Hepcidin-DMT1 interaction and GPRC5D-targeting bispecific antibody for MM

Summary

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Blood Podcast Episode Summary

Episode Title: Hepcidin-DMT1 Interaction and GPRC5D-Targeting Bispecific Antibody for MM
Date: March 12, 2026
Host: Dr. Laura Michaels (American Society of Hematology)

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Episode Overview

This episode explores two major topics in recent hematology research as published in Blood:

1. The efficacy and safety of talquetamab plus daratumumab in relapsed/refractory multiple myeloma (TRMM2 study), with Dr. Ajay Chari (UCSF)
2. The role of intestinal hepcidin overexpression in anemia and iron overload—mediated by DMT1 downregulation, with Dr. Marian Fallabreg (Université Paris)

The conversations combine cutting-edge clinical findings with insights into mechanisms and future research implications.

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Segment 1: Talquetamab + Daratumumab in Relapsed/Refractory Multiple Myeloma

Guest: Dr. Ajay Chari (UCSF)
Timestamps: 01:14–09:34

1. The Evolving Landscape of Myeloma Therapy

• Remarkable progress: “Patients who were going to hospice are now in stringent complete remissions off therapy... It’s a large testament to T cell redirection therapies, both CAR Ts and bispecifics.” (Dr. Ajay Chari, 01:47)
• Talquetamab is currently the only approved agent targeting GPRC5D, a transmembrane protein.
• Monotherapy outcomes: 60–70% response rate, PFS ~11 months in a heavily pretreated population.

2. Rationale for Combination Therapy

• Study explored talquetamab plus daratumumab, targeting “what do you get when you combine talquetamab with other agents?”

• Host raises a mechanistic concern about DARA’s (daratumumab) impact on T-cell activity:

  "I sort of have thought about daratumumab as sort of being anti-T cell to some extent... I wouldn’t always expect it to cooperate with something that requires T cells to work." (Podcast Host, 02:50)

• Dr. Chari addresses this:

  • While DARA does decrease certain immune cell populations, combination strategies in myeloma have historically yielded better outcomes.
  • “Do the immune activating benefits of DARA offset some of the immune suppression? And I think that’s the question being asked.” (Dr. Ajay Chari, 03:08)

3. Efficacy Highlights from the TRMM2 Study

• Impressive efficacy, even in heavily pretreated patients (median: 5 prior lines; 80% refractory to CD38)
• “To take such a heavily treated population and get such an impressive PFS of over 20 months I think speaks to... compared to 11 months.” (Dr. Chari, 04:14)
• For patients previously refractory to bispecific antibodies:
  • Monotherapy PFS drops to ~4 months, but with combo: jumps to 15 months
    • “Those differences, I think, are hard to ignore.” (Dr. Chari, 04:14)
• Emerging evidence from other studies (e.g., teclistamab + DARA) also supports synergy—especially improvement in PFS, not just response rates.

4. Unique Toxicities and Clinical Insights

• GPRC5D therapies’ unique side effects:
  • “The toxicities you raise reflect where else GPRC is expressed... particularly palms and soles of the feet, nails... diffuse rashes...” (Dr. Chari, 06:44)
  • Oral manifestations: dry mouth, dysgeusia, weight loss, difficulty swallowing
  • “Patients who had these AEs tended to have about a 20% higher response rate.” (Dr. Chari, 08:15)
    • Possibly analogous to rash-response correlations in some solid tumor immunotherapies
• Good news: Co-administration with DARA did not increase frequency of these adverse events.

5. Looking Ahead: Randomized Trials

• The Monumental-3 phase 3 trial will evaluate different combinations of talquetamab and DARA.
  • “It’s accruing well—it might have even completed accrual—so we eagerly await that.” (Dr. Chari, 09:14)

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Segment 2: Intestinal Hepcidin Overexpression, Iron Deficiency, and Iron Overload

Guest: Dr. Marian Fallabreg (Université Paris)
Timestamps: 09:39–14:55

1. Background: The ‘Gut Hepcidin’ Paradigm

• Historically, gut production of hepcidin was only loosely investigated—main data were from colorectal and immune cell contexts, not comprehensive studies.
  • “Not a lot of things known about the role of gut hepcidin. So that’s pretty new in the field.” (Dr. Falabreg, 10:06)

2. Novel Mouse Model Insights

• Dr. Fallabreg’s team developed mice overexpressing hepcidin exclusively in gut tissue.
• Findings:
  • These mice developed microcytic anemia, with iron deficiency (low ferritin and transferrin saturation). (10:48)
  • Key novelty: This anemia occurs via downregulation of DMT1 (an iron importer), not just by the established pathway of ferroportin inhibition.
  • “We showed that there is a new target for hepcidin, i.e., DMT1... This is the first time that is shown in vivo.” (Dr. Falabreg, 11:51)

