Boris On Myeloma: The Faucet And Tub Model Of Multiple Myeloma
One of the lessons I have learned over time is that models are really valuable for making sense of things in life.
Now, the sort of models I have in mind aren’t the kind you build with plastic pieces and glue, or the kind you see in fashion shows.
The models I’m talking about are simplified versions of the real world, with the simplifications specifically designed to highlight the most important features of whatever it is that’s being modeled.
Given their purpose and design, I guess it’s not entirely surprising that models can be so valuable.
In basic chemistry and physics, for example, you can get a lot of mileage out of thinking about atoms as miniature solar systems.
Similarly, in economics, supply and demand are always a good starting point.
Psychology has the id-ego-superego model of the psyche. Business has the five forces model of corporate strategy. Astronomy had the (now discarded) geocentric model of the universe.
Models separate the wheat from the chaff, helping us focus on what’s important. They’re like the movie version of a long novel; you get the main plot and main characters without the distracting side stories and countless bit players.
But what model should we use to help us understand multiple myeloma?
To be honest, in the 15 years I’ve been researching, discussing, debating, and reporting about multiple myeloma, I have yet to come across a good, practical model of the disease. About the closest thing I have found is some of the research about evolution and how it applies to multiple myeloma. Yet, as valuable as that research is, I don’t think it offers the sort of framework that patients and medical professionals can use on a regular basis.
This is unfortunate. The lack of a practical model makes the disease much more confusing and mysterious than it needs to be. This confusion isn’t just an inconvenience. I believe it has a real impact on the quality of care multiple myeloma patients receive.
That’s why I’d like to remedy the situation a bit by describing the basic version of a model I’ve developed. It covers not just active (symptomatic) multiple myeloma, but also smoldering multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS).
I will admit that the model may seem odd at first, perhaps even crude or overly simplistic. I also will admit that this is the first time I’ve shared the model with a broader audience, so flaws may come to light that need some polishing.
That being said, I think you’ll find the model offers helpful insights, especially if you dig into it a bit, probing it here and there with questions.
The Basic Faucet And Tub Model
The model simplifies a person’s health and the myeloma disease process by asking us to think of a person’s body as a tub and the disease process as a faucet.
In a person who has neither myeloma nor MGUS, the tub (their body) is empty of myeloma cells, and the faucet is closed.
In some people, however, the faucet loosens, and myeloma cells start flowing into the tub. If the flow of cells entering the tub is not too high, the body’s immune response – the drain in the tub – can handle the disease, and the tub stays empty.
In some cases, the immune response is not enough to handle the faucet flow, and myeloma cells start accumulating in the body. When the accumulation of cells is very low, you have MGUS. When it is a bit higher, you have smoldering myeloma. When it is even higher, you have symptomatic multiple myeloma.
If nothing is done to empty the tub (body) of myeloma cells, the tub overflows. The body is overwhelmed by the disease.
Fortunately, myeloma can be treated, and myeloma treatments in the model are depicted as buckets. In the basic version of the model, each bucket represents the full effect a single treatment can have on a person’s disease, so there is one bucket for each possible treatment.
One bucket, for example, might represent Velcade (bortezomib) and the impact it can have when a patient is treated with the drug until their disease no longer responds to it. Another bucket might represent the full impact Darzalex (daratumumab) can have, a third bucket might represent melphalan, and so on.
When a bucket (treatment) is used, it lowers the level of cells in the tub (body). This response to treatment causes a period of time when the level of cells in the tub are low (remission), and it extends the patient’s survival by lengthening the amount of time until the tub overflows.
Some Quick Insights From The Model
What I have just described is the basic version of what I call the faucet and tub model of multiple myeloma. In my next column, I'll describe a slightly more complex version of the model, one that many researchers would argue is a better reflection of reality.
I'd argue that's up for debate. I'd also say we shouldn't downplay the insights to be gained from the basic version of the model. Allow me to list two that spring to mind.
