Daratumumab, isatuximab (CD38 drugs)

Just wanted to put this all in one spot:

Subcutaneous Daratumumab injection schedules from Fluge’s group.

Pilot group 1 Week 0,2,8,10
Pilot group 2 0,2,4,6,14,22,30

Amendment to pilot: 0, [10], 24, 48
(Week 10 only if no response)

Phase 2 0,2,4,24,26

Based on what Fluge et al. wrote in their dara article and comments by @Jonathan Edwards that dara likely kills cells very quickly, I’d posit that the amendment protocol would be/should be effective and the most cost effective.

In the pilot there wasn’t much/any difference between the 4 and the 7 injection treatments.

Plus dara has a long half life of about three weeks.
 
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Also Fluge note that even with the high dara dosage protocols for Multiple myeloma, NK cells are not completely depleted.

They also note in their article that for other autoimmune diseases there didn’t appear to be a relationship between effectiveness and the number of dara injections.
 
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Also Fluge note that even with the high dara dosage protocols for Multiple myeloma, NK cells are not completely depleted.

They also note in their article that for other autoimmune diseases there didn’t appear to be a relationship between effectiveness and the number of dara injections.

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?
 
Scheibenbogen seems to be doggedly perservering nonetheless...

Glad to see this isa trial though. CD38 is all the rage it seems.

From her latest interview:

The most promising approaches are based on monoclonal antibodies that target the cells producing autoantibodies – in other words, B cells or plasma cells. More than ten years ago, there was already a pioneering study from Norway with the drug rituximab. Many of those treated responded well to it, and some even had lasting responses; some were even completely cured. Unfortunately, the subsequent multicenter clinical trial produced a negative result.

There were many reasons for this. On the one hand, the dosage was probably not sufficient; in addition, four of the centers had less experience and may not have included the right patients. Today there are more effective B-cell antibodies with fewer side effects. Moreover, the approach has gone a step further and now directly eliminates the plasma cells, that is, the mature B cells.

 
This is credible, I admit. Multicenter trials tend to recruit patients with little chance of response. The motivations are wrong.
Why should it matter? If the box has no eggs inside it doesn't matter whether the imaginary eggs are green or yellow?

The response was higher to placebo than to Rituximab across the different centers and in most of the individual centers. Fluge and Mella had a higher response to the placebo than most other centers and their placebo response was substantially higher than the response to the drug. In fact it is precisely Haukeland where the response to placebo is much higher than the response to the drug (40% response to placebo, 20% response to drug), so the argument is exactly the opposite. So if they selected patients correctly and all others didn't, the eggs are still non-existent, in fact they are even more rotten in imagination.
 
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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?

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).
 
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).
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?
 
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