Breakthroughs in Multiple Myeloma Treatment and Von Willebrand Disease Mechanisms

Summary

Blood Podcast Episode Summary

Podcast: Blood Podcast – Conversations with Blood Authors
Host: American Society of Hematology
Episode: Breakthroughs in Multiple Myeloma Treatment and Von Willebrand Disease Mechanisms
Date: October 23, 2025
Moderator: Dr. James Griffin

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Overview

This episode explores two recent studies published in Blood:

1. The feasibility and safety of using the bispecific antibody talquetamab as bridging therapy before BCMA-targeted CAR T-cell therapy in relapsed/refractory multiple myeloma.
2. The discovery of impaired exocytosis as a novel cause of Type 1 von Willebrand disease via biallelic mutations in the MADD (MEDI) gene, offering new insight into the disease mechanism.

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1. Talquetamab as Bridging Therapy Before CAR T in Multiple Myeloma

Guest: Dr. Benad Dakal (Medical College of Wisconsin)
(Discussion: 00:31–13:33)

Background & Motivation

• Need for Bridging Therapy: BCMA-targeted CAR T therapies (Cilta-cel, Ide-cel) offer transformative outcomes for multiple myeloma but require a 6-8 week manufacturing process. During this period, 10-15% of patients, especially those with aggressive disease, do not survive to receive the therapy.
• Challenge: There is a need for an effective and safe intervention to bridge patients during CAR T manufacturing without compromising subsequent CAR T efficacy.
• Talquetamab, a GPRC5D-targeting bispecific antibody (non-BCMA), was recently approved and shows promise in patients after multiple prior therapies.

Key Data on Talquetamab as Single Agent

• Trial Data: In the MonumenTAL-1 trial, talquetamab demonstrated an overall response rate (ORR) of ~70% in heavily pretreated patients, compared to historical ORRs of 20-25% with other late-line therapies.
• Duration of Response: Median ~1 year; progression-free survival ~7–8 months.
• Unique Toxicity Profile: GPRC5D is also expressed in hair follicles, skin, nail epithelium, and oral mucosa, leading to:
  • Oral toxicities: dysgeusia, dysphagia (70% of patients)
  • Skin and nail changes (rash, non-rash)
  • Mostly grade 1–2 CRS and ICANS (50–60%)
• Quote:

  “To have a response rate of 70% as a single agent with this drug was quite remarkable.”
  — Dr. Benad Dakal [02:23]

Real-World Cohort Study: Talquetamab as Bridging Prior to CAR T

• Design: Multicenter retrospective cohort (134 patients, 20 centers: 18 US, 2 Germany)

• Key Outcomes (Bridging Feasibility):

  • Proceed to CAR T: 89% (119/134 patients)
    • Cilta-cel: 98 patients; Ide-cel: 21
    • 7 progressed before CAR T; 6 had manufacturing failure; 2 remained on talquetamab
  • Response to Talquetamab during Bridging: 71% ORR
  • Median talquetamab duration: 23 days (~<1 cycle)

• Post-CAR T Outcomes:

  • Response rate: 88% (54% complete response)
    • Cilta-cel patients: 55% CR; Ide-cel: 45% CR
  • Toxicity Post-CAR T:
    • Mostly grade 1–2 CRS/ICANS; grade 3+ rare and largely in patients with high-risk features
    • GPRC5D toxicities (oral, skin, nail): 50–70%, resolved in 60% by 7 months
    • Long-term cytopenias (60+ days): 10%; grade ≥3 infections: 5%
    • Rare delayed events: cranial nerve palsy (2 cases, full recovery), 1 post–CAR T AML

• Cellular Kinetics:

  • No excessive CAR T-cell expansion or loss of efficacy was observed.
  • Soluble BCMA (disease burden marker) declined steadily before and after CAR T.

