Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma
An important new concept in our understanding of multiple myeloma traces its origins back to the great nineteenth century scientist, Charles Darwin.
In his writings, Darwin described how characteristics of animal and plant species can change over time. Slight differences in inherited characteristics within a species, combined with variations in the environment, can lead to certain characteristics becoming more common in environments favorable to those characteristics.
A good example of what Darwin described is the range of size and shapes of beaks seen on Galápagos finches. The different beaks allow the birds to eat the different types of seeds found in their environments, making them specialists for those seeds. It is clear that all of these birds are related and belong to the finch family, but they are all subtly different species.
This process of “adaptation” to the environment leads to “evolution” of the species, making them better suited to their surroundings — in this case, eating a specific seed. The essential features of this process are genetic characteristics that are inherited, and a “selection” process related to the environment.
Intra-Clonal Heterogeneity
It is now thought that cancer behaves according to the principles described by Darwin that we outlined above. An essential feature of this process is variability within the cancer cells, which is called intra-clonal heterogeneity (ICH).
ICH is an important new concept which recognizes that myeloma tumor cells are not all identical, and that, when a myeloma patient is diagnosed, he or she has at least three to six major subpopulations of cells, all of which have different biological characteristics and clinical aggressiveness.
Below the level of sensitivity used for the detection of these major subclones, there is likely much more diversity, which is responsible for the emergence of drug resistance and relapse following exposure to the selective pressure of treatment.
The consequences of ICH also explain the progression of myeloma from a more benign to a more aggressive malignancy over time, as the most aggressive subclones come to dominate the others. The competitive behavior of residual myeloma cells means that they behave in a Darwinian fashion.
This competition is also present after treatment, where the rare variants which grow and survive the best come to dominate the population within the bone marrow — that is, lead to relapse.
How Is ICH Recognized In The Clinic?
There are several ways myeloma specialists see evidence of ICH as they treat and monitor the progress of their patients.
One is by using imaging technologies that don’t just look at lytic bone lesions, but which also assess the extent and aggressiveness of the myeloma both within and outside the bone marrow. PET scans and diffusion weighted MRI both can be used for these purposes.
The use of these techniques can show different sites and different disease activity within the bone marrow. Importantly, the techniques often show different responses to treatment at different sites in the body. This is consistent with the presence of different subclones at the different sites — some being sensitive, and others resistant, to treatment.
Other technologies can directly show ICH. For example, cytogenetic and gene expression profiling of bone marrow and focal lesion biopsies reveal different genetic features at different biopsy sites. Massively parallel sequencing can describe in detail the genetic differences between the myeloma cells at the different sites. It remains clear, however, that these cells are related, but with slight differences. This observation is exactly what would be expected for an evolutionary system.
Why Is ICH Important?
The evolutionary nature of multiple myeloma is important because the related subclonal cells, each derived from a myeloma stem cell that is subtly different, compete for space to grow within the bone marrow.
In this context, treatment can be considered as a “selective pressure.” It can kill most subclonal cells, but rare, resistant subclones can survive. And, in this setting, the resistant subclones will have more space to grow, leading to relapse.
Patients and doctors need to take these aspects of the ICH phenomenon into account when considering how to treat myeloma. The diversity that is present means that there are cellular subpopulations that are resistant to single treatments and can be responsible for relapse.
In this respect, using a combination of treatments that kills the maximum number of subclones is an important strategy. Indeed, such a strategy is relevant even if there is a single dominant clone that is not aggressive. That clone, by filling all of the space in the bone marrow, is likely to be suppressing the growth of more aggressive subclones. Using a small number of treatments targeted at just the dominant, less aggressive clone will leave the more aggressive subclones untreated and with more space to grow, leading to relapse.
Dealing With ICH Therapeutically
One of the key strategies of induction treatment for myeloma that is intended to deal with ICH is the use of multiple different therapies in combination with one another. This approach works by achieving the maximum cell kill to ensure the eradication of as many subclones as possible that could lead to relapse.
