I read today that Velcade (bortezomib) is a reversible proteasome inhibitor and Kyprolis (carfilzomib) is an irreversible proteasome inhibitor. This description kind of states the obvious – one is reversible and the other is not. But what just does this mean to reversibly inhibit the proteasome and to not reversibly inhibit the proteasome? What are the ramifications to the cell of doing one and not the other?
My understanding is that all cells are affected by proteasome inhibitors, but myeloma cells are particularly susceptible to dying from them. But are all cells affected by an irreversible proteasome inhibitor like Kyprolis and, if so, does that mean for the rest of the cells life and what are the consequences of that?
In what I have read, the irreversible aspect of Kyprolis inhibits the proteasome longer than Velcade, and that appears to be one of the reasons it works well. I did not find anything on if that means indefinitely or for just a long period of time. My thinking is irreversible proteasome inhibitors are safe to use, but I am curious about the science behind the differences between the two.
Forums
Re: Reversible vs. irreversible proteasome inhibitors?
Hi Eric,
I think of proteasomes as parts of cells that are like the chippers and mulchers you use for yard waste.
The proteasomes take proteins that aren't needed anymore by the cell, or which will get in the way of the normal operation of the cell, and break the proteins down into their amino acids. (Proteins are made of amino acids.)
Once the proteins have been broken down into amino acids, those building blocks can either be used to create new, useful proteins, or they can be sent out of the cell as waste.
Proteasome inhibitors "gunk up" the chipping / mulching process by binding to a site within proteasome that is important for the process of breaking down proteins. They are the moral equivalent of throwing lots of grass into the chipper.
Reversible proteasome inhibitors are like dry grass. They'll gunk the chipper up for a while, but eventually the chipper may be able to throw the grass off and starting chipping again.
Irreversible proteasome inhibitors are like wet grass – or grass that's been coated with tar or glue. They get into the chipper and they stay there, permanently reducing its ability to do its job.
In both cases, inhibiting the proteasome may be enough to kill off the cell, as waste protein builds up in the cell and not enough amino acids are around to build new proteins needed by the cell.
However, both Velcade and Kyprolis only target one particular type of proteasome. I believe myeloma cells have more than one type of proteasome, so those may be able to work overtime, compensating for the (temporary or permanent) loss of the proteasome targeted by the drugs.
Also, I believe cells, if they can survive the proteasome inhibitor attack long enough, can build new proteasomes, or they can reproduce and their daughter cells will be able to have new, functioning proteasomes.
So there are various ways for cells to survive the attack of even irreversible proteasome inhibitors. Evolution, of course, means that those cells that are able to survive the attack will then produce more myeloma cells, which are genetically inclined to be better able to survive treatment with proteasome inhibitors.
Hope this helps a bit. I should add that I'm no expert on these issues, so if someone feels that I've been misleading in some way in what I've written, please ... let us know.
I think of proteasomes as parts of cells that are like the chippers and mulchers you use for yard waste.
The proteasomes take proteins that aren't needed anymore by the cell, or which will get in the way of the normal operation of the cell, and break the proteins down into their amino acids. (Proteins are made of amino acids.)
Once the proteins have been broken down into amino acids, those building blocks can either be used to create new, useful proteins, or they can be sent out of the cell as waste.
Proteasome inhibitors "gunk up" the chipping / mulching process by binding to a site within proteasome that is important for the process of breaking down proteins. They are the moral equivalent of throwing lots of grass into the chipper.
Reversible proteasome inhibitors are like dry grass. They'll gunk the chipper up for a while, but eventually the chipper may be able to throw the grass off and starting chipping again.
Irreversible proteasome inhibitors are like wet grass – or grass that's been coated with tar or glue. They get into the chipper and they stay there, permanently reducing its ability to do its job.
In both cases, inhibiting the proteasome may be enough to kill off the cell, as waste protein builds up in the cell and not enough amino acids are around to build new proteins needed by the cell.
However, both Velcade and Kyprolis only target one particular type of proteasome. I believe myeloma cells have more than one type of proteasome, so those may be able to work overtime, compensating for the (temporary or permanent) loss of the proteasome targeted by the drugs.
