Daratumumab, isatuximab (CD38 drugs)

ryanc97 said:
If you look at the NK cell plots for the pilot study a few of them had NK cells go to almost 0 after the first dose.


Is this because ME patients have lower NK than MM patients?
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Chat GPT says MM patients in active disease have low NK cells. I am guessing lots of injections are needed in MM because a lot of cells are tied up in various tumors.


  • Active multiple myeloma:
    • NK cell numbers often decrease compared to healthy people.
    • Function is impaired: the NK cells that remain are less effective at killing myeloma cells because:
      • Myeloma cells shed ligands that block NK cell activating receptors.
      • The bone marrow environment becomes immunosuppressive (lots of T-regs, myeloid-derived suppressor cells, cytokines like TGF-β).
      • Chronic stimulation leads to NK cell “exhaustion.”

  • After treatment (esp. with daratumumab):
    • Daratumumab depletes CD38+ NK cells (since NK cells also express CD38).
    • This sounds bad, but paradoxically it helps restore a healthier immune environment, because daratumumab also removes suppressive CD38+ regulatory cells and allows T cells to rebound.
    • NK cell function can partially recover during remission or after immune-boosting therapies (like lenalidomide).
 
Jaybee00 said:
Chat GPT says MM patients in active disease have low NK cells. I am guessing lots of injections are needed in MM because a lot of cells are tied up in various tumors.


  • Active multiple myeloma:
    • NK cell numbers often decrease compared to healthy people.
    • Function is impaired: the NK cells that remain are less effective at killing myeloma cells because:
      • Myeloma cells shed ligands that block NK cell activating receptors.
      • The bone marrow environment becomes immunosuppressive (lots of T-regs, myeloid-derived suppressor cells, cytokines like TGF-β).
      • Chronic stimulation leads to NK cell “exhaustion.”

  • After treatment (esp. with daratumumab):
    • Daratumumab depletes CD38+ NK cells (since NK cells also express CD38).
    • This sounds bad, but paradoxically it helps restore a healthier immune environment, because daratumumab also removes suppressive CD38+ regulatory cells and allows T cells to rebound.
    • NK cell function can partially recover during remission or after immune-boosting therapies (like lenalidomide).
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I mean here with CFS we are hoping to get away with a single shot. Meanwhile MM patients are taking like 14 shots of it?
 
OrganicChilli said:
From the Fatigatio live stream today: Carmen Scheibenbogen says they have secured funds to trial Isatuximab (she mentioned a CD38 depleting drug from Sanofi and there's only one).

She says Sanofi are interested in cooperating based on recent results.

Edit: Updated video at 23:50

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I found it notable that her slide shows the trial (AIM-ME) starting early-to-mid 2026.

Might be a bit ambitious, especially if they are waiting for the CD19/20 funding.
 
fst said:
I found it notable that her slide shows the trial (AIM-ME) starting early-to-mid 2026.

Might be a bit ambitious, especially if they are waiting for the CD19/20 funding.
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That does sound very ambitious. If it wasn't for her apparantly saying they want to start at the same time I'd say that meant they were starting AIM ME before PIONEER. Which frankly sounds like a better plan than stalling until the CD19/20 trials can go ahead.
 
V.R.T. said:
That does sound very ambitious. If it wasn't for her apparantly saying they want to start at the same time I'd say that meant they were starting AIM ME before PIONEER. Which frankly sounds like a better plan than stalling until the CD19/20 trials can go ahead.
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I agree. However, she explicitly says they want to do it in parallel. This doesn't necessarily imply exact same starting date to me, but probably funding for both arms first. So i don't think plans have changed.
 
fst said:
However, she explicitly says they want to do it in parallel. This doesn't necessarily imply exact same starting date to me, but probably funding for both arms first.
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Why don't they start with AIM-ME asap? Is there an advantage to doing everything at the same time in terms of resources or recruitment?
 
OrganicChilli said:
Why don't they start with AIM-ME asap? Is there an advantage to doing everything at the same time in terms of resources or recruitment?
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I am baffled by this. Why anchor a funded trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
 
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V.R.T. said:
I am baffled by this. Why anchor a trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
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Weirdly, AIM-ME has gained no traction on social media. German patients are normally up in arms about lack of government funding, but now that funding is available and a researcher is blocking progress, everyone's quiet. Maybe people missed the announcement?
 
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V.R.T. said:
I am baffled by this. Why anchor a funded trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
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Combination therapy, or control group maybe? I haven't really thought this through, but it could be an interesting approach. I assume the experience of being administered either drug A or B would be less distinguishable.
 

Effect of daratumumab on normal plasma cells, polyclonal immunoglobulin levels, and vaccination responses in extensively pre-treated multiple myeloma patients - PMC

pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

In conclusion, our data show that daratumumab reduces the frequency of normal PC, which is reflected in reduced levels of polyclonal IgA, IgE and IgM upon initiation of daratumumab treatment. However, our data also demonstrate that a proportion of normal PC persists during daratumumab treatment, which may be related to downregulation of CD38 on their cell surface. These resistant, normal PC are likely responsible for the stable levels of polyclonal IgG during treatment. The recovery of polyclonal IgM and IgE to baseline levels, as well as the generation of protective IgG antibodies following vaccination during daratumumab therapy, to a similar extent as observed in daratumumab-naïve patients, indicates that B cells can differentiate into PC during daratumumab treatment, which is in contrast to data obtained from vaccination studies with B-cell-depleting therapies such as rituximab.<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7271608/#b15-105e302">15</a> We therefore recommend routine vaccination, also in patients undergoing daratumumab treatment, to reduce infection-related morbidity and mortality. Furthermore, daratumumab-treated patients with low IgG levels and recurrent infections may benefit from IgG replacement therapy.
 
