system. Also, what percentage of patients with MGUS go on to develop 'smouldering' and full fledged MM? Thanks so much.
Dr. L,
Have you given consideration to adding an arm or arms with some of the non-patented remedies that appear to have efficacy in holding patients in the smoldering category? Low cost, numerous willing subjects available instantly.
You could study curcumin (see Aggarwal, M.D. Anderson, and others) on smoldering, mgus, and CR patients instead of maintenance. Curcumin, for example, already has GRAS status from the FDA (generally recognized as safe).
Hopefully your research isn't totally tied to money from drug companies whose only interest is the use of their own produicts. Myeloma patients of all stripes are depending on the scientific community to take a serious look at things that may not be patent-able. At this time all we hear is "well, there aren't studies to back this up, so take Major Manufacturer's drug instead."
There are many - many - patients available for studies on curcumin and similar therapies. Instantly available. Why overlook it and concentrate solely on the most potent side effects and costly therapies?
-Julie in Iowa
I think this is a great interview and I appreciate Dr. Landgren taking the time to share his thoughts with us.
Regarding the comment just made by Julie Zimmer, I think Dr. Landgren makes it clear that, if something is myeloma -- "early" or not -- he thinks it's best to treat it relatively aggressively. So I doubt he would see the sense in testing something like curcumin as a potential treatment when there are other treatments which have had a clear role in myeloma patients living longer today than they did 10 years ago.
For Dr. Landgren, treating "early" myeloma with curcumin probably would be like "bringing a pop gun to a gun fight."
The other thing that I think is important to mention is that Dr. Landgren works for the NIH. If I'm not mistaken, NIH studies are funded solely by the government. NIH employees also are tightly restricted in terms of what sort of funds they can accept (if any) from pharmaceutical companies or other private companies.
The same can't be said about most university researchers, who can make lots of money consulting for, or carrying out research funded by, pharmaceutical companies.
But that really isn't true for NIH employees.
So comments like "Hopefully your research isn't totally tied to money from drug companies" are not only impolite, they disregard where Dr. Landgren works and what that shows about his motivations.
As a patient of Dr. Landgren's, I can attest to the fact that he has never, ever pressured me into any clinical trials. In fact, he admitted me into his study without treatment as a smolderer. Another so-called expert doctor was already sizing me up for an allogeneic SCT last year. I believe he has no agenda whatsever other than the well-being of his patients. He has always been absolutely transparent with me in every single aspect of his care. He never has to disclose any conflicts of interest because frankly he doen't have any. I am sure I speak for many of his patients who are readers and posters here. Getting the myeloma diagnosis was devastating for me and my family. Finding Dr. Landgren was a godsend and I believe I am in the ablest hands in his care. He is not motivated by commercial interests but by a desire to beat this damn disease and for a man of his high intelligence and education, he is very humble and compassionate.
First, I like the way Dr. Landgren talks about smoldering myleloma as early myeloma. It's always bothered me to think of smoldering myeloma as something different then active myeloma - it's just not as active. I tend to think that after someone has the disease, it progresses very slowly as it tries to take hold within the body, but at some point it reaches critical mass and takes off.
Secondly, I like that he questions the traditionally held concepts of high and low risk myeloma. How can we categorize something as complex as this disease and how it interacts with our DNA into two simple categories, particularly given our limited knowledge in this area.
Finally, if you agree with his assertion that smoldering myeloma is early myeloma, doesn't it make sense to treat it right away as he suggests (I think that would be my approach). This gets back to the idea that it needs to reach critical mass to really take of and start causing the symptoms assoiciated with it. If you can hit it before then, it's not as strong, and I would think you could significantly delay it onset.
Think of the cancer as a binomial progression, replicating from a single cell (i.e., 1,2,4,8,16,32,64..). You probably need to get into the billions or more before symptons occur, but by that time, it has a strong foothold. If you could disrupt it while the number of cells is considerably less, you considerably slow (or perhaps even stop) the progression.
I don't really have any scientific justification for this reasoning, it's more my way of thinking with my engineering and mathematics background.