Also, I believe cells, if they can survive the proteasome inhibitor attack long enough, can build new proteasomes, or they can reproduce and their daughter cells will be able to have new, functioning proteasomes.
So there are various ways for cells to survive the attack of even irreversible proteasome inhibitors. Evolution, of course, means that those cells that are able to survive the attack will then produce more myeloma cells, which are genetically inclined to be better able to survive treatment with proteasome inhibitors.
Hope this helps a bit. I should add that I'm no expert on these issues, so if someone feels that I've been misleading in some way in what I've written, please ... let us know.
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JimNY
Re: Reversible vs. irreversible proteasome inhibitors?
Thanks that does help. I think what you said about a cell possibly being able to make new proteasomes, and daughter cells being unaffected, is why an irreversible proteasome inhibitor does not last forever in a cell and is not permanently damaging to healthy cells.
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Eric Hofacket - Name: Eric H
- When were you/they diagnosed?: 01 April 2011
- Age at diagnosis: 44
Re: Reversible vs. irreversible proteasome inhibitors?
From what I've read, myeloma cells also tend to develop other ways of dealing with the "yard waste" outside of the proteosome. I believe there are drugs in development that target these alternative chipper/shredders.
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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: Reversible vs. irreversible proteasome inhibitors?
Thanks for the question, Eric, and for your answer/analogy, JimNY. I'd never even heard of reversible vs. irreversible proteasome inhibitors before. I've learned something new today thanks to you guys. One of the reasons I like reading the Beacon forum!
Mike
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: Reversible vs. irreversible proteasome inhibitors?
What a great job teaching, Jim from NY!
I wish I could look up other comments by you - I would love to hear your explanations of how Revlimid works. I have seen that Revlimid impacts the immune system, but I have not understood how it impacts it.
Does Revlimid strengthen the immune system or weaken it?
Cathy
I wish I could look up other comments by you - I would love to hear your explanations of how Revlimid works. I have seen that Revlimid impacts the immune system, but I have not understood how it impacts it.
Does Revlimid strengthen the immune system or weaken it?
Cathy
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antelope1225 - Name: Cathy1225
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: May 25 2012
- Age at diagnosis: 55
Re: Reversible vs. irreversible proteasome inhibitors?
Glad you liked my explanation, Cathy.
Unfortunately, I don't have a similar explanation for how Revlimid works. I also don't think its "mechanism of action" in myeloma is as well understood as is the case for the proteasome inhibitors.
If you read the drug's prescribing information, which I consider a reliable source for these sorts of things, you'll see that the drug is described as having "immunomodulatory, antiangiogenic, and antineoplastic properties". The main description of how the drug seems to work, however, is this one:
"Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes"
So, to your question, it does seem to work -- at least in part -- through the immune system, causing the body to produce more white cells which, presumably, attack tumor cells. But that's about as specific as the description in the prescribing information gets.
While Revlimid does have this effect, it also suppresses the production of blood cells in many myeloma patients. You see this mentioned here in the forum by people taking Revlimid and, especially, Pomalyst, which is in the same class of drugs as Revlimid.
So it has this weird combination of opposite effects.
Confusing, eh?
Unfortunately, I don't have a similar explanation for how Revlimid works. I also don't think its "mechanism of action" in myeloma is as well understood as is the case for the proteasome inhibitors.
If you read the drug's prescribing information, which I consider a reliable source for these sorts of things, you'll see that the drug is described as having "immunomodulatory, antiangiogenic, and antineoplastic properties". The main description of how the drug seems to work, however, is this one:
"Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes"
So, to your question, it does seem to work -- at least in part -- through the immune system, causing the body to produce more white cells which, presumably, attack tumor cells. But that's about as specific as the description in the prescribing information gets.
While Revlimid does have this effect, it also suppresses the production of blood cells in many myeloma patients. You see this mentioned here in the forum by people taking Revlimid and, especially, Pomalyst, which is in the same class of drugs as Revlimid.
So it has this weird combination of opposite effects.
Confusing, eh?