• Quote:

  “These patients can go on to receive the CAR T and derive the benefit... without any additional or increased toxicities and perhaps even less toxicities than what we observed before in the clinical trial.”
  — Dr. Benad Dakal [09:34]

Limitations & Future Directions

• Retrospective study; no control arm

• Short follow-up (~7 months)

• Next Steps: Phase 2 prospective study, more granular analysis of antigen profiles, T-cell subsets, long-term toxicities. Need to determine:

  • Best patient selection (high-risk, extramedullary disease)
  • Impact on future GPRC5D therapy eligibility
  • Applicability as CAR T is used earlier in treatment lines

• Quote:

  “[This] definitely establishes the safety and feasibility of this approach... But still, we need to look at it in a more prospective fashion to see the wider applicability.”
  — Dr. Benad Dakal [10:59]

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2. Impaired Exocytosis as a Novel Cause of Type 1 von Willebrand Disease

Guest: Dr. Reuben Bearings (Erasmus University Medical Center)
(Discussion: 13:35–23:34)

Background & Discovery

• Research Focus: Mechanisms of exocytosis and secretion of von Willebrand factor (VWF) from endothelial cells

• Serendipitous Connection: Prior identification of MEDI (MAP kinase activating death domain protein) as a key regulator, and a chance Zoom seminar introduction to clinicians treating children with severe, unexplained bleeding and MEDI gene mutations.

• Ultra-rare Patient Cohort:

  • 30 children globally identified with biallelic pathogenic MADD (MEDI) variants.
  • Three European patients participated in this mechanistic study.

• Quote:

  “It was just an enormous coincidence... she got me in touch with Dr. Kirsten Kutcher from University of Hamburg... And this turned out to be a very ultra rare group of about 30 children worldwide.”
  — Dr. Reuben Bearings [13:50]

Experimental Approach & Key Findings

• Isolation of Patient Endothelial Cells:

  • Used ex vivo endothelial colony-forming cells from peripheral blood.
  • Whole proteome analysis showed complete absence of MEDI protein in patient cells.

• Cellular & Molecular Phenotype:

  • MEDI is an enzyme activating Rab GTPases (RAB3/27), vital for VWF granule exocytosis.
  • Mutant cells lacked recruitment of these GTPases to VWF-storage organelles → defective exocytosis.
  • Live-cell imaging: VWF granules rarely or only slowly released after stimulation.

• Functional Consequence:

  • Patients produced VWF protein, but could not secrete it, leading to very low circulating levels—qualifying them for Type 1 VWD per clinical criteria.
  • Severe bleeding tendency in some, including transfusion-dependent epistaxis.

• Quote:

  “It's basically the cells not being able to secrete von Willebrand factor into the circulation... all qualified for type 1 von Willebrand's disease.”
  — Dr. Reuben Bearings [19:26]

Clinical Implications

• Incidence: Biallelic MEDI mutations are exceedingly rare and won’t explain most "mutation-negative" Type 1 VWD, but:

• Significance: First time non-VWF gene (the exocytotic machinery) directly implicated as a causal factor for low VWF.

• Future Genetics: Suggests new avenues for looking at exocytosis-related genes as potential VWD modifiers.

• Quote:

  “Components of this exocytotic machinery... could potentially also hold causal mechanisms for vwd. So... if we would be doing large scale genetic surveys... those are the ones that we should really carefully have a look at.”
  — Dr. Reuben Bearings [20:26]

Therapy Considerations

• Role of DDAVP: Not expected to help, since DDAVP acts by inducing VWF release, but patients’ cells cannot exocytose VWF.

  • Quote:

    “The actual mechanism of DDAVP released [VWF] is impaired in these patients, so it wouldn’t help in the first place.”
    — Dr. Reuben Bearings [21:48]

Next Steps & Broader Insights

• Further cell biology underway: Analysis of co-regulated proteins—one new exocytosis component identified.
• Larger message: Patient-derived models provide vital insights into both clinical and basic endothelial cell biology.

