The bone marrow NK-cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy, Korst et al. 2025

[Jaybee00]

Key Points​

• A reduced proportion of CD16+ bone marrow NK cells at diagnosis was associated with decreased daratumumab-mediated NK-cell degranulation.
• Reduced BM CD16+ NK-cell proportion was associated with reduced likelihood of achieving MRD negativity upon daratumumab-based therapy.

Abstract
Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry, and functional assays to investigate the bone marrow NK-cell compartment of patients with MM at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK-cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving measurable (or minimal) residual disease (MRD) negativity after consolidation in patients treated with daratumumab, bortezomib, thalidomide, and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial. In contrast, NK-cell distribution did not predict MRD negativity in patients treated in the control arm without daratumumab. These findings highlight the impact of the bone marrow NK-cell compartment on therapeutic outcomes in patients with MM receiving immunotherapy with CD38-targeting antibodies.

https://ashpublications.org/blood/article/145/25/3007/535791/The-bone-marrow-NK-cell-profile-predicts-MRD

Commentary

A natural head start to MRD negativity in multiple myeloma​

https://ashpublications.org/blood/article/145/25/2936/537727/A-natural-head-start-to-MRD-negativity-in-multiple

 

[forestglip]

We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK-cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving measurable (or minimal) residual disease (MRD) negativity after consolidation in patients treated with daratumumab, bortezomib, thalidomide, and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial.

Nice find. From daratumumab for ME/CFS:

Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

Low baseline NK-cell count in blood was associated with lack of clinical response.

Plot of baseline NK count vs improvement from video posted here.

 

[Turtle]

That could mean even if there is treatment available it won't be successful in me, because of very low NK-cells

 

[V.R.T.]

That could mean even if there is treatment available it won't be successful in me, because of very low NK-cells

Perhaps that is true if Daratumumab works but it may well point the way to other treatments with a different mechanism that are more universally effective.

 

[forestglip]

Similarly:

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

Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment.

At baseline, nonresponding patients had a significantly lower proportion of CD16+ and granzyme B+ NK cells, and higher frequency of TIM-3+ and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR.

We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing.

 

[Turtle]

Perhaps that is true if Daratumumab works but it may well point the way to other treatments with a different mechanism that are more universally effective.

Maybe in how many years?
It would also block monoclonal antibody treatment JE wrote about.
I was once offered a DNA-test because there was a suspicion of a monoclonal T-cell population, the lab did not have enough blood tot test right away. Blood draws are often problematic. I asked my GP if the lab did find something could it be treated. He answered : No.
So I declined testing: why bother.
Maybe I would have taken that test now, having a little more knowlegde.

 

[V.R.T.]

Maybe in how many years?
It would also block monoclonal antibody treatment JE wrote about.

'In how many years' is the pressing question about all this no one can answer it seems .

Would it also block the monoclonals? Damn I didn't realise that.

 

[OrganicChilli]

Perhaps that is true if Daratumumab works but it may well point the way to other treatments with a different mechanism that are more universally effective.

Other mabs? That we already have maybe? And if not how long would it take to develop a new one from scratch?

It would also block monoclonal antibody treatment JE wrote about.

Why would it block monoclonals?

 

[V.R.T.]

Other mabs? That we already have maybe? And if not how long would it take to develop a new one from scratch?

JE has said a few times that there may be repurposeable mabs that will do the trick. I think it depends entirely on what drug targets come to light. For example yesterday:

If our proposal on Qeios is right then re-balancing T cell populations ought to return the system to normal. If the rogue T cells are an overexpanded CD4 cyttoxic population then a single dose of the right monoclonal antibody might sort that in a couple of hours. But clearly things are complicated, with various possibilities, some of which might require longer term treatment until we have the right technology.

As for developing a new one, here is JEs best case scenario from a while back. I think the broad point is that if pharma sees dollar signs they may accelerate development to warp speed. Of course if they walk a new drug through at normal pace it could be an eternity.

The very best thing would be that DecodeME would find a link to some very obscure but crucial control protein - let us say TWEAK (it exists). Suddenly we would realise that ME/CFS might be mediated by short range interaction between TWEAK and gamma-interferon sensitising nerve endings. The task is then to produce a specific TWEAK antagonist that competed for the interferon binding site. Setting up assays for competitive inhibition of binding might take 3-6 months I guess - assuming that either a drug company or a TWEAK biology lab had the wherewithal to get going as soon as the paper is read. I don't know how long it would take to synthesise candidate small molecular mass inhibitors (simple drugs) but I think these days much of that is streamlined. The task would be similar to the generation of protease inhibitors for AIDS, which was quite quick once the target was known. If the choice was to make a monoclonal antibody to do the job you just clone out antibodies with high binding, make some cDNA and go into production. I may be oversimplifying but the biotech people do all sorts of things very quickly these days.

To make the scenario even better we could make it that it was realised that this TWEAK pathway was a key factor in 'malaise' associated with all sorts of illnesses and post-surgery and whatever and looked a really good target for a drug with wide applicability. Lots of research groups would get on to it and just like the Covid vaccines you would have a product made by several in no time at all (under 2 years). Roll-out to clinical use, if the drug was really effective, could be six months, with two phase 3 trials in parallel and accelerated approval.

That is optimistic, but the main point is that once the companies have seen something as profitable they can get it through to the clinic pretty quick. There might even be repurposable monoclonals - similar to rituixmab - but which actually work.

I'm not a scientist so don't take my word for it, I'm just quoting (and hopefully not misquoting) what I've read on here.

 

[Jonathan Edwards]

Why would it block monoclonals?

NK cells can mediate cell clearance using a monoclonal drug but there are other pathways like complement so it isn't a 'block'.