The use of autologous transplantation can be considered an extension of this attempt to maximize the number of subclones eradicated, leading to complete response. Similarly, the use of maintenance treatment is another important step forward that seems to be improving outcomes. In this setting, the selective pressure of treatments can alter the behavior of the small number of remaining tumor cells present below the level of detection of our monitoring technology.
In general, Darwinian evolutionary concepts suggest that single drug exposure may not be the best approach to treating myeloma, as it may lead to the overgrowth of resistant clones. However, the issue of resistant clones could be overcome by either using combinations of different drugs, or using “cyclic” approaches that employ different combinations of drugs at different times, in an alternating fashion. The development of new oral and antibody myeloma therapies, with different modes of action, means that this type of strategy is now clinically possible.
ICH also implies that therapies can make an important contribution to the treatment of multiple myeloma even if they do not generate significant changes in standard disease markers, such as a patient’s M-spike.
For example, a key pathway in myeloma is the RAS/MAPK pathway, which is frequently mutated and can be treated with certain drugs. Mutations in the RAS/MAPK pathway, however, are not always present in all myeloma cells – as one would expect, given ICH. Treating the mutations may therefore result in only a minor response, even though all the cells with the mutations are being killed, with potentially significant implications for length of remission.
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This month marks the 155th anniversary of the publication of Darwin’s On the Origin of Species, the book that became the foundation for the field of evolutionary biology. In recent years, researchers have learned that evolution has a great deal to say not only about how cancer develops, but also how it should be treated.
These learnings, in turn, have led to a greater understanding of ICH and its role in multiple myeloma, improving how we treat and monitor the disease, and offering hope for further improvements in the prognosis of myeloma patients.
Gareth J. Morgan is Director, Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Dear Dr. Morgan,
Thanks for the insightful article.
I’m particularly interested in your comments regarding cyclic therapy to deal with ICH.
1.One sometimes hears about the philosophy of getting the most out of a given drug before moving on to the next drug. In the context of ICH, do you think this may be a flawed philosophy for treatment?
2.What are the some of the typical drugs or cocktails that are cycled through over a period of time and when and how would one decide to move from one cocktail to the next? With this cyclic approach, would one routinely re-use an earlier cocktail with this kind of approach?
Hello Multibilly,
In regard to your questions,
1. The goal is to deliver treatments that are effective at eradicating every last cancer cell. This includes getting the most out of a given drug and maximizing its killing power. Therefore, while a patient is responding, treatment should be continued.
2. It is important to rotate drugs, although the order of rotation is not so important. Drugs with different mechanisms of action should be employed. For example, rotations of drugs should include proteasome inhibitors, such as Velcade or Kyprolis; IMIDs such as Revlimid or thalidomide; and new drugs such as anti-CD38 antibodies.
That was great reading and gives us lots to think about. This is why I like seeing new myeloma treatments come out that target different pathways. I also wonder if a previous therapy that was tried and not that effective because it did not target the dominant clone may be more effective later if a new dominant clone arises. Hopefully the emerging immunotherapy treatments will show strong resilience to the ICH effect.
In the three years of reading the Beacon there have been lots of announcements of agents that have shown some level of anti-myeloma activity in vitro, but not necessarily better than what is already available. Maybe using as many of these as safely possible in combination with therapies that are already widely used and understood may have some benefit.
If this ICH mechanism is indeed what is going on with myeloma, I would be cautious about any treatment plan or approach that centers on / puts everything on the use of a single agent or therapy and disregards, or does not use, other agents or treatment approaches — which describes a lot of alternative medicine approaches.
Hello Eric,
You wrote "I also wonder if a previous therapy that was tried and not that effective because it did not target the dominant clone may be more effective later if a new dominant clone arises."
I would say: Absolutely. The myeloma subclonal structure changes over time, based on the complex physiology of the cells and their microenvironment - this is known as clonal tiding. Therefore, it can make sense to employ agents that might not have been previously effective and to which the myeloma at one time was resistant, if a different clone has become predominant.
You also wrote about "agents that have shown some level of anti-myeloma activity in vitro, but not necessarily better than what is already available", and wonder whether "using as many of these as safely possible in combination with therapies that are already widely used and understood may have some benefit.".