3. Reciprocal Regulation Between Gut and Liver Hepcidin

• Overproduction of gut-derived hepcidin leads to lower systemic (liver) hepcidin, revealing a feedback compensation mechanism.
  • “When you don’t have enough iron in the body, the hepcidin produced by the liver is decreased to compensate to improve iron absorption. But when we have too much hepcidin in the gut, you block iron absorption despite the decrease of... liver hepcidin.” (Dr. Falabreg, 12:51)

4. Clinical Applicability: Beta-thalassemia & Hemochromatosis Models

• Oral delivery of recombinant probiotics producing hepcidin:
  • In a mouse model of hemochromatosis, this strategy reduced iron overload, suggesting potential for orally administered hepcidin therapeutics.
  • “We have a decrease of iron overload... The objective is to use hepcidin in the oral way to block iron absorption and avoid iron overload.” (Dr. Falabreg, 13:44)

5. Future Directions

• Determining the precise molecular mechanism of DMT1 inhibition by hepcidin in the gut.
• Developing safe probiotic or protein-based oral hepcidin therapies for iron overload disorders such as hemochromatosis and beta-thalassemia.
  • “Maybe after, develop safe probiotics [or] protein hepcidin as new therapeutic tools for treating hemochromatosis...” (Dr. Falabreg, 14:34)

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Notable Quotes and Highlights

• On Myeloma Treatment Advances:
  • “Such an exciting time to be in myeloma. Patients who were going to hospice are now in stringent complete remissions off therapy...” (Dr. Chari, 01:47)
• On Gut Hepcidin Novelty:
  • “We showed there is a new target for hepcidin, i.e., DMT1... This is the first time that is shown in vivo.” (Dr. Falabreg, 11:51)
• On Clinical Potential:
  • “...Objective is to use hepcidin in the oral way to block iron absorption and avoid iron overload. That is really the point in hemochromatic disease.” (Dr. Falabreg, 13:44)

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Key Timestamps

• 01:47: Dr. Chari outlines recent advances in myeloma therapy
• 04:14: Discussion of PFS improvements with talquetamab + DARA, even in bispecific-refractory patients
• 06:44: Unique cutaneous and oral toxicities of GPRC5D-targeted therapy explained
• 09:14: Monumental-3 phase 3 trial and future directions for combo therapy
• 10:48: Dr. Falabreg summarizes the knockout mouse model findings
• 11:51: Discovery of DMT1 as a new in vivo target for gut hepcidin
• 13:44: Use of probiotic-produced hepcidin to prevent iron overload

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Summary

This episode delved into promising combination bispecific antibody therapies for difficult-to-treat multiple myeloma and introduced pioneering work on the role of gut hepcidin in iron metabolism. Listeners gained insight into both the mechanistic and translational aspects of these advances, with clear implications for future therapies in hematology.

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Transcript

[Dr. Laura Michaels]

Welcome to the American Society of Hematology Conversations with Blood Authors Podcast. This episode is hosted by Dr. Laura Michaels. She discusses talquetamab daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRMM2 study with Dr. Ajay Chari. She also discusses intestinal hepcidin overexpression, promotes iron deficiency anemia and counteracts iron overload via DMT one down regulation with with Dr. Marian Fallabreg,

[Podcast Host]

I'm happy to welcome Dr. Ajay Chari of the University of California, San Francisco, who's speaking on behalf of his research team on the clinical trial of Tachetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRMM2 study.

[Interviewer for Dr. Marian Fallabreg]

We'll also welcome Dr. Marion Falabreg from the Universite Paris to discuss the work that she and colleagues have done on intestinal hepcidin overexpression, promoting iron deficiency anemia and counteracting iron overload via DMT1 downregulation.

[Podcast Host]

Dr. Chiari, thank you so much for joining. We're going to talk today about your research and the publication here on the TRIM2 study for the Phase 1B study for relapsed refractory myeloma using talquetamab and daratumum. Thank you so much for this work. I'm also really interested in myeloma. In particular, maybe you could just describe the environment in which this study was done following the monotherapy publication on this bispecific antibody.

[Dr. Ajay Chari]

Such an exciting time to be in myeloma. I think literally in the last five years. Patients who were going to hospice are now in stringent complete remissions off therapy and some of the most durable remissions they've had. And it's a large testament to T cell redirection therapies, both CAR Ts and bispecifics. So talquetamab is the only approved agent so far targeting a protein called GPRC5D, which is a transmembrane protein. And the monotherapy showed a response rate in the 60 to 70% and a PFS of almost 11 months. And there were two different dosing schedules approved but the one that we're using is every two months weeks to have a 70% response rate lasting 11 months in triple class refractory. So we're talking PI IMID CD38 I think is amazing. But I think of course the question comes can we do better and how do combination therapies fare? And that's really what this study was about is what do you get when you combine talquetamab with other agents? And this particular cohort is looking at the combination with daratumumab.

