Review Mechanisms of resistance to daratumumab in patients with multiple myeloma, 2024, Iversen

hotblack

hotblack

Senior Member (Voting Rights)
Mechanisms of resistance to daratumumab in patients with multiple myeloma

Iversen KF

Abstract
Multiple myeloma (MM) is an incurable cancer in the bone marrow. The treatment of MM has developed significantly during the last 20 years, which has resulted in increased survival. Daratumumab is the first CD38 antibody approved for the treatment of MM. It has improved the treatment of MM even further. This is an evaluation of the modes of action of daratumumab and a description of the development of resistance with a focus on inhibitory checkpoint receptors on CD8+ T-cells, complement activation and extracellular vesicles.

Plain English Summary
Multiple myeloma (MM) is an incurable cancer in the bone marrow. The treatment of MM has developed significantly during the last 20 years, which has resulted in increased survival. Chemotherapy dominated the treatment landscape two decades ago, but it has been outpaced by immunotherapy. Daratumumab is the first CD38 antibody approved for treatment of MM. It has improved the treatment of MM even further. This is an evaluation of the modes of action of daratumumab and a description of the development of resistance with focus on how daratumumab interacts with different parts of the immune system.

Link (Basic Clin Pharmacol Toxicol)
https://doi.org/10.1111/bcpt.14054
 
This recent paper has a good overview of usage of daratumumab in multiple myeloma including methods of action, with the main focus on resistance to treatment, either primary (no effect at all) or acquired (initial effect but resistance to treatment later evolves). Four areas are covered. Complement, T Cells, NK Cells and Extracellular Vesicles

Not sure how much I understand or what to make of it tbh, there’s a lot in there. But could be a good reference for helping understand why daratumumab may not work for some people with ME/CFS.
 
Really interesting, thanks @ryanc97

Link to the full paper

From a quick scan… a few bits that stood out to me

Primary resistance to daratumumab is associated with a higher percentage of TIM-3+ and HLA-DR+ NK cells, and lower proportion of CD16+ NK cells in the BM
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Daratumumab resistance is associated with increased proportion of NK cells expressing inhibitory receptors and decreased proportions of CD16+ NK cells
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And that daratumumab itself changes that makeup

Rapid induction of phenotypic changes in NK cells by daratumumab treatment
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Daratumumab-induced NK cell activation results in downregulation of CD16 and upregulation of TIM-3 and HLA-DR
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In closing they say
In conclusion, primary daratumumab resistance can be explained in part by an exhausted NK cell phenotype. Furthermore, next to NK cell depletion, NK cell exhaustion may also contribute to acquired daratumumab resistance. Our data support ongoing studies, which are evaluating the value of adoptive NK cell therapy in combination with a CD38-targeting antibody.
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This seems to indicate the characteristics or quality of the NK cells as much as the quantity is important, especially for primary rather than acquired resistance?

I don’t think we had this level of detail on NK cell populations from F&M did we?
 
Yeah, there’s bound to be some differences in context. But if daratumumab ends up being the real deal and we can leverage all that work and research to help efficacy for ME/CFS that would be great. Understanding the complete mechanism involved would help.
 
Utsikt said:
What’s the purpose of dara for MM, and how does that compare to what we think we might be trying to achieve with dara for ME/CFS?
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I think the first bit is that CD38 is expressed on MM cells, and by blocking it some of the proliferation processes are aborted or attenuated. But of course cancers (and maybe people's own immune responses?) may eventually learn to nullify the effect of treatment.

The second bit I don't know, except that it's possible CD38 cells are in some way involved in perpetuating the doom loop we're stuck in. If daratumumab works and the improvements are sustained, it'll strengthen the evidence for that...though it might not tell us how they're involved and whether or not they're the most important target.
 
Kitty said:
I think the first bit is that CD38 is expressed on MM cells, and by blocking it some of the proliferation processes are aborted or attenuated. But of course cancers (and maybe people's own immune responses?) may eventually learn to nullify the effect of treatment.

The second bit I don't know, except that it's possible CD38 cells are in some way involved in perpetuating the doom loop we're stuck in. If daratumumab works and the improvements are sustained, it'll strengthen the evidence for that...though it might not tell us how they're involved and whether or not they're the most important target.
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MM is a cancer of plasma cells and Dara kills plasma cells. Simple
 
ryanc97 said:
MM is a cancer of plasma cells and Dara kills plasma cells. Simple
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Yeah, it’s covered in the paper, but I’ll try to expand on this a bit.

Daratumumab is a CD38 antibody, so binds to CD38.
CD38 is found on many immune cells but is particularly highly expressed on multiple myeloma cells. When it binds to them it can have various effects including
- tagging that cell to be attacked by NK cells (antibody-dependent cell-mediated cytotoxicity or ADCC)
- helping macrophages to engulf and eat the cell (antibody-dependent cellular phagocytosis ADCP)
- or by activating the complement system to punch holes in the cell (complement-dependent cytotoxicity CDC)

Due to effects on other CD38 expressing cells it may modify the overall immune environment, changing populations of other immune cells so changing how they interact with the myeloma cells.
It may also modify cell adhesion so weaken myeloma cells by reducing their bonds to supporting cells in the bond marrow.
And it may also reduce mitochondria transfer which can be used by myeloma cells to take energy from nearby cells.
(Hopefully that’s a fairly accurate summary)

So it may be best to say daratumumab binds to CD38 which is highly expressed on multiple myeloma cells and causes them to be killed or otherwise degrades them. It does not kill anything directly.

There seems to be other roles for CD38, some of which may be applicable to ME/CFS. It can change calcium signalling for example.

Utsikt said:
What’s the purpose of dara for MM, and how does that compare to what we think we might be trying to achieve with dara for ME/CFS?
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What we think we’re trying to achieve with it in ME/CFS is I think the big question, certainly the big question I have. I don’t think we know for sure. Others may disagree, but AFAIK there is no cohesive mechanistic theory here beyond ‘reduce long lived plasma cells’ with this sometimes being linked to reducing autoantibodies and other times some signalling theory.

If it works we’ll likely understand more about ME/CFS but even if it works I think they’ll have to be some thinking about exactly how and why. As there still is for how and why it works for multiple myeloma.
 
hotblack said:
What we think we’re trying to achieve with it in ME/CFS is I think the big question, certainly the big question I have. I don’t think we know for sure. Others may disagree, but AFAIK there is no cohesive mechanistic theory here beyond ‘reduce long lived plasma cells’ with this sometimes being linked to reducing autoantibodies and other times some signalling theory.

If it works we’ll likely understand more about ME/CFS but even if it works I think they’ll have to be some thinking about exactly how and why. As there still is for how and why it works for multiple myeloma.
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Thank you for explaining!

Assuming Dara actually works for ME/CFS, are we even sure it’s through cytotoxicity? Can Dara affect cells without getting them killed indirectly?
 
Utsikt said:
Thank you for explaining!

Assuming Dara actually works for ME/CFS, are we even sure it’s through cytotoxicity? Can Dara affect cells without getting them killed indirectly?
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I hope it’s all or mostly correct!

Yes, it can do things without killing cells, like the calcium, signalling and metabolic transfer changes I mentioned (see the wikipedia page for more info).

But I don’t know about ME/CFS. It’s probably unlikely these other effects would be the sole route of action, I guess it could be, but some sort of killing of immune cells seems likely to be important. But equally I can imagine that it’s more than just the killing of immune cells that is relevant. That’s all just my speculation though.
 
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