Jaybee00 said:

Effect of daratumumab on normal plasma cells, polyclonal immunoglobulin levels, and vaccination responses in extensively pre-treated multiple myeloma patients - PMC

pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

In conclusion, our data show that daratumumab reduces the frequency of normal PC, which is reflected in reduced levels of polyclonal IgA, IgE and IgM upon initiation of daratumumab treatment. However, our data also demonstrate that a proportion of normal PC persists during daratumumab treatment, which may be related to downregulation of CD38 on their cell surface. These resistant, normal PC are likely responsible for the stable levels of polyclonal IgG during treatment. The recovery of polyclonal IgM and IgE to baseline levels, as well as the generation of protective IgG antibodies following vaccination during daratumumab therapy, to a similar extent as observed in daratumumab-naïve patients, indicates that B cells can differentiate into PC during daratumumab treatment, which is in contrast to data obtained from vaccination studies with B-cell-depleting therapies such as rituximab.<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7271608/#b15-105e302">15</a> We therefore recommend routine vaccination, also in patients undergoing daratumumab treatment, to reduce infection-related morbidity and mortality. Furthermore, daratumumab-treated patients with low IgG levels and recurrent infections may benefit from IgG replacement therapy.
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Polyclonal IgG levels remained unchanged, which may be explained by a subset of normal PC with reduced CD38 expression that survived during daratumumab therapy.

That is a pretty striking finding. It seems to suggest that if daratumumab has any efficacy in ME/CFS it is not due to killing plasma cells!
 
Jaybee00 said:
Jaybee00 said:
But IGG did go down in Fluge et al.
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Someone who took the time to look at the paper (unlike me) has pointed out the baseline IGG was low due to pretreatment.
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I wondered that. So things do not necessarily go as pear-shaped as it seemed.
But resistant plasma cells are perhaps most likely to be the long lived bone marrow ones. So Fluge and Mella may just have killed the easy short lived ones that rituximab depletes. Ritux does tend to produce falls in IgM and IgA but not much in IgG.
 
Jonathan Edwards said:
I wondered that. So things do not necessarily go as pear-shaped as it seemed.
But resistant plasma cells are perhaps most likely to be the long lived bone marrow ones. So Fluge and Mella may just have killed the easy short lived ones that rituximab depletes. Ritux does tend to produce falls in IgM and IgA but not much in IgG.
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I mean, the drop with daratumumab was much higher than it ever happens from ritux so no, he didn't kill off only those, his IgG fell 54% in responders.
I think LLPC in the tissues like in Sjogrens in salivary glands are even more resistant than those in BM, at least based on the data from teclistamab, where IgG falls to < 4g/L for all autoimmune patients (n=4), regardless of the baseline which is interesting to me, but SSA, SSB were falling much less sharply, I think it was 80% for IgG vs 20% for SSA, or so, ... that might be concerning for autoimmune, I don't know if Sjogrens is exception there.

btw. I remember we were discussing this for SLE dual BCMA-CD19 CAR-T data, where Ro60 and Ro52 were very slow to fall, unlike other antibodies, you said it's a lab artifact, but it seems to be a pattern with other drugs as well, so I guess it is about the nature of LLPC produced in salivary gland, more protected in the niches, harder to access by drugs. It still went to 0 with CAR-T but I don't know is it really possible to clear all...
 
Pibee said:
I mean, the drop with daratumumab was much higher than it ever happens from ritux so no, he didn't kill off only those, his IgG fell 54% in responders.
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It isn't that simple. Dara kills the plasma cells. Ritux just prevents replacement. Some people on rituximab, although a small minority, do get deep IgG depletion on a single dose. I know because I was the first to do this in large numbers for autoimmunity. Moreover, if you repeat rituximab four or five times a substantial number get significant IgG depletion. The effect from dara is clearly more direct and a bit more powerful but I think we have to assume that there is a potential reservoir of dara resistant cells.
 
Jonathan Edwards said:
It isn't that simple. Dara kills the plasma cells. Ritux just prevents replacement. Some people on rituximab, although a small minority, do get deep IgG depletion on a single dose. I know because I was the first to do this in large numbers for autoimmunity. Moreover, if you repeat rituximab four or five times a substantial number get significant IgG depletion. The effect from dara is clearly more direct and a bit more powerful but I think we have to assume that there is a potential reservoir of dara resistant cells.
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I thought it was well known that there is a reservoir of daratumumab-resistant cells. And the average IgG drop with rituximab isnt 54%


You said it here: CAR-T thread
Johnathan Edwards: That looks like a calibration artefact to me. You have to be ever so careful about cross-calibrating these assays.
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