Terry is right on! I have recently spoke to Dr Landgren and he is Amazing. I am hoping to visit him soon and get some straight answers. I too was "sized up" by a so called expert for a combination auto/allo transplant. All this is tough enough and to then meet someone you are supposedly able to trust and see that they are possibly trying to take advantage of your situation is unspeakable. Dr Landgren is a class act and a Gentleman. I am counting the days until I hear back from his team and make an appt. I know this is a bit off topic but, anyone that questions Dr Landgrens motives clearly has never spoke to him. Thanks Terry! its because of you that I called him!!!!!
I agree with Kevin J that if we are talking about early myeloma, then treating it early may make the most sense.
This is particularly so, if -- as Dr. Landgren indicates -- the therapy is of low toxicity.
And it would be even more so, if such early therapy held the promise of longer overall survival along with high quality of life. Maybe this will be the case with the newer agents like Carfilzomib used in the Landgren study. I don't think it has been the case with earlier combinations of agents.
I forgot to mention: Dr. Landgren also points out that some SMM patients are really MGUS patients (for which no treatment is warranted). But as far as I can tell, we still don't have accurate diagnostic tools for distinguishing between the MGUS and early myeloma versiosn of SMM.
I am 70 years old and was diagnosed with Smoldering Multiple Myeloma 15 months ago. To date I have received no treatment (and quite frankly I'm not eager to start). Is there an outline of Dr Landgren's diagnostic and monitoring tests that he normally performs on patients? Also is Dr Landgren or staff availabe to consult with my Hematologist/Oncologist in Bend, Or?
Thanks for your input. Bob Davis
Lori, Bruce,
I think the issue of using the word cure has more to do with the nature of myeloma and our current testing techniques. Myeloma is a "patchy" disease. Tests like PET, MRI, 24 hour urine, bone marrow biopsies, PCR, etc are used, but none is a definitive test. When I try to explain what remission in myeloma means to friends, I always tell them I had the most sensitive tests done and the myeloma could not be found but that does not mean it is not there. There are subgroups of patients that have a very low chance of relapse, but no doctor that I have ever seen says publicly, with 100% certainty, that a particular patient will never relapse.
Mark
Terry, Art,
I am really surprised to hear you characterize doctors that use allos as "so-called experts". Allogeneic transplantation is considered by most doctors as the only current therapy that can potentially cure myeloma patients. The families of patients that do allos are just as devastated by their diagnosis as both of your families were.
Remember when you see studies showing 30-40% of patients that have never relapsed after doing allos as part of their upfront therapy are real people. I am sure they have the same great respect for their doctor as I do for mine. My doctor is quite capable of writing prescriptions for Revlimid, Velcade, etc. Judging from my experience of coming out of my allo with a molecular response and having no problem with GVHD, she also has great skill in applying allogeneic transplantation. I also have am very confident I will live a long, healthy life. I think doctors that attempt to give their patients the longest, drug free remissions possible should be applauded, not trashed.
Mark
Hi Mark, you make great points in your most recent post---and all of your other ones for that matter. I did not mean to disparage doctors who do allos or the procedure itself. I apologize to you and any others for any unintentional offense. In fact, one of my two doctors performs them successfully. My gripe was with a particular doctor, who will remain nameless, who brought up doing an allo in the first five minutes of our meeting. He was aggressive, curt, clearly hadn't read my file thoroughly and seemed not used to being questioned by a mere mortal. I had to travel a great distance to meet with him and my insurance was billed quite a lot for what, I believe, amounted to an inadequate evaluation. Two other MM experts at different hospitals during the same time frame (August, 2011) found that I was in fact smoldering and not in need of any treatment.
Hello.
Thank you Dr. Landgren for your informative article. Having been in healthcare for 30 plus years, your logic makes sense to me.
I understand very little of the complex spectrum of hetergenous abnormalities that comprise myeloma. I am thankful for researchers, such as yourself, who are working to dissect and understand this disease.
The early diagnosis, treatment, cure or control of any adverse health condition, before it becomes detrimental, is worthwhile. I am a diabetic educator and have found that educating or treating the "pre" diabetic is more beneficial for the patient than waiting to treat the complications of diabetes.