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Notable Quotes & Moments

• On bridging therapy and patient selection (Dr. Dakal):

  “Can the sequential strategy be adopted so that these patients (with high-risk/extramedullary disease) can have a durable remission like other standard-risk patients?” [12:49]

• On scientific discovery (Dr. Bearings):

  “At this interface it makes being a scientist so much fun.” [23:25]

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Timestamps for Key Segments

| Segment | Timestamp | |---------------------------------------------------------|----------------| | CAR T bridging: rationale & Talquetamab background | 00:56–05:02 | | Real-world Talquetamab bridging trial details | 05:07–10:40 | | Study limitations, future directions (MM bridging) | 10:40–13:26 | | Von Willebrand disease, MEDI mutation backstory | 13:35–16:18 | | Mechanistic studies, endothelial cell phenotype | 16:18–19:26 | | Clinical relevance and future research in VWD | 19:26–23:34 |

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Conclusion

This episode delivers cutting-edge insights into novel sequential strategies for treating relapsed/refractory multiple myeloma and uncovers a new mechanistic cause of Type 1 von Willebrand disease rooted in rare defects of secretory machinery. Both studies highlight how real-world patient data and fundamental cell biology can intersect to improve patient outcomes and advance disease understanding.
Listeners interested in more details are encouraged to consult the full articles in Blood.

Transcript

[Podcast Host]

Welcome to the American Society of Hematology Conversations with Blood Authors podcast. This episode is hosted by Associate Editor Dr. James Griffin. He discusses a novel cause of Type 1 von Willebrand disease, impaired exocytosis, sequential targeting in multiple myeloma with authors Dr. Reuben Bearings and Dr. Benad Dakal.

[Dr. James Griffin]

Hello everybody. My name is Jim Griffin. I'm at the Dana Farber Cancer Institute and I'll be moderating the podcast today. We have two excellent papers to discuss. We're going to start with Dr. DeKal, who is first author on a paper on multiple myeloma from the Medical College of Wisconsin. Dr. Dakal, how did this research come about? What were the questions that you were trying to answer?

[Dr. Benad Dakal]

Thank you for that question. As you know, BCMA targeted CAR T therapies, we have two that is approved right now. One is called Cilta, captazin, Ortolucil or Cilta cell and other one is ID captazin, veculecil or ID cell. Initially that was approved in the late line patients. That means patients who had four or more prior lines of therapy. That has really improved the outcomes of myeloma patients. But in the late lines, the key challenge is because of the nature of the product, we have to wait for six to eight weeks for the manufacturing time and other logistics. So that really is kind of limitation for the patients who are rapidly progressing disease to not to go to the treatment. And we see in the both in the real world in the clinical trial, about 10 to 15% of patients do not make it to the CAR T. So I think one of the key question is once the patients are collected for the T cells, can we give something that could work which is safe and effective while they're waiting for the CAR T manufacturing and so they can have a good outcome afterwards? In the later lab setting, patients have exposed to multiple lines of treatment before and fortunately we received the approval of a new bispecific antibody called Talquetamab which is A targeting of GPRC5D bispecific antibody, which is a non BCMA antigen targeting antibody and which is critical because if you use BCMA targeting therapy before the CAR T and data has shown that this is going to impact the outcome in terms of efficacy.

[Dr. James Griffin]

Can you give us a little bit more information about the use of this bispecific antibody by itself? What are the results there?

[Dr. Benad Dakal]

Yes. So this Talcatamab, As I said, GPRC5D bispecific antibody was approved and as an accelerated approval in patients with four or More prior lines of therapy after they're exposed to three major class of drugs in myeloma, which we call three major classes, proteasome inhibitor, immunomodulated drug and CD38 monoclonal antibody. And one trial. And in that monumental one trial, this drug was tested in patients with three or more prior lines of therapy in three different cohorts. One is weekly cohort of 0.4 milligrams per kilogram, other one is every other week cohort of 0.8 milligrams per kilogram. And there is another cohort called prior T cell directed therapy cohort. That means these patients are allowed to have both CAR T or bispecific antibody before they receive this talgotimab. And if you look at the overall data, the overall response rate is Quite impressive at 70% in the ballpark and with very good partial response rate of 55% and higher. So this is quite impressive. By itself as a single agent, this drug could give almost 70% response rate in all commerce, including the patients who had prior CAR TN bispecific antibody. In terms of duration of response, the duration of response, depending on the dose level on average is about one year and the progressive survival is about seven, eight months. So if you look at the patient population that was tested who had three prior lines of therapy and exposed to three major class of drugs, on average these patients would have a response rate of 20, 25% with other available therapies before we had all this immunotherapy. And also that would last for about less than five months. So to having a response rate of 70% as a single agent with this drug was quite remarkable. And that's why the FDA led to the approval, accelerated approval of this drug in this patient population. In general, this drug is well tolerated. It in terms of both cytokine release syndrome and immune effector acid neurotoxicity syndrome, the rates are about 50 to 60%, but mainly grades 1 and 2. But what is unique about this drug is GPRC5D related side effects. Because GPRC5D is expressed in addition to myeloma cells and also in hair follicles, in epithelial tissue, in oral cavities, in nails. And so patients will have oral toxicities with dysgeusia dysphagia. And there are almost 70% of patients would have that. Similarly, the patients could have skin changes, both rash and non rash, skin changes and nail change. So these are some of the side effects that is GPRC 5D related very unique to this product and this is something that comes into discussion, you know, when using this bispecific antibody. In addition, when you look at the subgroup analysis of the effectiveness of this drug, this drug really works in patients with high risk cytogenetics in extramedullary disease and is an important option for these patients in the later lab setting.

