Bristol-Myers Squibb says that Empliciti is the "first and only immunostimulatory antibody for multiple myeloma."
What exactly does "immunostimulatory" mean here, and how is Empliciti's means of working against multiple myeloma different from that of Darzalex (daratumumab), which is another monoclonal antibody?
Mike
Forums
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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: FDA approves Empliciti (elotuzumab)
Mike,
Let me try to explain it the way that I simplistically understand it.
Like daratumumab, elotuzumab targets a specific antigen that is commonly found on the surface of myeloma cells. Elotuzumab specifically utilizes the CS1 (aka SLAMF7) antigen marker for this purpose. Dara uses the CD38 marker.
But it turns out that CS1 is also found on the surfaces of natural killer cells. So elotuzumab will bind with both myeloma cells AND with natural killer cells. When elotuzumab binds to the CS1 receptor on the natural killer cells, this in turn activates those natural killer cells to go after the myeloma cells and subsequently induces apoptosis (cellular death) in the myeloma cells. So, in a sense, elotuzumab has a dual-pronged approach to killing off myeloma cells. Elotuzumab is considered to be an immuno-stimulatory monoclonal antibody for treating multiple myeloma because it has this additional and unique action of enlisting natural killer cells to help eliminate multiple myeloma cells.
At least that is how I have come to understand it. Somebody that understands this better might want to chime in.
Let me try to explain it the way that I simplistically understand it.
Like daratumumab, elotuzumab targets a specific antigen that is commonly found on the surface of myeloma cells. Elotuzumab specifically utilizes the CS1 (aka SLAMF7) antigen marker for this purpose. Dara uses the CD38 marker.
But it turns out that CS1 is also found on the surfaces of natural killer cells. So elotuzumab will bind with both myeloma cells AND with natural killer cells. When elotuzumab binds to the CS1 receptor on the natural killer cells, this in turn activates those natural killer cells to go after the myeloma cells and subsequently induces apoptosis (cellular death) in the myeloma cells. So, in a sense, elotuzumab has a dual-pronged approach to killing off myeloma cells. Elotuzumab is considered to be an immuno-stimulatory monoclonal antibody for treating multiple myeloma because it has this additional and unique action of enlisting natural killer cells to help eliminate multiple myeloma cells.
At least that is how I have come to understand it. Somebody that understands this better might want to chime in.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: FDA approves Empliciti (elotuzumab)
Hello MikeB:
Based on my layman's reading of the issue, and from what I understand what some researchers have been reporting, whether or not elotuzumab is "immunostimulatory" is a secondary issue. To me, it smells like a statement put out by a marketing person, and not a medical person.
My understanding is that the issue and question that researchers ask first for immunotherapies is "What's the target"; and the second question is "How effective" on the target. So elotuzumab will work for an individual if they have a lot of SLAMF7, and not work for an individual when they have only a little bit of SLAMF7. The ability to test for this is still not well developed, it's a specialty test, but I am hopeful that this will improve quickly. This is actually a very good thing in the long term, in that when other MABs are developed, the MAB can be selected specifically for the individual's situation.
Elotuzumab relies on the Revlimid combo to "rev" up the immune system (sorry for the pun). In fact, studies have shown that elotuzumab does not have single-agent activity. At this stage, until a highly respected doctor comes out and explains this issue, I would assume that it does not mean anything with regards to the "immunostimulatory" properties of elotuzumab. Still, the primary issue is the "on target" activity of the combo treatment including elotuzumab.
And to try and finish the thought, daratumumab works against a different target, CD38.
The various targets are markers or proteins on the surface of the multiple myeloma cells (as opposed to the interior of the cells. IMiDs and proteasome inhibitors (PI's) (and dex) work on the cellular composition (the interior) of cells, so combining interior agents with surface agents is potentially a very good thing. It's in theory a more potent and more complementary combination.
