ME vs. MM: Potpourri
I recall first encountering the word 'potpourri' as a category on the game show Jeopardy when I was a kid. I wasn't sure what the word meant because the answers that came up in that category never seemed to have anything in common.
Years later, I came across jars of foul-smelling bits of dried plants that were also called potpourri. My curiosity was roused because I had no idea how this related to what I had seen on Jeopardy. So I looked up the definition and discovered that potpourri is basically a random collection of stuff (my paraphrasing of the dictionary’s definition).
Everything made more sense then, but I decided this was one of those words that while interesting, probably wouldn't be of much use unless I was looking for something to mask the odors in a bathroom.
As I've accumulated ideas for columns, though, I realized potpourri would be an appropriate title for a column covering several questions I’ve considered writing about in my column, but didn't seem to warrant a column in and of themselves.
So, without further ado …
Why is treatment so ordered and regimented?
One of the problems with treatment is that cancer becomes resistant to chemo over time. An advantage of multi-drug treatment is it makes it more difficult for cancer to adapt. Therefore, why not mix up treatments, or mix up the frequency with which treatments are given, similar to the principles of muscle confusion used in strength training (e.g., cancer confusion)?
For example, I was treated on a 28-day cycle. I received Kyprolis (carfilzomib) on days 1, 2, 15, and 16, Revlimid (lenalidomide) on days 1 to 21, and dexamethasone (Decadron) on days 1, 8, 15, and 22. I would be curious to see a study to determine the efficacy of treating patients less predictably and with other drugs mixed in.
I do something similar with my weight lifting where I break my lifting into six different sets of exercises and group any three together for my workouts each week, never repeating the same combination two weeks in a row. I also vary the amount of weight I lift and therefore the number of repetitions I do. I've been doing this for over a year now, and the results have been superior to routines I've used previously.
Why are, according to some statistics, people over 65, more men than women, and more African-Americans than whites likely to get multiple myeloma?
I can't help but wonder about these statistics, particularly the first and third. Given all the people I know with multiple myeloma, most seem to be younger than 65, and I have yet to meet one African-American with multiple myeloma. Is this just indicative of the communities I'm part of, such as The Myeloma Beacon, or the patients receiving treatment through the University of Michigan, or the support groups and conferences I've attended?
I also wonder if more people under 65 are being diagnosed due to better diagnosis techniques, or perhaps because more people with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma are being diagnosed, or perhaps people are being exposed to agents that cause multiple myeloma sooner than people use to be?
Do patients relapse after an autologous stem cell transplant because the cancer was not fully eradicated from their body prior to reintroducing their stem cells, or because the cancer is present in the reintroduced stem cells?
This topic has already been discussed in the Beacon forums. It appears the relapse is due to residual disease still in the body, since a study showed virtually no difference in survival based on whether the harvested cells were purged of cancerous cells or not.
So now my question is whether the residual disease in the body is in the form of stem cells that were not killed off prior to the transplant, or is the source of the cancer something other than the stem cells and the transplant is just attacking a byproduct of the cancer, and not the source itself.
But if that's the case, why is a donor (allogeneic) transplant a potential cure? Shouldn't the source of the cancer still be present when the donor stem cells are introduced into the body? Perhaps the donor stem cells prevent the source of the cancer from proliferating any more because there is a crucial link or compatibility required between the source of the cancer and the stem cells.
Speaking of allogeneic transplants: I also wonder whether one could be at risk of reacquiring multiple myeloma through a donor transplant if the donor has multiple myeloma.
Has anyone thought about how some of the money spent on multiple myeloma research could be spent more wisely?
For example, I came across the following study:
Physical Activity Declines After Myeloma Diagnosis - Results of an Australian study show that levels of physical activity decline after people are diagnosed with multiple myeloma. The researchers identified fatigue, injuries, and pain as the strongest perceived barriers to participation in physical activity.
Well, duhhh! This seems to be another example of money spent on verifying common sense. Anyone that's been on chemo, or has experienced the symptoms of this disease could easily have told them this.
Other examples of research I've come across include a study indicating patients handle pain better if they participate in a pain management program and a study indicating patients with MGUS or smoldering myeloma are more likely to eventually be diagnosed with active multiple myeloma than those who don't. Perhaps I could have found enough examples like this to fill a column.
Hopefully my potpourri hasn't smelled things up too bad.
Peace, and live for a cure.
Kevin Jones is a multiple myeloma patient and columnist at The Myeloma Beacon. You can view a list of all his columns here.
If you are interested in writing a regular column for The Myeloma Beacon, please contact the Beacon team at .