[Podcast Host]

Why would there be synergy with daratumumab and a bispecific antibody? I sort of about daratumumab as sort of being anti T cell to some extent. And so I wouldn't always ask it to cooperate with something that requires T cells to work in order to be effective.

[Dr. Ajay Chari]

That's a great point. I think CD38 is obviously overexpressed on myeloma cells, but also expressed on many other parts of the immune system, including T cell, both factor and regulatory cells, but also NK cells. So sometimes you do see with daratumumab a decrease in the total counts or nk. But we also have to keep in mind that that may not completely represent what's happening in the patient. So, for example, you may see CD38 expression gone very quickly, but you still see deepening of responses. But I think here the reason, of course, in myeloma and in all diseases, we've seen that combination strategies work, but I think the proof is always in the pudding. And also, of course, we have to think about safety as well. But I think the thought here specifically is if you think about the pros versus the cons, do the immune activating benefits of DARA offset some of the immune suppression? And I think that's the question being asked.

[Podcast Host]

But it seemed like it did based on the fact that 80% of the population here was already DARA exposed or even progressed after dara. Correct.

[Dr. Ajay Chari]

I'm glad you said that, because I think so. It's always hard to interpret combination studies when you have a single arm. Right. And I think that's always a critical criticism of science. If A plus B looks good, how do you know it's better than A followed by B or something else? And I think you hit it on the head. The fact that this is a median of five lines of prior therapy, the fact that 80% of these patients were refractory to CD38 tells us that it's unlikely that giving these patients more DARA would have done much right. And to take such a heavily treated population and get such an impressive PFS of over 20 months I think speaks to compared to 11 months. Now, again, we need a randomized phase three study to confirm, but lemon versus 20 months is not something you would normally see by chance alone. I would say an even bigger pressure test is what happens in the prior bispecific patients. Because what we know for the monotherapy with talquetamab is that yes, the overall pfs with every 2 week dosing was 11 months, but if you had prior bispecific, it was actually about four months. This is despite target switch, right? Because many of these patients would have had BCMA targeting bispecific and switched to gprc. And, and you would think, oh, we're switching targets, it should be fine. But I think that data shows how much T cell exhaustion can impact even a new target. And here in that cohort of patients, admittedly it's about a quarter of the population, so and the overall population is about 60 patients. But these patients who are bispecific refractory had a PFS of 15 months. So I think 15 versus 4 for bispecific refractory, 21 versus 11 for the overall population. Those differences I think are hard to ignore. Maybe we can talk more. But we also now have some additional data sets that were super exciting at ASH and beyond about another bispecific teclistamab and those combinations with dara. When you, I think, interpret all of these data sets in their entirety, it does seem like CD38 addition to bispecific is improving efficacy. And particularly it's not so much the response, it's the pfs. And that's what we really care about.

[Podcast Host]

So I'm really interested in some of the unique toxicities with the GPRC agents. We had a talk recently here about a CAR T with that as a, as a target and this toxicity of nails and the dyscusia, can you eliminate what you guys saw in your study with that?

[Dr. Ajay Chari]

Luckily, because these toxicities with GPRC are so unique, they don't overlap with other myeloma agents. So you can combine these agents very easily. And I think that's an important point because bcma, which is perhaps there's more agents approved for bcma. The challenge with that target is it's very immunosuppressive and you literally can take somebody's immunoglobulin and make it zero and stay zero. You, even after you stop a BCMA bispecific with talquetamab, you don't see that. You actually see in responding patients, you see an improvement in immunoglobulins, you don't see that infection signal. And so we think that's because GPRC is probably more expressed on malignant plasma cells than normal plasma cells and less so even the more immature components of the ontogeny of B cell development. So you really restrict it to these malignant plasma cell. However, the toxicities you raise reflect where else GPRC is expressed. Okay, so it's restricted to malignant plasma cells, but also heavily keratinized tissues. So skin, particularly palms and soles of the feet, nails, and overall, you can have diffuse rashes. So there's a cutaneous component to this, and then there's also an oral component to this, which we don't completely fully understand because GPRC is expressed in some papillae of the tongue, but those parts of the tongue actually don't mediate taste. One hypothesis that maybe what we're seeing is GPRC is being expressed in maybe some of the resident plasma cells in those areas. And because of that density, we're seeing some bystander effect. But we do see dry mouth, difficulty swallowing, weight loss, and decrease in taste. So I would say there's the skin. The nails are also heavily keratinized. So skin, nails and oral tox, and those are quite common. The additional comment I would say about this is that we saw in the monotherapy, patients who had these AES tended to have about a 20% higher response rate. This may be one of those things that we don't normally see in hematology as maybe as much as solid tumor, where you get a rash and it correlates with response. It's not to say that you get an AE and you will have a response. If you don't, you won't respond. But Statistically, there's a 20% higher likelihood of having a response if you have one of these on target off tumor AES. And in this combination study, we did not see an increase in the frequency of those AES in combination.