Still, this activity, so far, works reasonably well when the myeloma tumor burden is at a low level. It tends to deepen response and extent duration to first (or second) relapse. The myeloma doctor community has not figured out yet to make these combos work reasonably well at the later stage situations (though it does appear to be an improvement, even so, up to now, for more advanced disease). I hope the new drugs, and the knowledge of how to effectively administer them, continues.
Good luck,
Based on my layman's reading of the issue, and from what I understand what some researchers have been reporting, whether or not elotuzumab is "immunostimulatory" is a secondary issue. To me, it smells like a statement put out by a marketing person, and not a medical person.
My understanding is that the issue and question that researchers ask first for immunotherapies is "What's the target"; and the second question is "How effective" on the target. So elotuzumab will work for an individual if they have a lot of SLAMF7, and not work for an individual when they have only a little bit of SLAMF7. The ability to test for this is still not well developed, it's a specialty test, but I am hopeful that this will improve quickly. This is actually a very good thing in the long term, in that when other MABs are developed, the MAB can be selected specifically for the individual's situation.
Elotuzumab relies on the Revlimid combo to "rev" up the immune system (sorry for the pun). In fact, studies have shown that elotuzumab does not have single-agent activity. At this stage, until a highly respected doctor comes out and explains this issue, I would assume that it does not mean anything with regards to the "immunostimulatory" properties of elotuzumab. Still, the primary issue is the "on target" activity of the combo treatment including elotuzumab.
And to try and finish the thought, daratumumab works against a different target, CD38.
The various targets are markers or proteins on the surface of the multiple myeloma cells (as opposed to the interior of the cells. IMiDs and proteasome inhibitors (PI's) (and dex) work on the cellular composition (the interior) of cells, so combining interior agents with surface agents is potentially a very good thing. It's in theory a more potent and more complementary combination.
Still, this activity, so far, works reasonably well when the myeloma tumor burden is at a low level. It tends to deepen response and extent duration to first (or second) relapse. The myeloma doctor community has not figured out yet to make these combos work reasonably well at the later stage situations (though it does appear to be an improvement, even so, up to now, for more advanced disease). I hope the new drugs, and the knowledge of how to effectively administer them, continues.
Good luck,
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JPC - Name: JPC
Re: FDA approves Empliciti (elotuzumab)
JPC,
Respectfully, the concept of immuonostimulatory mAbs is not "marketing hype". You can easily find a lot of papers on the web that go into the medical and technical details of the immunostimulatory mechanism for this aspect of elo, as well as the exciting promise of using immunostimulatory mAbs for treating cancer in general.
And here you can find Dr. Lonial citing the unique dual properties of elo.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570078/
Flow cytometry for identifying specific proteins on a cell's surface is actually a very well understood and mature technology. One only has to configure the flow cytometry rig to specifically look for a given protein such as CS1 (or CD38, or a specific handful of clusters of differentiation and/or other proteins).
Respectfully, the concept of immuonostimulatory mAbs is not "marketing hype". You can easily find a lot of papers on the web that go into the medical and technical details of the immunostimulatory mechanism for this aspect of elo, as well as the exciting promise of using immunostimulatory mAbs for treating cancer in general.
And here you can find Dr. Lonial citing the unique dual properties of elo.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570078/
Flow cytometry for identifying specific proteins on a cell's surface is actually a very well understood and mature technology. One only has to configure the flow cytometry rig to specifically look for a given protein such as CS1 (or CD38, or a specific handful of clusters of differentiation and/or other proteins).
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: FDA approves Empliciti (elotuzumab)
Now boys, let's play nice ... 
Both of you (Multibilly and JPC) are probably partly correct in this case.
The FDA watches carefully what companies say about what their drugs do, including how they work. And the FDA has approved the description of Empliciti as an "immunostimulatory" drug in Empliciti's prescribing information, while that description is not in the prescribing information for Darzalex. (Let's pull up and post the relevant language later in this thread -- I don't want this posting to get even longer than it is.)
