We often hear that multiple myeloma is a heterogeneous disease making treatment decisions difficult. A recent article on this topic, not geared to myeloma but to cancer generally, is interesting. One thought provoking idea, which I have seen mentioned before, is the risk of permitting the proliferation of drug resistant clones by "hitting hard" at the tumor burden at the outset of treatment, thus creating an environment in which the resistant clones can better thrive. This is explained at the end of the article with the suggestion that less aggressive treatment, especially in terms of duration, with breaks may be the best strategy. Interesting stuff.
De Lartigue, J, "Tumor heterogeneity: a central foe in the war on cancer," Journal of Community and Supportive Oncology, June 2018 (full text of article, also available as in PDF form)
Excerpt from article:
"The current treatment paradigm is to try to eliminate tumors by hitting them hard and fast with the maximum tolerated dose (MTD) of a drug. However, there is increasing appreciation that this may be inadvertently fostering more rapid disease progression because it selects for the emergence of resistant cells and eliminates all their competitors ...
This is driving a potential paradigm shift, in which researchers are applying concepts from evolutionary biology and the control of invasive species to the treatment of cancer. Instead of completely eliminating a cancer, a strategy of adaptive therapy could be used to set up competition between different subclones and keep tumor growth in check by exploiting the high cost of resistance.
Adaptive therapy involves the use of treatment holidays, intermittent dosing schedules or reduced drug doses, rather than using the MTD. Adaptive therapy was tested recently in mice with triple-negative and estrogen receptor-positive breast cancer. The standard maximum dose of chemotherapy was compared with adaptive therapy with either reduced doses or skipped doses as the tumor responded. Tumor growth initially decreased with all 3 treatment scenarios, but then regrew when chemotherapy was stopped or doses were skipped. However, adaptive therapy with lower doses resulted in long-term stabilization of the tumor where treatment was eventually able to be withdrawn.23 Clinical trials of several different types of adaptive therapy strategies are ongoing ..."
Forums
9 posts
• Page 1 of 1
Re: Tumor heterogenity & "hitting cancer hard"
Thanks, Andrew, for posting this article. I think that many patients have had the sort of 'adaptive' treatments described, inadvertently, in terms of not having such a wide array of treatment options available, and also having 'maintenance' treatments of a low dosage. Many have had 'treatment breaks' in between treatments. That happens quite a bit with myeloma I think. In the table of genetic 'signatures' describing differing sorts of DNA damage relating to types of cancers, I didn't see multiple myeloma though.
-
Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Tumor heterogenity & "hitting cancer hard"
Great article Andrew.
I've long subscribed to this philosophy and chose my specialist based on his belief in many of the principles put forth in this article. To quote my specialist "myeloma is not a sprint to the finish line, but rather a marathon." He also believes that it is OK not to be MRD-negative and that MRD negativity shouldn't necessarily be an end goal of any treatment.
I've long subscribed to this philosophy and chose my specialist based on his belief in many of the principles put forth in this article. To quote my specialist "myeloma is not a sprint to the finish line, but rather a marathon." He also believes that it is OK not to be MRD-negative and that MRD negativity shouldn't necessarily be an end goal of any treatment.
-
Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Tumor heterogenity & "hitting cancer hard"
Fascinating article - thanks for posting it, Andrew.
The idea that maybe you don't want to select for the most aggressive possible clones has also occurred to me, but this is the first time I've seen it in the literature. It will be interesting to see how this approach pans out in the trials they list.
The idea that maybe you don't want to select for the most aggressive possible clones has also occurred to me, but this is the first time I've seen it in the literature. It will be interesting to see how this approach pans out in the trials they list.
-
Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: Tumor heterogenity & "hitting cancer hard"
Multibilly wrote:
Multibilly,
Could you please clarify a little bit more specifically this philosophy? What with this approach really can be a goal?
"MRD negativity shouldn't necessarily be an end goal of any treatment."
Multibilly,
Could you please clarify a little bit more specifically this philosophy? What with this approach really can be a goal?
-
borber - Name: borber
- Who do you know with myeloma?: me
- When were you/they diagnosed?: January, 2017
- Age at diagnosis: 60
Re: Tumor heterogenity & "hitting cancer hard"
Andrew,
Thanks for posting this. It is exactly the issue I’m facing now re future treatment.
David
Thanks for posting this. It is exactly the issue I’m facing now re future treatment.
David
-
Arizonan - Name: Arizonan
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2010
- Age at diagnosis: 54
Re: Tumor heterogenity & "hitting cancer hard"
Borber,
My specialist has the treatment philosophy of maintaining qualify of life while keeping the disease sufficiently under control so that it is not causing any end-organ damage. He's also concerned that aggressive, early treatment can indeed select for more virulent, treatment-resistant clonal lines down the road.
While deep responses are certainly welcome in a treatment, he doesn't necessarily believe in throwing everything at the disease and / or using high doses of a drug to knock one's numbers down to zero to achieve that goal. Rather, he takes a longer term view of the disease and likes to keep as many drugs and drug combinations in reserve for future relapses.
There are a lot of really smart specialists out there that take a different view of treatment than that of my specialist.
My specialist has the treatment philosophy of maintaining qualify of life while keeping the disease sufficiently under control so that it is not causing any end-organ damage. He's also concerned that aggressive, early treatment can indeed select for more virulent, treatment-resistant clonal lines down the road.
While deep responses are certainly welcome in a treatment, he doesn't necessarily believe in throwing everything at the disease and / or using high doses of a drug to knock one's numbers down to zero to achieve that goal. Rather, he takes a longer term view of the disease and likes to keep as many drugs and drug combinations in reserve for future relapses.
There are a lot of really smart specialists out there that take a different view of treatment than that of my specialist.
Last edited by Multibilly on Mon Jul 09, 2018 8:51 pm, edited 1 time in total.
-
Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Tumor heterogenity & "hitting cancer hard"
This is a fascinating subject (one I wrestle with almost every day). Treating multiple myeloma is not the same as treating an infection with an antibiotic. Quality of life is certainly important, but not easy to quantify. There are different ways to measure disease progression. And a fairly easy one to measure is overall survival. It seems like most doctors think we should stay on maintenance forever. But as Andrew implies from his article and Multibilly seems to agree, "drug holidays" may effect quality of life in a positive way, and maybe not affect disease progression or overall survival at all. (I hope I didn't put words in you mouth, Andrew and Multibilly.)
-
coachhoke - Name: coachhoke
- When were you/they diagnosed?: Apri 2012
- Age at diagnosis: 71
Re: Tumor heterogenity & "hitting cancer hard"
For what it's worth, here are a couple of links describing heterogeneity in multiple myeloma. There are more if you search. The point of this post is to show that multiple myeloma is distinctly heterogeneous and this therapeutic approach could be very relevant in the future.
First:
de Mel, S, et al., "Implications of Heterogeneity in Multiple Myeloma," 2014 (full text of article)
Abstract:
Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the "same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.
Second, the Bianchi and Ghobrial article mentioned in the initial post in this forum thread started three years ago:
""Clonal heterogeneity & evolution in multiple myeloma"" (started March 4, 2015)
First:
de Mel, S, et al., "Implications of Heterogeneity in Multiple Myeloma," 2014 (full text of article)
Abstract:
Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the "same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.
Second, the Bianchi and Ghobrial article mentioned in the initial post in this forum thread started three years ago:
""Clonal heterogeneity & evolution in multiple myeloma"" (started March 4, 2015)
-
Foundry738 - Name: Biclonal
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: 2016
- Age at diagnosis: 67
9 posts
• Page 1 of 1