Treatment options – The basic model underscores just how important treatment options are for the survival of myeloma patients. More treatments (buckets) lengthen the time a patient has until their disease can't be stopped. Myeloma patients today are surviving longer than patients 25 years ago because they have many more “buckets” to keep their “tubs” from filling up with myeloma cells.
Note, however, that the lesson here is not just a big-picture lesson about the survival of myeloma patients in general. There’s also a lesson for individual patients.
In particular, if an individual myeloma patient wants to maximize their survival, they need to avail themselves of as many effective and safe treatment options as possible, and they need to exploit each option to the fullest extent possible.
This won’t be the case, though, if older myeloma therapies are excluded from consideration, if creative combinations (such as nelfinavir and Velcade) are off the table, and if there are no plans for the patient to participate in clinical trials testing potential new myeloma therapies.
Treatment response, length of remission, and overall survival – The basic model also explains why multi-drug therapies almost always lead to deeper treatment responses and longer remissions. Two or three buckets will scoop out a lot more cells, and lower the level in the tub a lot more, compared to what a single bucket can do, thus increasing the time a patient is in remission (that is, the time it takes for the faucet to fill the tub back up to a high level).
Note, however, that the model also highlights why you can’t necessarily assume that deeper treatment responses and longer remissions automatically lead to longer overall survival. Using more drugs to get a deeper response has, with this version of the model, a kind of “robbing Peter to pay Paul” effect.
If you use two buckets (treatments) instead of one, you will get a deeper response and a longer remission. However, you also will have one less treatment option at relapse.
So in this version of the model, multi-drug treatment leads to deeper treatment responses, but the deeper responses do not lead to longer overall survival. The version of the model I’ll discuss next time, on the other hand, allows for a possible improvement in survival.
Putting The Model Through Its Paces
There are many additional applications of the basic version of the faucet and tub model, and I encourage you to explore them. How would you use the model, for example, to explain high-risk versus standard-risk multiple myeloma? What does the model say about treatment sequencing? Does it have anything to say about maintenance therapy or autologous stem cell transplants?
As you explore the model further, I am sure you’ll find predictions it makes that don’t seem right to you. When that happens, keep in mind that one of the purposes of the model is to help us understand why our assumptions are what they are, and whether the assumptions, or the model, need to change.
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This is the first in a regular series of columns I will be writing for The Beacon. As the Beacon’s founder, it’s been my pleasure to be involved in the preparation of many of the articles and announcements you can find here. I will continue to make similar contributions in the future, but I also will be sharing in these columns some of the broader perspectives and insights I’ve gained during my tenure in the myeloma community.
Thanks for the interesting analogy, Boris! I have heard more than once when attending talks about myeloma geared to patients, by myeloma specialists, that it is good to use the best treatments first. There is a protocol of how to treat a newly diagnosed patient in Canada. They are considered to be eligible for stem cell transplant or not. So for newly diagnosed multiple myeloma, usually the treatment is CyBorD for transplant patients, but if they are not doing transplants, Revlimid may also be used. It is unclear to me as to whether the 'transplant ineligible' include those who don't want transplants even if they could have one. (High-risk patients may have different considerations though). It is not until a relapse occurs, which could mean that a treatment becomes ineffective, or that a patient has been off medications and relapsed, that other drugs can be used. For example, that could include Pomalyst, Kyprolis, and very recently, Darzalex.
But in your 'bucket' analogy, fewer buckets might be needed to clear the system of myeloma cells, if they were more effective. Those could include the newer drugs too. So I guess that the studies that might show just how effective is one drug compared to another, or groups of drugs, could determine which drug is used first. For example, if the use of Darzalex in combination with Revlimid plus Dex gave a longer progression free survival than other combos, then it could be used first for new patients. That might prolong survival, since it would take longer for the patient to get to their first relapse.