My example is oversimplified, but makes the point that most illnesses, cancer included, progress on a continuum. The rate that they progress is dependant on multiple factors. Your statement regarding tumor burden in smoldering (early) myeloma essentially reflects that the contiuum that myeloma progresses along is based on tumor load.
The challenge is to classify what causes some smoldering patient's tumor load to progress more rapidly than others. These are the people who may potentially benefit from the risk involved in early treatment, over watchful waiting.
I have what is at present termed, "high-risk" smoldering myeloma and am in the NIH observation study. I may at some point consider enrolling in a treatment clinical trial. I am not anxious to do so, but if the lab values keep moving in the wrong direction, I feel fortunate to have an option.
Terry,
Thanks for the clarification. I also wanted to mention something you may find useful. I had mentioned to you in another post (in another thread) that I had used Velcade/Doxil/Dex as my Induction and had very good results. I had suggested it may be helpful for a patient long term if they did not use both an IMID and a proteasome inhibitor as Induction. There is a great slide on Page 8 of this presentation by Dr. Durie of the IMF that compares the efficiency of different Induction regimes. Note Velcade/Cytoxan/Dex performs just as well as Velcade/Revlimid/Dex. Also interesting to note that Velcade/Cytoxan/Revlimid/Dex does not show much improvement over either 3 drug combo.
http://myeloma.org/pdfs/Best-of-ASH-2011_01-25-12.pdf
Another great slide is on Page 16. Look at how much more sensitive Immunophenotypic and Molecular Responses are compared to CR with negative Immunofixation. I have pointed out how valuable these levels of responses are in the Allo setting. It would be great if more research was done in the non-Allo setting using these tests. The Beacon reported on a European study from last year that showed the benefit of attaing a Molecular response in the non-Allo setting.
http://www.myelomabeacon.com/news/2010/04/06/velcade-thalidomide-dexamethasone-therapy-after-stem-cell-transplant-improves-response-in-multiple-myeloma-patients/
Hope these are helpful to you.
Mark
Mark,
thanks for those great slides.
Mark
I have to once again concur with Terry. I am sorry if I was not specific but this was also a bad experience. The Dr was in an obvious rush to finish with me (i was his first appt. at 7 am) He stated in his dictation that he examined me when in fact he never even touched me. And in his report reported on my physical conditions when there is no way he could know any of these. He had not even read over my records until he got into exam room and was more interested in telling me how he could "cure" me than listening to my concerns and answering my questions. So all in all I just had a bad experience and he was someone who came highly regarded and is supposed to be an "expert" maybe i caught him on a bad day. But, it was more about him than me. So maybe I should have billed him $450 for the 1/2 hr. I was there.
I do appreciate your point and agree with you. I am glad you have a wonderful physician and wish you the best.
Art
With respect to Mark's comments about allos, I am not familiar with the observation that 30-40 percent of such patients have never relapsed. How long out has this been examined? I certainly recall that a high fraction of allo patients die as a result of the procedure or have life-time issues with host versus graft rejection.
I have also heard from my oncologist that 50 percent of patients remain in remission 8 years after VRD therapy and a standard autologous transplant.
Art,
No problem - just wanted to mention that all of them are not evil. I did read your Introductory post in the forum and I did find it strange that a Doctor was not sure if you were active or smoldering but made the great leap to assessing you as High Risk and recommendeding an Allo transplant. I did one because I thought it was best for me - it certainly is not a procedure that that should be "pushed" on a patient. You also mentioned that the other Doctor did not think a PET scan was necessary - I would not be comfortable with that Doctor either.
I think you made a great decision going to see Dr. Landgren. I have only read great things about him. It was also mentioned above that he has no Conflicts of Interest on his research papers. I always check that after I read anything a Doctor writes. I personally have no interest in being treated by a Doctor that is a paid consultant or sits on a Board of Directors of a Drug company. That eliminates many of the well known treating facilities but I am very happy with my decison.
Good luck with everything,
Mark
Eb,
Hope you are doing well. With all due respect to your Oncologist, I have never read a study that shows 50% of patients that do VRD and than do an Auto get 8 years of continuos remission. If anyone can show me some research that shows this, please post it here. This comes right off the IMF website with respect to Auto transplants:
Q Can I relapse after a transplant?