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Kevin: Loved your article. It points out our lack of knowledge of how to treat MM . Some of the stuff we do and the research we support is downright silly. For example, you describe your treatment "For example, I was treated on a 28-day cycle. I received Kyprolis (carfilzomib) on days 1, 2, 15, and 16, Revlimid (lenalidomide) on days 1 to 21, and dexamethasone (Decadron) on days 1, 8, 15, and 22". Have you ever heard of something so ridiculous. The basis is obviously from rats. Even more amazing is the application of the same regimen to all patients. There is an infinite combination of drugs and regimens that have never been tested. Aren't there enough rats available. Maybe we need rat farms. Perhaps we might want to use the research dollars spent on really "common sense" projects that provide little knowledge into drug combination research to individualize the treatment regimen for each of us. It can be done but it takes money the only person's that seem to be interested are patients like you and me.
Kevin,
I enjoyed your article. Perhaps when we are visiting Ann Arbor this summer for my sons to see the UM campus and the Big House, my alma mater, we'll get together for a cup of coffee. My husband is African American and has MM.
Several African Americans have written in the Myeloma Beacon and/or have been featured in the IMF newsletter. Check out this URL on the MMORE website. http://www.mmore.org/PatientStories.html#
Cheryl Boyce, patient advocate and the former Executive Director of the Ohio Commission on Minority Health, has been very active in community outreach. http://www.patientpower.info/bio/cheryl-boyce
I do understand your question, though, when you reflect on the statistics. Thank you for sharing through your writings. Best regards, Cheryl
Potpourri - hmmm how's that pronounced -is the "T" silent - liked your thought process - so many of our Researchers seem to stumble along in their own little world ignoring the realities of life - another thing came to mind while reading this -what exactly is an African American - Africa is a very large Land Mass consisting of several country's housing many different Races of folks some of whom are not even distant relatives of each other and probably have different genetic diversities so how is it we lump them all together when coming to medical terms ? This would be a kin to lumping all the people from Germany-France-England- Italy- Spain-Poland-and Hungary as European Americans and expecting identical results in their treatment - regards N.G.
Kevin thanks for the article.
In regard the survival of MM after SCT my understanding is that myeloma persists as a network of myeloma 'clones' which could even be considered separate forms of the disease. When you have the SCT many of these are destroyed but not all. Thus it's only a matter of time until one of the clones develops a new phase of the disease. Whether this is 'attack of the clones' or 'the empire strikes back' who knows.
In regard criticising research priorities I think we need to be careful. There is a reason we have experts and that's because it takes years to be trained to the depth of understanding required to understand the subject enough to design and carry out research.
To be able to identify 'common sense' research you would need to have complete oversight and understanding of the subject area. The majority of us will never have that.
Kevin J,
Thought provoking column. I definitely agree with your first idea and I like that term - cancer confusion.
I will try to answer as best I can about your questions related to allo transplant. While no definitive myeloma stem cell or progenitor cell has been identified there is obviously something that the drugs we use do not kill since most non-allo patients relapse. Here is an example of research that Dr. Shain was part of that is a good example of this:
"Both CD19+/CD34+ and CD19+/CD34- cells showed colony formation activity, with colony growth efficiency optimized when stroma-conditioned medium was used. B-cell progenitors showed resistance to melphalan, lenalidomide, and bortezomib."
http://www.ncbi.nlm.nih.gov/pubmed/22988056
So yes, it is very likely that the source that can cause relapse is present when the donor cells are given the recipient during allo transplant.
An allo transplant is the most comprehensive form of immunotherapy that there is. They destroy the patients immune system and put in a healthy donors immune system. A myeloma patients problem is their immune system. It created a plasma cell that turned to myeloma and then it does not identify the myeloma as a threat and allows it to grow. An allo is the only solution to that problem currently.
To answer your last question donors go through extensive medical testing. My donor described the medical testing as the most thorough she has ever been through and that she learned a lot about her health as a result of all the testing. It is possible that a donor immune system could end up malfunctioning like ours did and create another blood cancer but it is at the very low rate of the general population. Myeloma is a very rare cancer so that chance is very slim. The recipients Doctor decides if the donor is healthy enough to donate.
It is the immunotherapy from the donor cells that provide the potential cure. As you noted molecular purging of the graft in auto studies show no benefit. Studies from the early 2000's showed allo patients gaining a molecular response at a rate of 50% while auto patients were between 7-16%. The chemotherapy was similar so it is the immunotherapy of the donor cells that lead to the deeper response and potential cure.
Sometimes you will hear a patient say that they found a "perfect match" on the donor registry. That is actually not true. The only truly perfectly matched donors are exact twins. What we are matched on are between 6-10 major histocompatibility antigens (HA). The minor HAs are different. Due to that difference in the minor HA's the donor immune system can identify the myeloma cells including the progenitor cell(s) the chemo did not kill as foreign and kill them and that is how a patient is potentially cured.