[Dr. James Griffin]

Tell us about the trial that you did. That's the focus of this article.

[Dr. Benad Dakal]

The goal of the research in this study was to evaluate in a real world multicenter retrospective cohort the safety, efficacy and the feasibility of using talquetamab as a bridging therapy prior to BCMA directed CAR T therapy, which is being given in a standard of care in relapsed refractory multiple myeloma patients in the late relapse setting after four or more prior lines of therapy. So the key aims included assessing what proportion of patients who received talquetamab were able to proceed to CAR T, that is Success of the bridging, then measuring responses to talquetamab in the bridging window, then evaluating post CAR T outcomes both in terms of response and toxicity in those bridged with talquetamab and characterizing the safety safety for both talquetamab as well as the CAR T in a sequential manner. So for example, some of the there is overlapping toxicities with CRS and icans with both talquetamab and the CAR T to see how that impact that toxicities. And also looking at the toxicities associated with the talquetamab and especially as a bridging where it is given us for short course, how does that impact this overall the GPRC 5D related toxicity. So these are some of the aims of the research. So some of the major findings. I would summarize some of the major findings. You know, the patient cohort and bridging feasibility. You know, we looked at 134 patients across 20 centers. There are 18 centers from the US and two centers from Germany that looks talquetamab as a bridging to CAR t. Of those 134 patients, 119 patients, that is 89% were proceeded to CAR T cell therapy out of which 98 received Cilta CEL and 21 received IDESOL. And of those remaining patients who did not proceed to CAR T, seven patients had disease progression, six patients had manufacturing failure and two patients decided to continue on talclutamab. They decided not to go for CAR T. Now if you look at the efficacy and response to talcrutamab the response rate was about 71% which is consistent with what was observed in the clinical. And the median duration of talquetamab used was about 23 days. So if you look at in that ballpark, about less than one cycle of talquetamab was used. Now I think the key thing is about the safety. When you look at the safety, there are mainly grades one and two of CRS and ICANS. There were 2% grade three ICANS. But this patient, one of the patient had, you know, CNS myeloma. And if you look at the non CRS toxicities or GPRC 5D toxicities, this is expected in terms of both oral skin and nail events, 50 to 70%, mainly grades one and two. And what is interesting is that when you follow these patients for about seven months of follow up, 60% of those toxicities are completely resolved at the time of the last follow up. Now when you look at the patients who received CAR T there's 119 patients who received Cilta Cell and IDE CEL, 88% response rate and there was 54% achieved complete response. The rates of complete Response in Cilta CEL was about 55% and 45% ID cells. So there is half of the patients had complete response and better. Now when you look at the toxicities post CAR T look at the crs, there are mainly grades one and two. Two patients had grade three and higher crs, mainly grade three. There's one patient at grade three icans. These are the same patient who had grade three ICANS with talquetamab as well. And then the cytopenias, especially looking at the long term cytopenias like especially lasting for 60 days was happening in only 10% of patients. 5% of patients had grade 3 and higher infections. In terms of delayed toxicities, there are some unique delayed toxicities that could be associated with the CILTA cell. For example cranial nerve palsies, parkinsonism. We saw only two cases of cranial palsy. Mainly those two cases were facial palsy and both of them had complete resolution of the facial palsy. At the time of last follow up. There are no cases of any Parkinsonism or any Guillain Barre syndrome or any other delayed neurotoxicities that were observed with the CT cell. In both clinical trial as well as in the real world study. There is one case of secondary AML that was observed about four months after CILTA cell and this patient had DNAmt3a and T2 mutation on the bone marrow biopsy. Some of the Things that we also looked at looking at the expansion of the CAR T. One of the hypothesis was if the talquetamab used just prior to the CAR T could lead to unproliferated or significant expansion of the CAR T. And so look at the caria T expansion in select two centers that had the data. And what was encouraging to see was that the CAR T expansion was peaking of day 14, which is consistent with what was observed initially in the other clinical trials. It's consistent with their kinetic profile. And there was no any cases of uncontrolled proliferation of any of the CAR expansion. We also looked at the soluble bcma, which is a marker of disease burden as well as the resistance to the BCMA CAR T. What we observed was the soluble BCMA was declining continuously after the start of talclitamab and there is continued decline with the CAR T suggesting the continued response of the CAR T. Now we looked at the deepening of the response. More than half of the patients who received CAR T after talcitamab had deepened the response and 45% of patients had the same level of response. And we'll need to follow these patients as we go forward to see if there is more deepening of the response. And these patients are very heavily treated patients. Half of the patients are high risk cytogenetics. Almost half had extramedullary disease. And if you look at this patient and compared to the patient that was tested in the Prevotal trials, 85% of patients would not have made the clinical trial eligibility. So this is really a challenging patient to treat and it is very encouraging to see that these patients can go into receive the CAR T and derive the benefit of the CAR T without any additional or increased toxicities and perhaps even less toxicities, perhaps than what we observed before in the clinical trial. When you use this talclutamab bridging.