Probably not. Agents currently in use in the clinic are effective at killing cell lines. However, current cell line models do not predict the effectiveness of a drug in the clinic. Therefore, studies need to focus on better ways of evaluating drugs that may show efficacy in the laboratory before they are introduced for use in humans.
Dr. Morgan,
Please answer Multibilly's questions as this is hugely important to everyone that reads this article.
Thanks,
Dr. Don Hoke
Dr. Morgan,
Thanks very much for this very informative column. You've tied together a lot of different pieces of information that help clarify things for me. Naturally, though, an article like this raises more questions for us myeloma patients. Multibilly and Eric have asked some good ones. I have a few more to add, if you have time for some more.
1. Compared to other cancers, does multiple myeloma show more of a tendency toward ICH? If so, would that be a reason why it is so hard to treat/cure multiple myeloma?
2. I'm wondering about what you might think of as the flip side of your comment about myeloma maintenance therapy being important because of ICH. Is it possible that maintenance therapy (typically done today with only one agent like Velcade or Revlimid) could have the effect of targeting only one sub-clonal population, allowing other, more aggressive sub-clones to grow and create larger problems later. Would you recommend the use of multiple agents during maintenance therapy?
3. I assume that researchers and clinicians understand multiple myeloma well enough to know which agents target which pathway mutations, such as the RAS/MAPK pathway that you mentioned. Do we also understand which genetic mutations are associated with which pathway mutations? If so, is it possible to determine through deep sequencing which agents should be optimal for a given patient's myeloma genetic profile?
4. How common across patients is the ICH evolution sequence (in a time sense, not genetic sense)? Is it the case that the same sub-clonal populations tend to be the ones that linger and grow in lots of different patients after treatment? If so, would that imply that new agents should be developed that target those "late-stage" sub-clones?
Thanks again for this thought-provoking article.
Mike
Hello Mike,
Myeloma does not show more of a tendency toward ICH than other cancers. For example, colon cancer and breast cancer are more complicated and exhibit more ICH and are not curable. This compares to acute leukemia in children, which has one of the simplest clonal substructures and thus is curable. Understanding myeloma biology and genetics is a good model for understanding more complicated cancers.
It is certainly possible that targeting only one subclonal population could enable other populations to gain strength and proliferate. That is why it is so important to rotate the use of effective agents that have different mechanisms of killing and that target different mutations.
Some clones are more resistant to treatment than others. For example, cases with mutation of the P53 gene are extremely resistant to treatment; patients with this mutation are known to experience a greater number of relapses. There is a need to continually develop new agents aimed at killing cells that carry resistant mutations.
Thanks, it is a great article.
Thank you for posting the information about ICH. My husband and I have been battling his myeloma for over 10 years. We find information such as found in this article very helpful in understanding why specific testing is done and specific treatments are prescribed for him.
Very interesting article, thank you very much.
Exceptionally clear and thorough explanation. I am a long-term survivor (11 years) and read everything I can find on myeloma. I have never seen ICH explained so well for the layperson. I would think that any patient and caregiver primer on the nature of the disease should include this article.
Great read, the comments especially the questions are very interesting and thought provoking. I'm part of the TT3 group of patients and participated in maintenance therapy afterwards.
I'm in CR and have been since 2006. I'm currently not taking any MM drugs. Yet I wonder when (not if) the myeloma the myeloma will return. I took dex and thalidomide, was switched to Revlimid in 2008. I was taken off dex in February 2008. I then took myself off Revlimid in August 2011.
Although I'm still in remission, the question remains will/when well I relapse, or am I cured. My doctors at home are having me just do blood work. Yet I'm concerned that by the time my blood work indicates abnormal blood levels, I will have relapsed. In your opinion, is this approach enough to detect a relapse? Here's a Little background. Since treatment, I had a total knee replacement in 2012 and spinal fusion in 2013 and doing feeling great. I could go on on and on, but I won't.
Thank you again for your article and thought-provoking conversation.
Hello Cynthia,
Blood work every couple of months is sufficient, as it will indicate M-spike and serum light chain levels. This approach will almost always detect relapse before clinical symptoms develop.