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JimNY
Re: Reversible vs. irreversible proteasome inhibitors?
Yes, it is confusing, but thank you for confirming that Revlimid seems to both stimulate some parts of the immune system but also suppresses some blood cell production.
I could tell by the term "immunomodulatory" that Revlimid modulates the immune system, and I know it suppresses my WBC. I had read that it is antiangiogenic - but to suppress blood vessels in the bone marrow might be the reason why it suppresses my WBC. (inhibits the bad as well as the good)
It is encouraging to understand that Revlimid also
1. stimulates T-Cells
2. stimulates Natural Killer Cells (Love that technical term)
3. increases the number of NKT cells
4. inhibits the pro-inflammatory cytokines TNT - alpha and IL-6
I have read that the patients with longest term survival with multiple myeloma have strong immune systems so this is reassuring to find out.
I appreciate you taking the time to respond.
Cathy
I could tell by the term "immunomodulatory" that Revlimid modulates the immune system, and I know it suppresses my WBC. I had read that it is antiangiogenic - but to suppress blood vessels in the bone marrow might be the reason why it suppresses my WBC. (inhibits the bad as well as the good)
It is encouraging to understand that Revlimid also
1. stimulates T-Cells
2. stimulates Natural Killer Cells (Love that technical term)
3. increases the number of NKT cells
4. inhibits the pro-inflammatory cytokines TNT - alpha and IL-6
I have read that the patients with longest term survival with multiple myeloma have strong immune systems so this is reassuring to find out.
I appreciate you taking the time to respond.
Cathy
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antelope1225 - Name: Cathy1225
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: May 25 2012
- Age at diagnosis: 55
Re: Reversible vs. irreversible proteasome inhibitors?
JimNY - That explanation on the difference between the PI's was impressive!
My patient level read on the effect of Revlimid on the immune system is that it is likely stimulatory during early use but probably weakens it with long term use. I base that on multiple studies of how it effects patients that had previously done allo transplants, both for myeloma and other blood cancers. In the short term those studies typically show responders having an increase in t cells/NK cells and GVHD. Here is one example.
"Lenalidomide may prevent relapses after allogeneic stem cell transplantation by promoting the immune-mediated graft-versus-tumor effect. We performed a prospective phase I/II study to define the dose-limiting toxicity and the immunologic effects of lenalidomide given early (day 100-180) after allograft for four cycles in patients with multiple myeloma. According to the Fibonacci design, 24 patients with a median age of 53 years were included. Dose-limiting toxicity was organ toxicity owing to graft-versus-host disease, and the maximum tolerable dose was 5 mg. The incidence of graft-versus-host disease after lenalidomide was 38%, occurring after a median of 22 days, and was beside organ toxicity, a leading cause to discontinue the study in 29% of the patients. Immune monitoring revealed a significant increase in peripheral γ-interferon-secreting CD4(+) and CD8(+) T cells within the first week of lenalidomide treatment followed by a delayed increase in T regulatory cells. Furthermore, natural killer (NK) cells isolated from the peripheral blood of patients evidenced a significantly improved antimyeloma activity after lenalidomide treatment. The immune effect might have contributed to the increased CR rate from 24-42% after lenalidomide treatment because nonresponding patients showed significantly less natural killer and T cell activation."
http://www.ncbi.nlm.nih.gov/pubmed/23085463
However, another study shows a clear decrease in long term thymic t cell constitution for patients that did autos followed by lenalidomide consolidation/maintenance. One of the cells mentioned is CD4. CD4 are the cells that the AIDS virus attacks and is why AIDS patients have such weak immune systems.
Here is a link about what CD4 cells do.
https://aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/
Here is the study I mentioned above.
"Whether the efficacy of lenalidomide in the treatment of multiple myeloma (multiple myeloma) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with multiple myeloma who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with multiple myeloma received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 - effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 - /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance."
http://www.ncbi.nlm.nih.gov/pubmed/24237448
Again, just my patient level read.