A Yes. Unfortunately, the majority (at least 50%) of all multiple myeloma patients relapsed 18 to 36 months after their transplant was completed.
http://myeloma.org/ArticlePage.action?articleId=40
With respect to Allo transplants, I have posted many links in the forums with regard to current research about them. My experience with it has been a positive one so far. Treatment Related Mortality is typically between 10-14% in current studies using a Tandem Auto-Allo RIC approach. Graft vs Host disease is controlled in a majority of patients when ATG is used prior to transplant. Allos are far from a perfect form of therapy in Myeloma and they are not appropriate for many patients. Just like Myeloma therapy in general, there have been great strides made in Allo transplantation and much more improvement is necessary.
Good luck and hopefully you will be in that group of patients that enjoy a long Remission.
Mark
Hi Mark
Well I had never heard of such great results following VRD treatment and an ASCT either. But this is what my oncologist - supposedly the local expert -- asserted for his patients. But he may have been bull-shi##ing me or engaging in a post-hoc whitewashing of his results. He clearly was someone who likes to give drugs as soon as possible; in my case, he was scheduling infusions the following week without even establishing my baseline condition.
So in fact, he no longer is my oncologist for a number of reasons. I am not a cell biology experiment -- even if I am largely screwed. So I will be looking carefully into the studies you mention.
Thanks
Although just to defend my former oncologist: What about the greater to 50 percent of patients that did NOT relapse within 36 months after an ASCT. And more importantly, to what extent are these data based on the latest-- and apparenty superior -- front line treatments such as VRD?
After reading all the comments made by leading Oncologists concerning Smoldering Myeloma, which I have, I am still confused about this disease. Is Monoclonal Gammopathy of Uudetermined Significance more serious than MGUS? I haven't been told by my Oncologist, yet, which type I have. I'm not being treated, so far, just getting blood tests and urine tests every 2-3 months.Should I undergo treatment of some type at this early stage? Should I be on a special diet? Should I be working out to strengthen my body?I walk 4 miles every day, is this doing any good for my diagnosis? I'm 74 years old and very concerned about my health. My family doctor thinks the reason I have Smoldering Myeloma is because I sprayed Herbicides (Agent Orange)from a helicopter, when I was in my 20's and 30's, for 14 years. Could this be the cause? Please answer my questions since I need to know. Thank You!!!
Hi Steve
MGUS and Monoclonal Gammapothy of Undetermined Significance are one in the same. The Dr can say that your MGUS is related to Agent Orange but, they dont know that. They dont know what causes Myeloma or the precursor states.I am a Commercial HVAC service tech. and they can blame Refrigerants, Asbestos, Phosgene Gas (a result of refrigerant vapors burning) and a slough of other exposures Ive had to various Gasses. But, that is all speculation. Personally I think is more all of the crap we put into our Bodies via our contaminated food and water supply. I recommend you read a book called "natural cures they dont want you to know about" by Kevin Trudeau. I look at things very differently after reading that.
At your age Steve, I would not worry too much at all. It most likely would take years to advance if ever. Now of course I am not a Doctor but I have been told that there is a very good possibility that 3-4 percent of the population has MGUS. But they would never know because they would normally not have the tests necessary to diagnose this. I personally am a 40yo with SMM. (smoldering Multiple myeloma). It sounds like you are doing well and remember MGUS IS NOT Myeloma it is a precursor. SO enjoy life and keep an eye on it.
Best Wishes
Art
Hi Steve
I just read you post again. In the beginning you said you had MGUS. And at the end you said you were Smoldering. Or at least that is how I understood it. Which do you have? SMM and MGUS are two very different things. Just wondering
Thanks
Art
Hi all,
Two months since the latest post here, and I've returned and re-read them all and I think it's a very good thread of comments to an excellent interview!!
I'd like to clarify my only post, a long one -- which I have to say, upon re-reading, does in fact represent my views in great detail but is obscured by that detail. (I can't claim I was on a dex high, and in many ways I don't look forward to seeing what I'm like when I am!).
