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RVD - Why does it stop working & how to stop that?
I believe I read that RVD [Revlimid, Velcade, and dexamethasone] has a close 100% response rate in new patients. Of course the problem is that people become refractory to the drug regimen. So I'm curious if there is research going on that tries to figure out how the drugs stop working and if there is a way to stop it from happening?
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blair77 - Who do you know with myeloma?: My husband
- When were you/they diagnosed?: April 2013
- Age at diagnosis: 43
Re: RVD - Why does it stop working & how to stop that?
Hi blair77,
You've asked the $64 billion (or more) question! There has been and currently is a huge amount of research trying to answer your question, not only for multiple myeloma, but for many cancers.
I am no expert on this topic, but I'll point you to a couple of resources to check out. Other folks in the Forum will probably have other suggestions. I think one of the leading current theories about why chemo agents eventually stop working for most myeloma patients is the idea of intra-clonal heterogeneity. Dr. Gareth Morgan wrote an excellent guest column for the Beacon last fall that explains this concept a lot better than I can:
G Morgan, "Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma," The Myeloma Beacon, Nov 3, 2014
But your question is really at the heart of so much cancer research, going back at least to the work of Dr. Sydney Farber after World War II. The recent PBS documentary series "Cancer: The Emperor of All Maladies," did an excellent job of tracing the history of research trying to answer your question, as well as projecting forward in time too. The three-part series is available online at http://video.pbs.org/video/2365450686/.
That series is based on the book "The Emperor of All Maladies: A Biography of Cancer," by Dr. Siddhartha Mukherjee. It is a fabulous book if you want to dive into the details of your question.
Mike
You've asked the $64 billion (or more) question! There has been and currently is a huge amount of research trying to answer your question, not only for multiple myeloma, but for many cancers.
I am no expert on this topic, but I'll point you to a couple of resources to check out. Other folks in the Forum will probably have other suggestions. I think one of the leading current theories about why chemo agents eventually stop working for most myeloma patients is the idea of intra-clonal heterogeneity. Dr. Gareth Morgan wrote an excellent guest column for the Beacon last fall that explains this concept a lot better than I can:
G Morgan, "Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma," The Myeloma Beacon, Nov 3, 2014
But your question is really at the heart of so much cancer research, going back at least to the work of Dr. Sydney Farber after World War II. The recent PBS documentary series "Cancer: The Emperor of All Maladies," did an excellent job of tracing the history of research trying to answer your question, as well as projecting forward in time too. The three-part series is available online at http://video.pbs.org/video/2365450686/.
That series is based on the book "The Emperor of All Maladies: A Biography of Cancer," by Dr. Siddhartha Mukherjee. It is a fabulous book if you want to dive into the details of your question.
Mike
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
Re: RVD - Why does it stop working & how to stop that?
RVD is a triplet of drugs: Revlimid, Velcade and dexamethasone. Revlimid is known as a immunomodulatory agent, Velcade is a proteasome inhibitor, and dexamethasone is a corticosteroid. Both Velcade and Revlimid are referred to as being novel agents.
It has been shown that the three-drug combo works better than as a single agent or with one of the two novel agents being combined with dexamethasone.
The study you were referring to was issued back in 2010, here is link to it.
PG Richardson et al, "Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma," Blood, August 2010 (link to full text of article)
In many cases, RVD is given as upfront induction treatment, then is followed either by an autologous stem cell transplant (ASCT) or, if not, is given until the patient reaches the highest response he/she can. Then the patient is taken off of RVD and many are put on some form of maintenance, usually with Revlimid, with or without dex. Some patients following an ASCT are taken off of treatment completely. Upon relapse, RVD may be given again to drive the myeloma back down.
Almost all multiple myeloma patients eventually relapse. RVD is used in both the initial treatment setting and as a combo upon relapse. Since the triplet attacks the myeloma in more than one way, and seems to work in a synergistic manner, it works better and longer than any single agent.
However, it normally cannot be given for indefinite periods, since it suppresses / weakens the immune system over a period of time. Thus, it is generally used only as induction and with relapsed patients for a limited period of time depending upon how the individual patient can tolerate it. There are other proteasome inhibitors available now, such as Kyprolis, or will become available shortly (ixazomib / MLN9708) that give patients other options. Each of these have their own side effect issues. The same is true with immunomodulatory agents such as thalidomide and Pomalyst, which are available.
Multiple myeloma has many clones or pathways that lead to cell growth. The proteasome inhibitors and immunomodulatory agents block certain pathways which causes the myeloma cells to die. Some of the clones mutate to find an alternative pathway and over time reproduce. That is why multiple drugs are used so as to make it more difficult for the disease to build resistance. This is similar in the virus setting where AIDS has been successfully treated with multiple drugs and is now a chronic controllable disease. That is where multiple myeloma appears to be heading.
The key is getting therapy that both works long term but can be tolerated long term by the patient.
It has been shown that the three-drug combo works better than as a single agent or with one of the two novel agents being combined with dexamethasone.
The study you were referring to was issued back in 2010, here is link to it.
PG Richardson et al, "Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma," Blood, August 2010 (link to full text of article)
In many cases, RVD is given as upfront induction treatment, then is followed either by an autologous stem cell transplant (ASCT) or, if not, is given until the patient reaches the highest response he/she can. Then the patient is taken off of RVD and many are put on some form of maintenance, usually with Revlimid, with or without dex. Some patients following an ASCT are taken off of treatment completely. Upon relapse, RVD may be given again to drive the myeloma back down.
