Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?

[poetinsf]

Why can’t we state that Ritux might have worked for a subgroup?

Such speculation is useless unless you can identify that subgroup somehow. Then you could run the trial again only on that subgroup to validate the theory. Otherwise, it's no different than saying that anything is possible. And that is how some people try to get away with failed trial.

 

[forestglip]

For the studies, are there studies that showed difference in blood vs bone marrow NK cells? They have to measure both.

For this one, frequency of total NK cells wasn't different between multiple myeloma responders and nonresponders in either bone marrow or blood.

What was different was higher proportion of CD16+ NK cells and lower TIM-3+ NK and HLA-DR+ NK cells in the bone marrow in responders. I'm not sure if they looked at the frequency of CD16+ NK cells specifically in the blood.

NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma, 2023

To this end, we compared BM [bone marrow] samples obtained from 21 responding patients (≥PR) with those from 30 nonresponding (primary refractory) patients by using flow cytometry (Figure 2A).

The proportion of NK cells was similar between both the groups.

Interestingly, nonresponding patients had higher proportions of HLA-DR+ (15.3 versus 9.3%, P = 0.043) and TIM-3+ NK cells (median 9.0 versus 5.6%; P = 0.005). In addition, nonresponders also had a lower proportion of CD16+ NK cells (73.3 versus 85.8%; P = 0.017).

Similar to what we observed in the BM samples, the baseline frequency of NK cells in PB [peripheral blood] was comparable between responding and nonresponding patients.

 

[Utsikt]

Such speculation is useless unless you can identify that subgroup somehow. Then you could run the trial again only on that subgroup to validate the theory. Otherwise, it's no different than saying that anything is possible. And that is how some people try to get away with failed trial.

Isn’t the easier answer that if you argue that ritux worked for some, then you’re also arguing that saline worked for some because the groups were identical?

 

[forestglip]

I'm not sure if they looked at the frequency of CD16+ NK cells specifically in the blood.

If I understood it correctly, this study looked at absolute count of CD16+CD56+ cells at baseline in the blood, like the ME/CFS study, and found no correlation with response to daratumumab:

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma, 2017

Total (CD16+CD56+) and activated (CD16+CD56dim, measured only in the SIRIUS study) NK cells were measured by real-time flow cytometry.

logistic regression analyses confirmed the lack of a statistically significant relationship between ORR [overall response rate] and baseline NK-cell counts (P = .76)

No significant differences in PFS [progression-free survival] were observed for baseline NK-cell counts [...] (P = .7 [...])

 

[ryanc97]

If I understood it correctly, this study looked at absolute count of CD16+CD56+ cells at baseline in the blood, like the ME/CFS study, and found no correlation with response to daratumumab:

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma, 2017

That is interesting.

I wonder if the problem is with ORR, basically they did not regress the severity level in the patient alongside the NK cell baseline?

basically more severe MM patients might have had higher levels of NK and the effect cancelled out.

 

[OrganicChilli]

It was made in the context of eveyone here assuming that CD38 was just the killing target on plasma cells. I can now see that there are reasons to question that assumption. I have emailed Oystein Fluge to see if he has considered this and what his take is.

Curious if Fluge has responded yet?

 

[Jonathan Edwards]

Curious if Fluge has responded yet?

I have not had a reply. This may be somewhat old history for him. As @MelbME pointed out CD38 being in itself a target was flagged up with his paper with Jo C some time back.

 

[Pibee]

Such speculation is useless unless you can identify that subgroup somehow. Then you could run the trial again only on that subgroup to validate the theory. Otherwise, it's no different than saying that anything is possible. And that is how some people try to get away with failed trial.

It is not clinically useless; there are many conditions where rituximab has not been proven as an effective treatment, and the subgroup for which it works is not identified, and they just give it to everyone because it still helps some %.... until they have better guns.

 

[Utsikt]

It is not clinically useless; there are many conditions where rituximab has not been proven as an effective treatment, and the subgroup for which it works is not identified, and they just give it to everyone because it still helps some %.... until they have better guns.

Do you have any examples?

 

[Jonathan Edwards]

Do you have any examples?

There are plenty of conditions for which doctors give rituximab to everyone without knowing if it works. But of course that doesn't mean it helps some % in those conditions. Whether or not it is clinically useless there is unproven. The original suggestion was useless not because we don't know the subgroups in ME/CFS but because we can be fairly confident there aren't any and nobody is going to repeat the trial so we might as well keep our speculations free of suggestions it might work

 

[Utsikt]

There are plenty of conditions for which doctors give rituximab to everyone without knowing if it works.

That’s what I figured

we might as well keep our speculations free of suggestions it might work

Agree.

 

[DHagen]

The original suggestion was useless not because we don't know the subgroups in ME/CFS but because we can be fairly confident there aren't any and nobody is going to repeat the trial so we might as well keep our speculations free of suggestions it might work

Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out? I have not been able to find one and, given the popularity of the idea among so many ME/CFS clinicians/researchers/patients (and yes, I know that can be said of all kinds of wild notions and speculation), I would be curious.

 

[Jonathan Edwards]

Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out?

The argument is simple common sense, which you can give statistical numbers to if you want.

The changes in scores seen after both rituximab and placebo were not trivial in a good number of cases. So we are not looking for a subgroup with a slight improvement. If a measly 10% of cases are responders then you would expect at least some difference between the two groups. There is a small chance it would not show up but the groups would need to be weighted quite a bit to give the completely null difference seen.

The other important argument is that any claim that there is a subgroup can only be based on some people getting quite a lot better. But people on placebo must have done to the same extent so the argument from cases is empty.

And I don't think you will find many clinicians or researchers who would be persuaded. There are always a few enthusiasts and unfortunately, in this age of social media, the enthusiasts dominate the narrative in the gossip space. Ask any intelligent clinician or researcher what they think from the results and they will say there was no evidence of a responder subgroup.

 

[DHagen]

The changes in scores seen after both rituximab and placebo were not trivial in a good number of cases. So we are not looking for a subgroup with a slight improvement. If a measly 10% of cases are responders then you would expect at least some difference between the two groups. There is a small chance it would not show up but the groups would need to be weighted quite a bit to give the completely null difference seen.

Thank you very much for the response and explanation - I believe I may have misunderstood the initial post, as I took it to indicate the absence of any ME/CFS subgroups overall, rather than with specific reference to the rituximab study. This is also useful information, however, at least for me - even if it may be merely common sense.

 

[ryanc97]

Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out? I have not been able to find one and, given the popularity of the idea among so many ME/CFS clinicians/researchers/patients (and yes, I know that can be said of all kinds of wild notions and speculation), I would be curious.

I used to believe in subgroups but I believe now with the Dara trial there are no subgroups.