If you read my posts you will notice me say that some graft vs host disease is a really good thing. Limited amounts of GVHD are a great thing because it is a sign that the donor immune system is active and recognized you and the cancer cells as foreign. It is only when the GVHD is extensive chronic GVHD or a Grade 3 or 4 acute GVHD that it is considered a problem because that means the patient has significant side effects. Allo transplant studies show that patients with limited GVHD have the best chance of not relapsing and being a long term survivor.
I hope that helped with some of your questions.
Mark
Hi Kevin,
I can remember being given bags of potpourri as birthday presents when I was young. One problem living in a humid place potpourri starts growing things and then smells really bad (worse than before!).
You have asked "Do patients relapse after an autologous stem cell transplant because the cancer was not fully eradicated from their body prior to reintroducing their stem cells, or because the cancer is present in the reintroduced stem cells?"
In my case it was the former. Melphalan only knocked out ~16% of my myeloma cells, the other 84% were happy to keep on dividing. Technically I didn't relapse coz I never was in remission.
"Why is treatment so ordered and regimented? One of the problems with treatment is that cancer becomes resistant to chemo over time. An advantage of multi-drug treatment is it makes it more difficult for cancer to adapt."
This is an interesting question. Things that would need to be considered (for example):
How the resistance develops,
What the chemo is targetting,
How many different mutations are present,
What type of mutations are present
The efficacy of the chemo agent (ie is it 100% effective - probably not).
If your myeloma was one mutation and resistance to a chemo agent developed due to repeated exposure to that agent then a bit of mixing of a treatment regimen would probably be worthwhile. That is if more than one chemo agent targetted that mutation. I had a brief look at a paper on melphalan resistance in a myeloma cell line, resistance developed quite quickly but was also lost when the melphalan was no longer present. However, I had never had melphalan previously so the resistance in my melphalan resistant myeloma cells was due to another reason(s).
The type of mutation in the myeloma cell and how many different mutations there are is also going to have an impact. For example if you had 5 different mutations and one of these effected pathway A (clone A) and another pathway B (clone B)and the wonderful chemo agent X kills clones with a mutation in pathway A. Then treatment with X is going to kill your A clones and only your A clones. Clone B and all the other myeloma clones are free to do what they want. Other chemo agents may make it hard for them to grow (immunosuppressors and ones targetting angiogenesis) but the clones will still be present. If clone A was 95% of the the myeloma population then after ~6 cycles of an agent with a 90% efficacy it will look like you are in remission or pretty close. Clone A may not develop drug resistance but its numbers are low. How can you tell if it has developed drug resistance. When the paraprotein starts increasing again it may be due to Clone B.
Treating MM is a bit like a dogs breakfast - a really messy affair.
Libby
Dear Kevin,
I couldn`t agree more with your comments on some of the studies. LOL! How about the on where they have found out that cancer patients have a higher rate of depression - can´t recall the source but it was a study!
Regards from Oslo and all the best
Gary,
Thanks for the response. I think there will be changes in treatments in the future, particularly with the research that's starting to take place regarding more individualized treatment. However, I think it's probably a ways off yet before it becomes common practice.
Cheryl,
Let me know when you'll be in AA, I'd love to meet you. However, I don't actually live in AA, so hopefully it would coincide with one of my visits. I was at an IMF regional workshop yesterday and actually met another African American with MM. Just seems I would have met more by now. And obviously, I don't know the background of everyone that post here, so I more than likely have interacted with a few more that I wasn't aware of. Thanks for the links - these were two sites I had not come across before.
Nipon,
Yes, the "T" is silent (po-pour-ee). Very interesting observations on "African American" - I particularly thought the analogy to "European Americans" was intriguing.
Tom,
I got a chuckle to of your Star Wars references. Regarding the myeloma clones, this is similar to what I've also read and why cleansing the harvested stem cells of the cancerous cells didn't provide any improvement. However, why is this not as much an issue with the allogeneic transplant - do the donor stem cells destroy the myeloma clones that still exist?
Tom,
Not sure if this is the same Tom or a new one. Regardless, I understand that as patients, and not experts, we do not necessarily understand all the nuances associated with research studies, but you have to admit that some of them seem a bit lame. In all fairness though, I expect the vast majority of research dollars go to very useful studies, so I'm not ready to advocate for an oversight of research funding.
Mark,
Thanks for all the info on allo transplants - in reading other posts that you have made I never realized you had an allo transplant. Looks like there would easily have been enough info for a column on that - I just would have needed you to write the column for me. Seems likely it is the donor cells that keep the cancer from redeveloping, which is similar to what I responded to Tom above - I've also seen LibbyC post similar comments.
LibbyC,
Thanks for your comments on the considerations for varying treatment. These are the kinds of mental discussion I have with myself. If I had gone into medicine/research, Id probably be likely to pursue this type of research. I wonder how much research there is along these lines.
Christine,
Thanks for providing another example of what appears to be a common sense research study. I think MM research is like any other research topic - the majority of research is probably very useful, but a few questionable ones are bound to slip in now and then.
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