In short, what I wanted to say is: I don't think Dr. Landgren over-reached when he spoke of possible cure. His speech was measured, and he made excellent distinctions in making his points. Though I have a watchful eye for conflicts of interest and such, I have no reason to suspect an issue with his motivations; on the contrary my impression is that he is among the best of us in wanting evidence and truth and patient health, not personal gain, to prevail.
Soon I'll post some more targeted responses, in case anyone is still following this discussion.
-- Bruce P.
Julie (1/14/2012 12:30pm) --
Personally from a long-term perspective I support the search for natural, non-pharmaceutical-company aids to fight MM.
I recently decided to try curcumin for at least 3 months. Unfortunately (going from memory now), upon further investigation I decided that, at "best", not only does it likely have less efficacy than I want -- in part due to its limited bioavailability when orally administered, even with bioperine and maybe with more extreme enhancements -- but also, at perhaps-adequately high dosages, the curcumine and/or the bioperine are aomewhat likely to have some undesirable health consequences. Those include not only what we usually call side effects, such as diarrhea, but also stuff having to do with reduced iron retention and perhaps carcinogenicity. I don't say that dogmatically, and let me know if you know otherwise and/or you want references for why I say it.
Anyway I applaud MD Anderson for their trials, despite presumably relatively very minimal or no industry funding. I'm awaiting their solid data.
But so far I'm inclined to agree with what TerryH posits that Landgren might say. That is, with our current understanding, though curcumin may well have benefit, it is likely much too weak to treat (with patients' generally desired effectiveness) the vast majority of patients who are .... in my own words ........ "currently classified as smoldering but are at what we would consider high risk of advancing to what we would classify as active MM".
(Even with all those parentheses and quotation marks, I have to qualify it a little more. That is, I think it's worth pointing out that among those at high risk of advancing to what we call symptomatic, some are at high risk of dying soon, some are not; and for those that are, some are at high risk of non-response to various interventions, some are not. Lots of our efforts need to be directed toward discerning who is who, and why).
Anyway now I've regrettably cancelled my order for curcumin. Open to suggestions and counter-arguments.
-- Bruce P.
It would be nice to hear success stories from people on this site who had treatment with few side effects, went into remission, and have enjoyed a healthy life ever since. It seems instead that this site is focused on patients with horrible pain, side effects, and complications from therapy, and stem cell transplants. And that includes those who have undertaken total therapy.
It is quite horrible and disheartening. And while this perspective may be biased, it certainly keeps me from rushing to push toxic drugs in my blood.
There is a book called "Living Proof: A Medical Mutiny," that I plan to get. It tells the story of Michael Gearin-Tosh, an English scholar with multiple myeloma who refused medical treatment and instead chose the "crazy" approach of good nutrition, accupuncture, visualization, and vitamins. And he lived for more than ten years and probably would be alive today: he dying from a non-cancer cause: sepsis from refusing antibiotics for a tooth infection.
He was never cured and was always somewhat anemic, but he lived largely a normal and full life with NO conventional therapy. He also reached a chilling conclusion when examining chemotherapeutic options that doctors would not prescribe for themselves: Touch it, and you are a goner."
I am certainly intrigued and disturbed.
TerryH, Terry, Art, Mark, Julie --
Regarding conflict of interest, I'd like to add my voice in saying that although anything is possible, to me it seems exceedingly unlikely that there's an issue here with Dr. Landgren. Julie, you didn't by any means claim that Dr. Landgren's motives were impure, but you raised the legitimate issue that there certainly are other cases where researchers have conflicts, and you hoped it isn't the case presently. No doubt, you and countless others are like myself until recently, not likely to know much or any of the following, so here are my thoughts.
Even if Dr. Landgren wanted to be heavily financially intertwined with pharmaceutical companies, we're fortunate that he is at NIH where there is the following policy to require otherwise: http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf. Does the policy require zero personal financial involvement with a pharmaceutical company, not even buying small amounts of public stock? No. Is enforcement of the policy foolproof? No. But if you'll read the document, you'll see that it's rather solid, certainly nothing like what would be found at many major universities or research facilities, as TerryH pointed out.