Almost all multiple myeloma patients eventually relapse. RVD is used in both the initial treatment setting and as a combo upon relapse. Since the triplet attacks the myeloma in more than one way, and seems to work in a synergistic manner, it works better and longer than any single agent.
However, it normally cannot be given for indefinite periods, since it suppresses / weakens the immune system over a period of time. Thus, it is generally used only as induction and with relapsed patients for a limited period of time depending upon how the individual patient can tolerate it. There are other proteasome inhibitors available now, such as Kyprolis, or will become available shortly (ixazomib / MLN9708) that give patients other options. Each of these have their own side effect issues. The same is true with immunomodulatory agents such as thalidomide and Pomalyst, which are available.
Multiple myeloma has many clones or pathways that lead to cell growth. The proteasome inhibitors and immunomodulatory agents block certain pathways which causes the myeloma cells to die. Some of the clones mutate to find an alternative pathway and over time reproduce. That is why multiple drugs are used so as to make it more difficult for the disease to build resistance. This is similar in the virus setting where AIDS has been successfully treated with multiple drugs and is now a chronic controllable disease. That is where multiple myeloma appears to be heading.
The key is getting therapy that both works long term but can be tolerated long term by the patient.
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Ron Harvot - Name: Ron Harvot
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: Feb 2009
- Age at diagnosis: 56
Re: RVD - Why does it stop working & how to stop that?
mrozdav wrote:
I agree, well done Ron. I was on RVD for two years (I didn't have a transplant). I have stopped all drugs since September of last year. My light chain numbers have went up the last two times I was tested, so it looks like it's just a matter of time before I'll be back to the RVD regimen.
Hello, Ron Harvot. Excellent summary.
I agree, well done Ron. I was on RVD for two years (I didn't have a transplant). I have stopped all drugs since September of last year. My light chain numbers have went up the last two times I was tested, so it looks like it's just a matter of time before I'll be back to the RVD regimen.
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gmarv - Name: marvin
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: aug.2012
- Age at diagnosis: 57
Re: RVD - Why does it stop working & how to stop that?
Hey Marvin,
You may want to consider a SCT. Like you, my RVD treatment worked, but then, after treatment, my light chains increased slowly. I did more RVD treatment and then did a SCT and, with Revlimid maintenance, my light chains have been stable for over two years now.
Jerry
You may want to consider a SCT. Like you, my RVD treatment worked, but then, after treatment, my light chains increased slowly. I did more RVD treatment and then did a SCT and, with Revlimid maintenance, my light chains have been stable for over two years now.
Jerry
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JBarnes - Name: Jerry Barnes
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: Aug 17, 2012
- Age at diagnosis: 54
Re: RVD - Why does it stop working & how to stop that?
Hey Jerry,
I will cross the SCT bridge when I get there. I was supposed to have one back when I was first diagnosed, but the specialist at UAMS decided that I was too sick to survive one, as I had a very slow recovery physically even though my cancer was brought under control quickly. I stayed on RVD for two years. I will most likely go back to the RVD treatment first, as I handled it fairly well. Of course, all options are on the table.
I will cross the SCT bridge when I get there. I was supposed to have one back when I was first diagnosed, but the specialist at UAMS decided that I was too sick to survive one, as I had a very slow recovery physically even though my cancer was brought under control quickly. I stayed on RVD for two years. I will most likely go back to the RVD treatment first, as I handled it fairly well. Of course, all options are on the table.
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gmarv - Name: marvin
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: aug.2012
- Age at diagnosis: 57
Re: RVD - Why does it stop working & how to stop that?
Hey Jerry,
One other thing: it looks like we joined the exclusive multiple myeloma club about the same time.
Hope you have many good days ahead.
One other thing: it looks like we joined the exclusive multiple myeloma club about the same time.
Hope you have many good days ahead.
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gmarv - Name: marvin
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: aug.2012
- Age at diagnosis: 57
Re: RVD - Why does it stop working & how to stop that?
Blair77,
I remember reading either last year or the year before that researchers had discovered just why it is that Revlimid stops working, and I mean what is going on at the cell level as to how the drug resistance develops.
If I remember correctly, there was some protein or receptor on the cell membrane that has to be present for Revlimid to work and, in time, as others said above, the cells seem to evolve to not have that protein or receptor. This was cited as one of the year’s significant findings at the American Society of Hematology.
The next step with that knowledge of how Revlimid drug resistance develops is to find a way to prevent drug resistance from developing. I have also read that similar progress is being made with Velcade.
I remember reading either last year or the year before that researchers had discovered just why it is that Revlimid stops working, and I mean what is going on at the cell level as to how the drug resistance develops.
If I remember correctly, there was some protein or receptor on the cell membrane that has to be present for Revlimid to work and, in time, as others said above, the cells seem to evolve to not have that protein or receptor. This was cited as one of the year’s significant findings at the American Society of Hematology.
The next step with that knowledge of how Revlimid drug resistance develops is to find a way to prevent drug resistance from developing. I have also read that similar progress is being made with Velcade.
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Eric Hofacket - Name: Eric H
- When were you/they diagnosed?: 01 April 2011
- Age at diagnosis: 44
Re: RVD - Why does it stop working & how to stop that?
I think overcoming resistance should really be pursued! I feel like drug companies keep trying to come out with new drugs that don't really give that much benefit instead of trying to fix the problems with ones that can and do work!
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blair77 - Who do you know with myeloma?: My husband
- When were you/they diagnosed?: April 2013
- Age at diagnosis: 43
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