However, just because the language isn't in the Darzalex prescribing information doesn't mean that Darzalex doesn't have a similar "immunostimulatory" effect. Understanding how drugs work against myeloma is far from an exact science. I think it's been mentioned elsewhere here in the forum that doctors often describe diagrams depicting the mechanism of action of drugs as "cartoons". There's a reason for that.
Also, to lend some support to what JPC has said about marketing hype, if you Google "immunostimulatory antibody" or "immunostimulatory antibody cancer", you'll find that the other drug often associated with these phrases is Yerevoy (ipilimumab), which is sold by Bristol-Myers Squibb ... the same company that is marketing Empliciti.
More importantly, if you go back and look at early descriptions of Empliciti's mechanism of action, you'll see that they are very similar to the descriptions for Darzalex's mechanism of action, with an emphasis on "ADCC" (antibody-dependent cellular cytotoxicity). See,
http://static9.light-kr.com/documents/Richardson%20-%20ASH%202012%20-%20Elotuzumab%20Revlimid%20Dex.pdf
which references these studies from back in 2008
http://www.ncbi.nlm.nih.gov/pubmed/18451245
http://www.ncbi.nlm.nih.gov/pubmed/17906076
The claim that Empliciti is "immunostimulatory" is based, I believe, on this more recent paper,
http://www.ncbi.nlm.nih.gov/pubmed/24162108
which specifically puts forward the notion that Empliciti has anti-myeloma activity for reasons involving more than just ADCC.
Both of you (Multibilly and JPC) are probably partly correct in this case.
The FDA watches carefully what companies say about what their drugs do, including how they work. And the FDA has approved the description of Empliciti as an "immunostimulatory" drug in Empliciti's prescribing information, while that description is not in the prescribing information for Darzalex. (Let's pull up and post the relevant language later in this thread -- I don't want this posting to get even longer than it is.)
However, just because the language isn't in the Darzalex prescribing information doesn't mean that Darzalex doesn't have a similar "immunostimulatory" effect. Understanding how drugs work against myeloma is far from an exact science. I think it's been mentioned elsewhere here in the forum that doctors often describe diagrams depicting the mechanism of action of drugs as "cartoons". There's a reason for that.
Also, to lend some support to what JPC has said about marketing hype, if you Google "immunostimulatory antibody" or "immunostimulatory antibody cancer", you'll find that the other drug often associated with these phrases is Yerevoy (ipilimumab), which is sold by Bristol-Myers Squibb ... the same company that is marketing Empliciti.
More importantly, if you go back and look at early descriptions of Empliciti's mechanism of action, you'll see that they are very similar to the descriptions for Darzalex's mechanism of action, with an emphasis on "ADCC" (antibody-dependent cellular cytotoxicity). See,
http://static9.light-kr.com/documents/Richardson%20-%20ASH%202012%20-%20Elotuzumab%20Revlimid%20Dex.pdf
which references these studies from back in 2008
http://www.ncbi.nlm.nih.gov/pubmed/18451245
http://www.ncbi.nlm.nih.gov/pubmed/17906076
The claim that Empliciti is "immunostimulatory" is based, I believe, on this more recent paper,
http://www.ncbi.nlm.nih.gov/pubmed/24162108
which specifically puts forward the notion that Empliciti has anti-myeloma activity for reasons involving more than just ADCC.
Re: FDA approves Empliciti (elotuzumab)
Hi Cheryl,
Thanks for chiming in. Good points.
I also tend to agree that the paper you referenced (and I read when first trying to understand how elo works) was probably one of the key papers that led to the claim of elo being "immunostimulatory".
http://www.ncbi.nlm.nih.gov/pubmed/24162108
Thanks for chiming in. Good points.