Living in this era of research and the approval of new drugs quite frequently, means that many of us have seen a lot of changes in treatments of myeloma patients. Thanks to The Myeloma Beacon, we have a chance to learn about these issues and discuss them on an international level!
Excellent, intriguing perspective, Boris. Thanks! I'm looking forward to your next article.
Thanks for your comments, Nancy and Sean.
I have a couple of follow ups that may clarify some points I make in my article.
For example, I think it would be a mistake to characterize a complete response to treatment as "clearing the tub." One of the things that research into residual disease has taught us is that the tub is actually very deep, and that responses beyond what can be measured with M-spikes and light chain levels can make a big difference in terms of length of remission.
Second, one of the purposes of the model I've sketched is to encourage patients, caregivers, and medical professionals to question what they are told. If a physician says "You should use the best possible treatment when treating newly diagnosed multiple myeloma," the model encourages us to ask: What's the evidence supporting that strategy. As it turns out, the question of what treatment to use first is related to many other important questions in the treatment of multiple myeloma, and they are important questions precisely because there isn't always a consensus.
Finally, one of the main points of the basic model is to make clear that longer remission (progression-free survival) does not necessarily mean longer overall survival. Numerous studies that look at maintenance therapy, for example, find that it prolongs remission, but it doesn't always prolong overall survival. The point of the faucet and tub model is to help people understand why that's the case: it's because maintenance therapy uses up a treatment option (bucket).
Good to hear from you, Boris, and appreciate so much your insight and all you do.
Boris, on the topic of maintenance treatment using up an option, if the patient becomes resistant to it, that seems really relevant right now. Taking the example of Darzalex, I believe it has been shown that it is more effective when taken with Revlimid plus dex. So what was once a maintenance drug could now again be a main treatment drug! It is sort of contradictory, though, in that the maintenance feature of a drug is prolonging progression-free survival. Without the maintenance regimen, the relapse would have come sooner.
Dear Boris, thanks very much for your interesting article and analogy. I will try out this model at the next opportunity. I find it difficult to explain the disease and the treatments to friends and family. I like the way that the model includes the difficult business of explaining time to relapse vs. overall survival. Thanks for everything you do for this community.
Dear Boris,
I also thank you for the analogy of body / tub and multiple myeloma process / faucet. As Margorie said, this is an easily understood explanation, for both myself and others, of the basics of the disease.
Having been diagnosed with MGUS almost exactly 4 years ago, then high risk smoldering multiple myeloma 2 1/2 years ago, and, therefore, not being in treatment yet (thank you, God), I have no experience with the treatment world, but, I feel, a great deal of knowledge thanks to both my wonderful hematologist and the precious people who share their multiple myeloma stories at the Beacon.
I look forward to your next column and its more complex version of the model.
Thanks for sharing Boris. An interesting analogy. Certainly the move in treatment for multiple myeloma has been using the 3-drug approach, usually (in the U.S.) starting with Velcade, Revlimid, and dexamethasone as induction. There has been some discussion as to using a fourth, so we may soon see Darzalex, Velcade, Revlimid, and dex. Thus, using 4 buckets to empty the tub. The idea from what I can gather has been learned from the experience with HIV. That virus in unable to mutate to overcome the attack from multiple directions. However, once the treatment is stopped, the virus comes back. Thus, I think that the multiple bucket approach is also likely to spread to maintenance in multiple myeloma.
Ron
Really an excellent way of thinking about multiple myeloma. One of its virtues is its simplicity. As Marjorie observed, this makes it an excellent way to explain multiple myeloma to family and friends.
I look forward to learning more about this useful model in your subsequent columns.
Thank you, Boris.
I love analogies, so I love this. Thanks Boris.
Dear Boris,
Thank you so much for sharing your insights into this very challenging disease. I really appreciate the support of the Myeloma Beacon to help patients like me understand more about multiple myeloma. Thank you! I am looking forward to your next column.
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