Beyond that, more subjectively, I join others here in my assessment of Dr. Landgren's selflessness. I've seen his dedication and his personal sacrifice to beat this disease. He's one of those top researchers who shares his email address and phone number with his patients, responds rapidly to queries, and follows up on issues raised as necessary. I'm his patient and certainly nothing like an expert in myeloma research, but in our discussions he has treated me as much like a peer as could be possible; and when I had reservations with a course of action, he respected my concern and he supported altering our course of action. And I happen to know that just this past Sunday he called and spoke with another patient and the patient's wife, for over an hour, to discuss the patient's case. And so on.
Clearly all of that is anecdotal, and the scientist in me can never take that as proof of sincerity (not even if he were my own father/brother/son!). But I'm lucky enough to somewhat know him and his work environment and character. So with that: if someone disparages or even seriously challenges Landgren's sincerity, then for me, as a bare minimum, the onus is on that person to present some evidence, not innuendo. Otherwise in this case I can't get too interested in spending bandwidth to consider impropriety.
-- Bruce P.
Ma Larkey, the individual who you say died of a noncancer cause from sepsis is not really accurate. Being immunocompromised , the commonest cause of death with multiple myeloma is from infection. If he had been aggressively treated for the infection early there is a good chance that he would be here now as you say. In other words, he died from a complication of multiple myeloma. The disease is an individual thing as to its course and we don't know that individual's stage, cytogenetics etc. You are right that the forum is not indicative of the broad myeloma population as the patients are younger with more aggressive disease; 64 years old would be the average age for diagnosis and 60% of patients have normal cytogenetics and are standard risk as a result my hematologist says ( he runs the Stem Cell Lab and Bone Marrow Transplant Program at the university teaching centre that I attend ).
As to some patients with longer survival, there are some of us who have been fortunate; April 3rd marked my 21st anniversary. If you click on "opinion" at the top and return to Pat Killington's post in November on " Team Myeloma " there are some details as to my course if you are interested.
Ma Larkey
You write:
"It would be nice to hear success stories from people on this site who had treatment with few side effects, went into remission, and have enjoyed a healthy life ever since"
Ma Larkey, those people are probably out living life to the fullest, and not posting in a forum..as they have no need to. I am overjoyed that they make such a choice.
SR
If what you say is true -- and I hope it is -- then my wish is that you too will soon be a mamber of full-life group and will never be heard from again on this site! Here's hoping....
Kevin J 1/15/2012 4:22pm --
Like Dan D, I also want to say your points make sense to me. As for scientific justification for your point about binomial progression and the seeming reasonableness of treating some "smoldering" myeloma early, here are some speculations from someone who has a limited background in myeloma biology.
Note: I'm not at all sure I have some of this right, so don't trust it. And anyone who sees I'm in err here, please jump in.
Myeloma cells, maybe all cancer cells, have the ability to enhance their own microenvironment. For example, they have ways of promoting angiogenesis in their own local environment, that is, they can cause blood vessels to grow near them such that they (the cancer cells) will have more nutrients etc.. It's like they're in little houses in a neighborhood, and they go out and build streets, and electric power & water & sewer & phone lines ... and of course cellphone towers and internet lines ... all of which strengthen their defense. It takes some time for them to build that community. So if we go after them early, we have a better chance at killing them, and it's not just a matter of getting to them before they're too numerous -- it's also easier because they haven't built up as much infrastructure yet. (Gee, it almost makes me feel sorry for the poor little buggers).
Here's another possible mechanism, don't know if it really happens this way. Lots of the cancer cells mutate, and some of the mutants survive. Some mutations can confer greater resistance to such-and-such a drug than non-mutants or other-mutants have. The longer we wait to treat, the more diversity there is in the cancer cell population, and the higher the likelihood that at least some cells will be resistant to our rather blind-but-best-guess treatment.
One more reason to consider treating earlier is more of a clinical thing. We don't know when an 'SMM' patient is going to break a bone or get pneumonia or sepsis from a tooth infection or have some other end-organ MM-related problem.