I also tend to agree that the paper you referenced (and I read when first trying to understand how elo works) was probably one of the key papers that led to the claim of elo being "immunostimulatory".
http://www.ncbi.nlm.nih.gov/pubmed/24162108
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: FDA approves Empliciti (elotuzumab)
Thank you very much, Multibilly and Cheryl. I appreciate great replies such as yours with really good information. I guess I did not (and still probably do not) understand exactly what is the meaning of immunostimulatory. I still don't entirely get why elotuzumab is, and daratumumab is not, but you both gave me a lot of home work, and maybe eventually I will get it. Thanks again and good luck.
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JPC - Name: JPC
Re: FDA approves Empliciti (elotuzumab)
Thank you, Multibilly, JPC, and CherylG, for your detailed replies to my question. I've learned a lot from your replies.
One of the things that I didn't understand was how elotuzumab could target CD1 on myeloma cells and cause apoptosis, but also target CD1 on NK cells and not kill them too. After reading the abstract of the paper Multibilly and CherylG linked to, I now see that CD1 is an activating receptor on NK cells. Somehow I had not thought of that possibility. Now it all makes a little more sense to me.
And because NK cells are part of the immune system, if elotuzumab activates NK cells to work against myeloma cells, then I guess the claim of "immunostimulatory" powers for elotuzumab makes some sense.
What I'm still not clear on is how the activated NK cells know to "go after" the myeloma cells in this scenario. But I still need to read the full paper; maybe that will provide an answer (and I'll be lucky enough to understand it!). That'll be part of tomorrow's assignment.
CherylG, I had to chuckle when I read your comment, "Understanding how drugs work against myeloma is far from an exact science." My myeloma specialist, whose research specialty is immunotherapy, told me once that even "the experts" don't fully understand how Revlimid works.
We all still have a lot to learn.
Thanks again for taking the time to write your detailed and thoughtful replies. Glad my question started a little discussion about this!
Mike
One of the things that I didn't understand was how elotuzumab could target CD1 on myeloma cells and cause apoptosis, but also target CD1 on NK cells and not kill them too. After reading the abstract of the paper Multibilly and CherylG linked to, I now see that CD1 is an activating receptor on NK cells. Somehow I had not thought of that possibility. Now it all makes a little more sense to me.
And because NK cells are part of the immune system, if elotuzumab activates NK cells to work against myeloma cells, then I guess the claim of "immunostimulatory" powers for elotuzumab makes some sense.
What I'm still not clear on is how the activated NK cells know to "go after" the myeloma cells in this scenario. But I still need to read the full paper; maybe that will provide an answer (and I'll be lucky enough to understand it!). That'll be part of tomorrow's assignment.
CherylG, I had to chuckle when I read your comment, "Understanding how drugs work against myeloma is far from an exact science." My myeloma specialist, whose research specialty is immunotherapy, told me once that even "the experts" don't fully understand how Revlimid works.
We all still have a lot to learn.
Thanks again for taking the time to write your detailed and thoughtful replies. Glad my question started a little discussion about this!
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: FDA approves Empliciti (elotuzumab)
I'd be extremely curious to see Emplicit's effect with other therapies like Velcade. I'd also really love to see if it works with Revlimid-refractory patients. Maybe that will be the next clinical trial involving this?
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BeatMyeloma - Name: BeatMyeloma
- Who do you know with myeloma?: My mother
- When were you/they diagnosed?: Jan. 2008
- Age at diagnosis: 54
Re: FDA approves Empliciti (elotuzumab)
BeatMyeloma,
A phase 2 trial done comparing elo+bortezomib+dex (EBd ) versus bortezomib+dex (Bd) was already conducted and the results were presented at ASCO 2015.
http://meetinglibrary.asco.org/content/144027-156
There is also an ASH 2015 abstract describing the results:
https://myelomabeacon.org/resources/mtgs/ash2015/abs/510/
A phase 2 trial done comparing elo+bortezomib+dex (EBd ) versus bortezomib+dex (Bd) was already conducted and the results were presented at ASCO 2015.
http://meetinglibrary.asco.org/content/144027-156
There is also an ASH 2015 abstract describing the results:
https://myelomabeacon.org/resources/mtgs/ash2015/abs/510/
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
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