[Dr. James Griffin]

Very nice results Dr. Dakal, but as you point out in your article, this is a retrospective study. It doesn't have a comparator arm, there's no control arm. And it's still relatively early in the course of these patients after the transplant to know exactly how they did. What are the next steps for this treatment.

[Dr. Benad Dakal]

Now, as you brought up very important points there, I think you rightly pointed out the follow up disorder is a retrospective study with a lot of confounders to account for that. We are right now doing a phase two study at our center prospective study to look at the use of talcitama bridging as bridging therapy. Before BCMA CAR T. So that is already about to start very soon. At our center we just got the IRB approval and at that we hopefully can more systematically define the benefit of this approach there. We'll also be looking at the antigen status before the talquetamab, both GPRC5D and BCMA antigen status and at subsequent time points to see how does it impact both the antigen as we go forward. And also looking at the T cell profile, how does it impact the other T cell profile beyond the CAR T. And this will be kind of interesting to look at in a prospective fashion. I think one of the things that definitely establish is the safety because the number of patients is quite large in this study and they definitely establish the safety and feasibility of this approach that can be done. But still I think we need to look at in a more prospective fashion to see have a wider applicability. Now one of the question that comes up is the order of the sequencing. You use BCMA and GPRC5D followed by BCMA and then whether this sort exposure can impact the GPRC 5D antigen status, especially for patients later on when relapse after the BCMA CAR T can Talcutamab still be a valid option for these patients? Or the short course of this antigen exposure could impact the outcome later on. So this is something that we need to look at. Similarly we need to look at the more larger cohort, the impact on the CAR expansion and also persistence and also to see if the long term risk, as I said, the follow up is still very short at seven months to see if that can be followed a bit longer to see if there's some other toxicity that can emerge with time. But lastly, I think the important thing that we need to look at is how we can use this in certain subset of patients. It's quite possible that with the CAR T being approved in early lines, we may not need the bridging, effective bridging like this because these patients are sensitive to other available options as well. But I think the critical question is can we use strategy to kind of to certain subset of unmet need patients, for example high risk patients, patients who are extramedullary disease. Can the sequential strategy could be adopted so that these patients can have a durable remissions like other standard risk patients.

[Dr. James Griffin]

Dr. Kakal, thank you for this discussion. Good luck with your future studies. This is a very nice finding that you published.

[Dr. Benad Dakal]

Thank you so much.