An excellent and informative article by Dr. Morgan. My husband was recently diagnosed with multiple myeloma at age 64. Like one of the other commenters, we read everything we can get on the disease, the treatment, and the future direction of diagnoses and treatments. We were very fortunate to hear Dr. Morgan speak on November 2, 2014 at the MD Anderson Cancer Center during a day-long seminar on multiple myeloma.
This article on ICH helped explain to us why the future may be fraught with uncertainties. We did not realize that myeloma "cells are not all identical, and that, when a myeloma patient is diagnosed, he or she has at least three to six major subpopulations of cells, all of which have different biological characteristics and clinical aggressiveness." Knowing this helps us understand why our oncologists at MD Anderson may recommend different drugs at different times through this lifelong journey we are taking.
During Dr. Morgan's presentation on Sunday, he discussed the different types of drugs used to treat myeloma and how they are designed to function in different ways against the myeloma cells. We have just begun this journey and it is information like this that helps us understand the path we are taking. We totally appreciate newsletters like the Myeloma Beacon and all the contributors who make it a valuable resource for multiple myeloma patients and their families.
My question would also be about maintenance. Would it make sense to combine or alternate, for example, a proteasome inhibitor and an imid as part of maintenance, to minimize the chance that a subclone that is not sensitive to the single maintenance drug will just quietly grow and then lead to a relapse?
Yes, Victor, it makes sense to combine and rotate various agents during the maintenance phase. This will minimize the risk of relapse from a resistant subclone.
Very interesting and I can see why myeloma needs varying strategies for treatment and why it can be difficult to "stay ahead of the game." Now I understand why SCT is still used or suggested for patients who achieve CR on drugs. I know that plasma counts can differ when different areas of bone are drilled for biopsy but I did not know that the cytogenics and genetic profile can vary also!
I am a 15 year survivor (woooohoooo, and thank you). At 46, and in great health, I believe we are gaining on a cure. This article again addresses treatment of the disease and its progression and relapse. I have had 3 different CR, and following each a relapse and have been given a new drug/treatment that has proved effective, which is good/bad. Good, that I have a cancer that is responsive to therapy, but bad, in the sense that each time it has found a way to "adapt" and come back.
Have alternating therapies been considered or tried so an "adapting" cancer would not have time to react to a single therapy, and if so with what effect?
Thanks for your hard work and dedication.
Stay Strong
Hello everyone,
Just so you don't miss them ... Dr. Morgan has provided replies to the questions asked prior to today in this commment thread. We have posted his responses above within the comment thread, after each of the comments to which he responded.
Hi,
Great article! I also have a few questions. Do you have a list of additional gene mutations like P53 that have been identified as resistant to treatment? Would one expect to see these genes, if present, reported on a past or current bone marrow biopsy report?
Is it your opinion that M spike levels can't be counted on to report accurate disease state, since measured level will not indicate whether it is of mostly non aggressive or aggressive plasma cells?
Are multiple myeloma oncologists familiar with ICH and varying medication, or is this a very new treatment theory?
Thank you for your attention.
Thank you Professor Morgan. The article is informative and explained well.
As you are well aware, in GB doctors have to follow NICE guidelines, plus most new treatments are only available on trials, which a patient has to match the criteria laid down by the trials!!
I can look back after my husband's death with hindsight and realise the hitting-it-hard regimen plus lack of choice of drugs was completely the wrong approach for someone who was high risk plus non secretory disease. As stated in your article, the destruction of good and bad cells left a vacuum for the very aggressive cells to have free range.
These trials are usually for a certain length of treatment, may be winning the battle, but not the war on cancer. When can we expect to see a better standard of treating high risk patients?! They may only be a 15% of myeloma patients, but their outcome through lack of individual treatment makes the prognosis very poor.
Thanks for a very useful, well written article.
There must be a time when the disease first appears when there is only one kind of clone. Mutations would gradually create other clones, one at a time, which may respond differently.
This would seem to favor hitting the disease with as many different chemo treatments as possible right at the start. At that point, the job is much easier, as all the cancer cells respond. Given more time, the job gets much harder. Like a garden full of weeds, it becomes very hard to kill the last bad cell.
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