[Interviewer for Dr. Marian Fallabreg]

Interesting. And is this headed to a randomized trial? I think I read that there is a randomized trial based on the original study, the monotherapy study.

[Dr. Ajay Chari]

Yeah. So there's Monumental 3, which basically has DPD, Darapom Dex, or Darapom decks with talquetamab, or just Dara and talquetamab. So we're looking at those three arms and Monumental three. We're hoping for a readout. It's accruing well, it might even completed accrual. So we eagerly await that.

[Podcast Host]

Great, very exciting studies that we talked about today. Thank you very much for your time.

[Interviewer for Dr. Marian Fallabreg]

Dr. Falabre. Thank you so much for joining. Very interested in the work that you and your colleagues did on this sort of new conception of hepcidin, especially hepcidin produced in the gut. I wonder if you could start off by just telling myself and the audience a little bit about what was known about gut produced hepcidin prior to your investigations.

[Dr. Marian Fallabreg]

Good question. Thanks for the invitation. But what we know before the Howard study is that in different pathology, in colorectal path, colon concept, there is a production of epcidin by the dendritic cells, can help the immune cells to contract the cancer, but not a lot of things new about the role of cut epcidine. So that's pretty new in the field.

[Podcast Host]

Maybe you can describe a little bit about your initial investigations and the development of the mouse model to better explore gut hepcidin and what were some of the surprise discoveries in the literature.

[Dr. Marian Fallabreg]

We saw that in the gut hepcidine can be produced in the gut in condition of pathogenic conjugal inflammation or infection. And so to understand the role of hepcidine in the gut, we generate a knocking mouse for hepcidins, specifically in the gut. And that's a strategy to see the role of epsodin in different organs. In our lab and in this mouse we observed the microcytic anemia with iron deficiency observed by the decrease of blood ferritin and transflin saturation in our mouse model. So that's this new point that we discover.

[Podcast Host]

So the mice, the knock in mice develop iron deficiency when they overexpress the hepcidin in the gut. Yes, that's how I understood it. And it looks like they do it by interacting with the DMT1 gene rather than through ferroportin. Is that correct?

[Dr. Marian Fallabreg]

Yes, surprisingly so. Ferroportin is the only target new for epcidine. It's an iron exporter. It's the only iron exporter. And we saw in our work that epcidine can produce in the lumen of second and targets DMT1, which is the importer of iron to absorb iron from the lumen to the blood for the body. So we showed that there is a new target for epicidine I.e. dMT1. But some studies propose this mechanism by in vitro or ex vivo study. This is the first time that is shown in vivo study.

[Podcast Host]

I thought that was very interesting. I also thought it was interesting that the overproduction of gut hepcidin appeared and maybe I got this wrong, but appeared to decrease the systemic liver production of hepcidin in the mice. Like it would toggle it back and forth. Is that right?

[Dr. Marian Fallabreg]

Yes, because when you don't have enough iron in the body, the hepcidin produced by the liver is repress, is decreased to compensate to improve iron absorption. But when we have too much epsidine in the gut, you block iron absorption despite the decrease of the good response of the liver that decreases hepcidin production.

[Podcast Host]

So not only did the work that you and your colleagues do demonstrate this new interaction of gut hepcidin and its target, but you also investigated how that might be clinically applicable, Right? In the second part of your study, maybe you could describe to the audience about the way it might be clinically applicable to patients with either beta thalassemia or hemochromatosis.

[Dr. Marian Fallabreg]

In order to evaluate the ability of epcidine present in the intestinal lumen to prevent iron overload in a mouse model of hemochromatosis, we choose to use the probiotics to produce this. Epsilon is a recombinant lactic acid strain. And after one month of treatment, when we treat our early hematop mice with this recombinant probiotic, we have a decrease of iron overload by trace. And the objective is to use hepcidine in the orally way to block iron absorption and avoid iron overload. That is really the point in hemochromatic disease.

[Podcast Host]

That's so interesting. And where do you want to take this research next? What are the next questions you'll be asking?

[Dr. Marian Fallabreg]

The first is understand the molecular Mechanism of the DMT1 inhibition by epcidin in the gut and maybe after they follow safe probiotics, protein epcidin as new therapeutic tools for treating hemochromatosis or erythropoiesis. Iron overload disorder.

[Podcast Host]

That's fascinating. Thank you so much for explaining this study, which I really found remarkably interesting and really great work. Thank you.

[Dr. Marian Fallabreg]

Thank you.

[Podcast Host]

This concludes our podcast. We of course thank both our authors today and invite everyone to check out this week's Blood with the Studies.

[Dr. Laura Michaels]

Thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.