I'm hoping some fellow forum members can give me some help with a simple question that probably has a complicated answer.
How do the targeted therapies we use in multiple myeloma actually work?
I'm looking for some very "lay person friendly" explanations. What is happening in my body? What are all these drugs doing?
If there is a journal article that has this sort of information, that would be great to know about.
For what it's worth, I currently take Kyprolis, Pomalyst, and dex (KPD) for maintenance after a stem cell transplant.
Thank you for your insights.
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Mark Pouley - Name: Mark
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2015
- Age at diagnosis: 53
Re: How do targeted multiple myeloma therapies work?
Interesting question, Mark. As you suspected, there isn't really a simple answer, for several reasons.
One reason is that the different targeted therapies work in different ways. When thinking about how they work and what's different about how they work, it's probably best to think of the three main categories ("classes") of novel myeloma therapies:
1. Immunodulatory agents ("imids") - thalidomide, Revlimid, and Pomalyst
2. Proteasome inhibitors - Velcade, Kyprolis, Ninlaro
3. Monoclonal antibodies - Darzalex, Empliciti, and others to come
(I'm leaving out HDAC inhibitors, such as Farydak, since they're not yet that important in the treatment of multiple myeloma. Ditto for one or two other classes of therapies.)
Each of these classes of drugs works in different ways. I won't try to explain how each class works, but I will point you to a description I posted in the past about how proteasome inhibitors work. Here is some of what I wrote in that posting:
I'll also add that proteasomes are sometimes described as cellular "garbage disposals". I prefer the chipper / mulcher analogy, but your mileage may vary.
One reason is that the different targeted therapies work in different ways. When thinking about how they work and what's different about how they work, it's probably best to think of the three main categories ("classes") of novel myeloma therapies:
1. Immunodulatory agents ("imids") - thalidomide, Revlimid, and Pomalyst
2. Proteasome inhibitors - Velcade, Kyprolis, Ninlaro
3. Monoclonal antibodies - Darzalex, Empliciti, and others to come
(I'm leaving out HDAC inhibitors, such as Farydak, since they're not yet that important in the treatment of multiple myeloma. Ditto for one or two other classes of therapies.)
Each of these classes of drugs works in different ways. I won't try to explain how each class works, but I will point you to a description I posted in the past about how proteasome inhibitors work. Here is some of what I wrote in that posting:
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.
I'll also add that proteasomes are sometimes described as cellular "garbage disposals". I prefer the chipper / mulcher analogy, but your mileage may vary.
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JimNY
Re: How do targeted multiple myeloma therapies work?
Nice job on describing proteasome inhibitors Jim.
As Jim mentioned, Pomalyst is what is known as an IMiD. IMiDs actually use quite a few different and complex mechanisms to help kill off myeloma cells. At a high level, IMiDs help modulate the immune system (hence the name "immunomodulating drugs") by turbocharging the immune system so that it can do its thing and kill the myeloma cells. IMiDs also help suppress angiogenesis (the development of new blood vessels) within the myeloma cells, thereby helping to starve them to death. IMiDs also help create a less favorable overall environment for the myeoma cells to grow and develop in.
The latest myeloma drugs include monoclonal antibodies (e.g. Empliciti and Darzalex) that specifically target meloma cells by using what are known as "clusters of differentiation" that uniquely (or at least, fairly uniquely) show up on the surface of only myeloma cells.
Clusters of differentiation are simply antigens (a type of protein) that present on the surface of a cell. The surface of myeloma cells tend to present with some relatively unique antigens such as CD38, CD319 (SLAM-F7), BCMA, etc. The monoclonal antibodies are engineered to recognize and bind with these antigens on the cell's surface and to then wreak havoc using multiple, different mechanisms such as directly killing the myeloma cells and/or enlisting the help of specialized immune cells such as "natural killer cells" to do their job (depending on the particular monoclonal antibody). Empliciti makes use of targeting CD319 (aka SLAM-F7) and Darzalex targets CD38.
All of these classes of drugs are often combined to help mount a multi-prong attack on the myeloma cells. Hope this helps a bit.
As Jim mentioned, Pomalyst is what is known as an IMiD. IMiDs actually use quite a few different and complex mechanisms to help kill off myeloma cells. At a high level, IMiDs help modulate the immune system (hence the name "immunomodulating drugs") by turbocharging the immune system so that it can do its thing and kill the myeloma cells. IMiDs also help suppress angiogenesis (the development of new blood vessels) within the myeloma cells, thereby helping to starve them to death. IMiDs also help create a less favorable overall environment for the myeoma cells to grow and develop in.
The latest myeloma drugs include monoclonal antibodies (e.g. Empliciti and Darzalex) that specifically target meloma cells by using what are known as "clusters of differentiation" that uniquely (or at least, fairly uniquely) show up on the surface of only myeloma cells.