[Dr. James Griffin]

This article is being presented by Dr. Reuben bearings from the Department of Hematology at Erasmus University Medical center in Rotterdam. The Netherlands. Dr. Beering, give us some of the background behind this interesting study.

[Dr. Reuben Bearings]

Yes, thank you very much. So this is actually a really nice example of serendipity. So if you have a minute. My lab studies the mechanisms of exocytosis in riboplatam. These are the secretory organelles of endothelial cells that contain a protein called von Wilben factor. And basically, my lab wants to know how cells know when to secrete from Wilben factor and what happens if this goes wrong. And So a previous PhD student in my lab, Dr. Maria Cott, had identified a new key regulator of this process, which was a protein called madd, which stands for MAP kinase activating that domain. It's a rather unpleasant name, so that's why we call it madi. Now, this was back in 20, 2020. So just when Covid hit really a way to go to conferences, as you might remember. So there was not really a good way to disseminate our results, but luckily there was initiative led by Dr. Kelly Mackless from Boston Children's Hospital, who organized the blood and bone seminars on Zoom. And of course, then you have a worldwide audience. So I presented some of the work there. And during that talk in the Q and A session, one of the audience members pops up and says, well, hey, this might be a coincidence, but I'm involved in looking into the cause of frequent nosebleeds in this severe pediatric patient with all sorts of unexplained abnormalities. And when we did the NGS at the end, it turned out that this patient had biallelic pathogenic variants in many. So it was just an enormous coincidence. She got me in touch with Dr. Kirsten Kutcher from the University of Hamburg in Germany, and she had gathered a number of pediatricians with similar patients via a platform called genematcher. And this turned out to be a very ultra rare group of patients of about 30 children worldwide, all with different biallelic mutations in the MEDIT gene. And from this cohort, there were three patients situated in Europe who were able to participate in our study, which was led by Sophie Hordak, a PhD student in the lab, who is also the first author of this work. So this meant that we had to fly into Prague or drive to Germany or Belgium to collect our blood samples and then immediately returning to a lab in Rotterdam to isolate their endothelial cells on the same day. And, you know, with all these travel restrictions, in fact, during that time, this was actually a challenging project, but with some participants we had to try a few times, but eventually it worked. So it was actually a very gratifying experience.

[Dr. James Griffin]

So it sounds like you were able to find three patients who were not too far away who had known deletions or had known mutations in the MADI protein. What did you do after you collected their cells?

[Dr. Reuben Bearings]

Yeah, these cells are the endothelial colony forming cells. Those are basically cells that we can isolate from peripheral blood samples. And they are a very nice ex vivo model system to study endothelial cell function from healthy individuals, but also from patients, of course. And then they provide a perfect model to study the pathogenic mechanisms. So one of the first things that we try to do is look at the molecular consequences of these mutations, because all these mutations were different. And we did didn't really know what what was going on. So what we did is that we teamed up with the mass spectrometrist from San Quinn Research in Amsterdam, the group of Mitra van der Bigela, and we performed whole proteome analysis on these cells and also from their unaffected heterozygous family members and compared it to two controls. And what we found in all three patients is that there is a total lack of the many proteins. So telling us that these cells that we have isolated from the patients are a model of complete deficiency of the mediprotein.

[Dr. James Griffin]

Very nice. So what happened then? How did you study the von Willebrand factor?

[Dr. Reuben Bearings]

What we then did is look at the function of this MEDI protein. So what we know is that MEDI is an enzyme that activates GTPases, RAP GTPases. And these are crucial mediators of ribopalanobody exocytosis. And when this protein normally activates these RAP gtpases, they are recruited to ribopilotomoboy. So the first thing that we then did, knowing that Maddie was no longer around, is look at the recruitment of these RABTPases. These are RAP3 and RAP27 on rival palataboids. And we found that they were totally absent of these organelles, telling us that the key elements of the exocytotic machinery of riboplatiboids was missing. Now, knowing that these molecules are no longer being recruited to the organelles, we wanted to know what actually happens to the itot exocytotic machinery of the exocytotic mechanism of these organelles. And for this we went to the lab, Professor Tom carter at East St. George's University in London, who has a very nice setup for studying lifestyle imaging of exocytosis of biopilabris that can be fluorescently marked and then really seeing as believing. So we can then stimulate these cells under the microscope and see what happens to the organelles. And what we noticed that in all patient cells that we had, the ribo pallaby asymptotic process was in. So hardly any of those granules were able to leave the cell after stimulation. And the ones that did had a very significant delay.