I don't say that any of the above biological mechanisms can currently be quantified, for any individual or even any class of individuals, such that we're ready to predict the future course of disease. And of course there are reasons not to treat early too, among them the quality-of-life of drug side effects, the cost, the disruption to a person's life, and so on. But it's good to see that we're moving in the direction of quantifying the mechanisms, and of reducing the negative impacts of therapy with *targeted* therapeutic substances and techniques.
-- Bruce P.
I totally agree with Dr Ola comments on these observation. this is true for patients who had access to all kind of facilities. But we at resource constraint area do not have all the facility to treat myeloma patients
Most of our patients can afford skeletal survey, bone marrow examination, CBC, Biochemistry, and Immunoelectrophoresis . They can not afford genetic analysis and with this we start the treatment either as MP or VAD if patients is young or Thailadomide/ Bortezam and Dexa or Lenalidomide and Dexa. Many of our patients develop neuropathy and we examine clinically and stop the drug if incapaciating him.
Globalization lead to availability of all the drugs at our place. They spent on drugs and not on frequent investigation and landed with complication. Even simple treatment like MP consume their major finance. we really have to look into this matter. Much systematic studies in this area has not been there.
As a doctor on the one hand we are to follow the guidlines and other hand we have to look at the patients on his intellectual, financial and social background
Sanchetee s
I just started the carfilzomib trial with Dr. Landgren this weekend. My tale is one that may be instructive for not just watching and waiting when you are SMM with a high risk of progression. A few weeks ago I almost died from a pulmonary embolism that was almost certainly myeloma related. My hemoglobin tanked at the same time and my FLC's exploded. Dr. Landgren offered me a slot in the carfilzomib trial and I am happy he did. If you are high risk SMM, youmay want to consider a clinical trial. Terry
What made you high risk for progression? Just curious. Did the NIH carry out GEP assays? Or was this based on genetic markers? Something else?
Hi, Terry:
I'm glad that you are under treatment with Dr. Landgren. But I don't understand how pulmonary embolism can be related to MM before treatment even starts. I thought blood clots are a dangerous side effect caused MM therapies.
Hope you are doing well with carfilzomib.
Ben
Hi Dan D, I had a very high PC infiltration--over 60 % and immune paresis for all immunoglobulins--I am light chain only kappa.
Hi Ben S., all of my doctors both at the NIH and UPenn said the PE was myeloma related---blood cancers or bone marrow cancers carry a high risk of PE's even without treatment, any malignancy for that matter. So far, I just feel some fatigue with the protocol but I look forward to someday having a normal CBC and the hemoglobin of an adult male. Dr. Landgren is super positive about the trial. I am too and have the greatest of confidence in him and his research team. He feels the protocol can knock down the disease for many years, maybe without a SCT. We will see. Terry
Thanks Terry. I feel your optimism and wish you the best of luck. Many years may buy us all the time for development of an operational cure.
Hi Dan D, thanks for the kind words. I am in a similar protocol to the one that Kevin J. is part of in Michigan. He started with Dr. Jakubowiak. I hope my treatment follows his footsteps and I get a CR which lasts and lasts. I really had hoped to smolder for years but, alas, this damn condition is relentless. I seriously believe doctors like Landgren and his fellow researchers at the NIH are going to figure out how to halt progression or stop it dead in its tracks within a few years. I am very optimistic and can't wait till myeloma is at the back of my mind for years.
Hi All,
I was just diagnosed with smoldering Myeloma after a bone marrow biopsy.
Dr. Landgren's interview was excellent and eye opening.
I have always been a positive person and Dr. Landgren's statements keep the door open to both a cure and a virtual cure due to slowing down the progression of the disease. I agree it could be next year or 1000 years from now and if it turns out to take longer than my lifetime, I will ultimately just live out my life accordingly.
I will be an eager reader of this website.
Thanks to all
Richard
I was diagnosed with MGUS in 1997, then in 2007 this changed to smouldering myeloma. I have blood tests every 8 weeks and thus far remain in the watch and wait, my haematologist recently told me that if I can go 5 years without needing treatment there is a good chance that i will never need treatment, I reach the 5 year mark in September 2012 so i am keeping my fingers crossed.
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