Clusters of differentiation are simply antigens (a type of protein) that present on the surface of a cell. The surface of myeloma cells tend to present with some relatively unique antigens such as CD38, CD319 (SLAM-F7), BCMA, etc. The monoclonal antibodies are engineered to recognize and bind with these antigens on the cell's surface and to then wreak havoc using multiple, different mechanisms such as directly killing the myeloma cells and/or enlisting the help of specialized immune cells such as "natural killer cells" to do their job (depending on the particular monoclonal antibody). Empliciti makes use of targeting CD319 (aka SLAM-F7) and Darzalex targets CD38.
All of these classes of drugs are often combined to help mount a multi-prong attack on the myeloma cells. Hope this helps a bit.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: How do targeted multiple myeloma therapies work?
Thank you Multibilly and Jim. Both explanations have been very helpful. I've heard bits and pieces of information, but haven't really been able to process it. I think part of the problem for me is hearing different explanations and different drugs and getting all confused. Also your explanations have helped put it in terms a non-scientist can process a bit easier.
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Mark Pouley - Name: Mark
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2015
- Age at diagnosis: 53
Re: How do targeted multiple myeloma therapies work?
Glad to help, Mark, and those are some very nice descriptions of how imids and monoclonal antibodies work, Multibilly.
I thought I would mention one or two other things that might be interesting to anyone stumbling onto this thread.
One is that the technical phrase used to describe "how a drug works" is "mechanism of action." So what Multibilly did in the first part of his post, for example, is describe the "mechanism of action" of immunomodulatory agents such as Revlimid and Pomalyst.
I mention this since it may help someone trying to learn more technical details about how individual myeloma therapy works. If you want to know details of how Velcade works, for example, just fire up your favorite search engine and search for "Velcade mechanism of action."
Another thing I'd mention is that it may help to understand how monoclonal antibodies work by keeping in mind that they are, indeed, ANTIBODIES. Or, to put it another way, they are monoclonal IMMUNOGLOBULIN (remember, "antibody" is just a synonym for "immunoglobulin"). They have the immune system functionality of immunoglobulin, but, as Multibilly mentioned, the functionality is targeted at cells that have specific proteins on their surface (CD38, BCMA, etc.).
The fact that monoclonal antibodies are monoclonal immunoglobulin is why they can interfere with the accuracy of serum immunofixation testing. The prescribing information for Darzalex, for example, points out that it is "a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays," which can interfere with the determination of a patient's response to treatment.
(Sorry if this is more than you bargained for, Mark. I hope some of it was interesting!)
I thought I would mention one or two other things that might be interesting to anyone stumbling onto this thread.
One is that the technical phrase used to describe "how a drug works" is "mechanism of action." So what Multibilly did in the first part of his post, for example, is describe the "mechanism of action" of immunomodulatory agents such as Revlimid and Pomalyst.
I mention this since it may help someone trying to learn more technical details about how individual myeloma therapy works. If you want to know details of how Velcade works, for example, just fire up your favorite search engine and search for "Velcade mechanism of action."
Another thing I'd mention is that it may help to understand how monoclonal antibodies work by keeping in mind that they are, indeed, ANTIBODIES. Or, to put it another way, they are monoclonal IMMUNOGLOBULIN (remember, "antibody" is just a synonym for "immunoglobulin"). They have the immune system functionality of immunoglobulin, but, as Multibilly mentioned, the functionality is targeted at cells that have specific proteins on their surface (CD38, BCMA, etc.).
The fact that monoclonal antibodies are monoclonal immunoglobulin is why they can interfere with the accuracy of serum immunofixation testing. The prescribing information for Darzalex, for example, points out that it is "a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays," which can interfere with the determination of a patient's response to treatment.
(Sorry if this is more than you bargained for, Mark. I hope some of it was interesting!)
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JimNY
Re: How do targeted multiple myeloma therapies work?
Thanks Jim, not "too much at all", it is very interesting. While I don't enjoy having multiple myeloma, the student in me enjoys learning new things.
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Mark Pouley - Name: Mark
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2015
- Age at diagnosis: 53
Re: How do targeted multiple myeloma therapies work?
The only thing I would add to the discussion is the role of corticosteroids, especially dexamethasone. For unknown reasons, dex actually enhances the effects of the Imids and the proteasome inhibitors. When I was starting to relapse, the first thing my oncologist did was increase my dex from 20 mg once every two weeks to 40 mg once every two weeks. I take it the same day as I get a Velcade shot. It slowed down the progression.
Most induction treatments use a triplet that includes an Imid, a proteasome inhibitor, and a corticosteroid (usually dex). The triplets appear to work better than doublets and single agents, and combined with dex, they work better than without.
Most induction treatments use a triplet that includes an Imid, a proteasome inhibitor, and a corticosteroid (usually dex). The triplets appear to work better than doublets and single agents, and combined with dex, they work better than without.
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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: How do targeted multiple myeloma therapies work?
Thanks for these helpful posts!
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Arizonan - Name: Arizonan
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2010
- Age at diagnosis: 54
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