Mark
My patient level read on the effect of Revlimid on the immune system is that it is likely stimulatory during early use but probably weakens it with long term use. I base that on multiple studies of how it effects patients that had previously done allo transplants, both for myeloma and other blood cancers. In the short term those studies typically show responders having an increase in t cells/NK cells and GVHD. Here is one example.
"Lenalidomide may prevent relapses after allogeneic stem cell transplantation by promoting the immune-mediated graft-versus-tumor effect. We performed a prospective phase I/II study to define the dose-limiting toxicity and the immunologic effects of lenalidomide given early (day 100-180) after allograft for four cycles in patients with multiple myeloma. According to the Fibonacci design, 24 patients with a median age of 53 years were included. Dose-limiting toxicity was organ toxicity owing to graft-versus-host disease, and the maximum tolerable dose was 5 mg. The incidence of graft-versus-host disease after lenalidomide was 38%, occurring after a median of 22 days, and was beside organ toxicity, a leading cause to discontinue the study in 29% of the patients. Immune monitoring revealed a significant increase in peripheral γ-interferon-secreting CD4(+) and CD8(+) T cells within the first week of lenalidomide treatment followed by a delayed increase in T regulatory cells. Furthermore, natural killer (NK) cells isolated from the peripheral blood of patients evidenced a significantly improved antimyeloma activity after lenalidomide treatment. The immune effect might have contributed to the increased CR rate from 24-42% after lenalidomide treatment because nonresponding patients showed significantly less natural killer and T cell activation."
http://www.ncbi.nlm.nih.gov/pubmed/23085463
However, another study shows a clear decrease in long term thymic t cell constitution for patients that did autos followed by lenalidomide consolidation/maintenance. One of the cells mentioned is CD4. CD4 are the cells that the AIDS virus attacks and is why AIDS patients have such weak immune systems.
Here is a link about what CD4 cells do.
https://aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/
Here is the study I mentioned above.
"Whether the efficacy of lenalidomide in the treatment of multiple myeloma (multiple myeloma) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with multiple myeloma who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with multiple myeloma received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 - effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 - /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance."
http://www.ncbi.nlm.nih.gov/pubmed/24237448
Again, just my patient level read.
Mark
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Mark11
Re: Reversible vs. irreversible proteasome inhibitors?
Thank you so much for the links and explanation, Mark.
I looked them up and followed other links. So, Revlimid seems to initially boost the T-cells but then "impaired long-term thymic T-cell reconstitution- decreased CD4 + and CD8 + CD45RA + CCR7"
I followed your links and found this description of CD4 and CD8 T cells on an AIDS forum:
http://www.thebody.com/Forums/AIDS/SafeSex/Q179329.html
The most famous are the CD4 "helper" T-cells, which serve both as coordinators (hence the name "helper") and participants in the immune response. CD8 T-cells are important partners and include cytotoxic T-lymphocytes (CTLs), which are also called "killer" T-cells. The primary role of CTLs is to eliminate cells from the body that are harboring infectious agents.
I also found this:
http://www.ncbi.nlm.nih.gov/pubmed/22571202
with this as the concluding sentence:
"Four years after randomization, overall survival was similar in the two study groups."
Thank you very much for taking the time to send your response.
Cathy
I looked them up and followed other links. So, Revlimid seems to initially boost the T-cells but then "impaired long-term thymic T-cell reconstitution- decreased CD4 + and CD8 + CD45RA + CCR7"
I followed your links and found this description of CD4 and CD8 T cells on an AIDS forum:
http://www.thebody.com/Forums/AIDS/SafeSex/Q179329.html
The most famous are the CD4 "helper" T-cells, which serve both as coordinators (hence the name "helper") and participants in the immune response. CD8 T-cells are important partners and include cytotoxic T-lymphocytes (CTLs), which are also called "killer" T-cells. The primary role of CTLs is to eliminate cells from the body that are harboring infectious agents.
I also found this:
http://www.ncbi.nlm.nih.gov/pubmed/22571202
with this as the concluding sentence:
"Four years after randomization, overall survival was similar in the two study groups."
Thank you very much for taking the time to send your response.
Cathy
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antelope1225 - Name: Cathy1225
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: May 25 2012
- Age at diagnosis: 55
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