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

Overview

This episode explores two recent studies published in Blood:

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.
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.

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]

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.

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]

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 |

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.

Blood Podcast Episode Summary

Overview

This episode explores two recent studies published in Blood:

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.
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.

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]

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.

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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Breakthroughs in Multiple Myeloma Treatment and Von Willebrand Disease Mechanisms

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Summary

Blood Podcast Episode Summary

Overview

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

Background & Motivation

Key Data on Talquetamab as Single Agent

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

Limitations & Future Directions

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

Background & Discovery

Experimental Approach & Key Findings

Clinical Implications

Therapy Considerations

Next Steps & Broader Insights

Notable Quotes & Moments

Timestamps for Key Segments

Conclusion

Summary

Blood Podcast Episode Summary

Overview

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

Background & Motivation

Key Data on Talquetamab as Single Agent

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

Limitations & Future Directions

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

Background & Discovery

Experimental Approach & Key Findings

Clinical Implications

Therapy Considerations

Next Steps & Broader Insights

Notable Quotes & Moments

Timestamps for Key Segments

Conclusion