[Dr. James Griffin]

So that would suggest that the endothelial cells were unable to secrete von Willebrandt factor in these three patients. And even though there weren't any mutations, there was von Willembrand factor protein being made, but it couldn't be secreted, is that correct?

[Dr. Reuben Bearings]

Yes, exactly. So it's basically the cells not being able to secrete formula factor into the cervix circulation. And that then prompted us to look at the circulating viruleman factor levels in these patients. And these were actually very severely reduced to the point that according to the current guidelines of the ASH and ISDH for women's disease, these patients all qualified for type 1 viruleman's disease. Interestingly also one of the patients that we included had a long history of severe bleeding, complex complications and nosebleeds up to the point that he needed to have blood transfusions. So this tells us that the impairment of the extras machinery is a possible new cause of type 1 srilman's disease.

[Dr. James Griffin]

Sounds like this is relatively uncommon though, since fairly small number of patients have been identified around the world with MADI mutations. Under what circumstances would you recommend screening for MADI mutations in patients that present with low.

[Dr. Reuben Bearings]

Yes, yeah, that's a very good point. So some in the audience might know. So in type 1 Wilman's disease, there's approximately 30% of the patients do not have pathogenic variants in the VDWF gene. That could explain their quantitative reductions in vf, which means that there have to be other causal mechanisms for Wilman's disease. And finding them has been a long standing pursuit in this field. So our study in MADI patients now identifies for the first time another causal gene which is MADI for people that don't carry Velo F variants. But I agree we don't have to. We should overstate things. Patients with biolytic MEDI mutations are extremely rare, so it's unlikely that they are going to account for a significant share of this 30% of patients with unexplained MEDI of Fe2OD. What it does tell us that components of this exocytotic machinery of vibropalata bodies could potentially also hold causal mechanisms for vwd. So I think if we would be doing large scale genetic surveys of these patients, I think genes encoding for modifiers of this process, those are the ones that we should really carefully have a look at.

[Dr. James Griffin]

Sometimes patients with von Willebrand's disease are treated with desmos. Would you predict that that would have beneficial effect or no effect in these people?

[Dr. Reuben Bearings]

Yes, we got this question actually quite a lot when we're presenting these data. So first of all, I have to stress that these three patients that we had weren't treated with ddavp. And I think you can understand that in severely diseased patients with all sorts of other abnormalities and conditions, you don't easily subject them to a DDAVP trial. But I think that actually would have been the wrong call anyway because what study shows is that the actual mechanism of DDAVP released fulminant factor, which is because of inducing the exocytosis of riboplantic bodies, is impaired in these patients. So it wouldn't help in the first place.

[Dr. James Griffin]

Very nice. Any further comments about next steps in studying this pathway?

[Dr. Reuben Bearings]

Yes. So as often in science, you know, studies raise new questions and sometimes in very unexpected affected ways. So when we were doing the proteomics of these MEDI cells, as a bonus, we got the expression profile of thousands of other proteins that are expressed in epithelial cells. And interestingly, we found a number of proteins that were all co regulated with MEDI specifically in these patient cells. So these were proteins that had not been implicated in VWF biology before, but we think that they can be functionally involved. And we are following up on this and also already identified one new component of this library release complex. So yeah, stay tuned, I would say, but I think what it really emphasizes that using cell biology we can learn a lot about new mechanisms of disease, while patient derived models can also tell us a lot about new things about basic biology of cells. And I think at this interface it makes being a scientist so much fun.

[Dr. James Griffin]

Thank you very much, Dr. Bearing. Very nice study. I enjoyed.

[Dr. Reuben Bearings]

Thank you.

[Dr. James Griffin]

I'd like to thank the two authors for their discussions of these nice papers and invite the listeners to go to Blood Journal and read the full articles to answer any further questions that they have about these topics. Thank you very much.

[Podcast Host]

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.