This episode provides comprehensive coverage of key clinical trial updates from the 2025 International Myeloma Society (IMS) Annual Meeting in Toronto, with special focus on bispecific antibodies and novel immunotherapies across the multiple myeloma disease continuum—from smoldering disease through relapsed/refractory settings. Dr. Alfred Garfall provides expert commentary on study design, efficacy, safety considerations, and clinical implications.

Topics Covered

1. SMOLDERING MULTIPLE MYELOMA

LINKER-SMM1

Phase 2, open-label study of linvoseltamab monotherapy (200 mg) in patients with high-risk smoldering multiple myeloma by 20/2/20 or PETHEMA criteria, with 2-year treatment duration.

Discussion Points:

• Appropriateness of 2-year treatment duration for precursor condition
• Efficacy and MRD-negative rates
• Safety considerations in asymptomatic population
• Patient selection if available today

2. NEWLY DIAGNOSED MULTIPLE MYELOMA

MajesTEC-5

Phase 2 trial evaluating three teclistamab-daratumumab-based induction regimens in 49 transplant-eligible NDMM patients, followed by auto-transplant and fixed-duration Tec-Dara maintenance.

Discussion Points:

• Post-induction MRD-negativity rates with Tec-DR and Tec-DVR
• Grade 3-5 infection rates and infection-related deaths
• Questionable utility of bortezomib and need for ASCT with 100% MRD-negativity
• High infection prophylaxis requirements

MagnetisMM-6

Phase 1/2 dose-finding study of fixed-dose elranatamab 76 mg Q4W with Dara-Len in 37 transplant-ineligible NDMM patients (median age 75 years).

Discussion Points:

• VGPR or better rates
• Safety profile including infections and CRS/ICANS
• Risk of continuous therapy in elderly/frail population

LINKER-MM4

Phase 1/2 study of linvoseltamab monotherapy in NDMM with both transplant-eligible and transplant-ineligible pathways, exploring three dose levels (50, 100, 200 mg).

Discussion Points:

• Efficacy of single-agent Linvo in NDMM
• Whether any NDMM population could achieve long-term control with single-agent BCMA BsAb
• Safety profile

3. RELAPSED/REFRACTORY MULTIPLE MYELOMA

CAMMA-1

Phase 1b randomized dose-expansion study of cevostamab (FcRH5×CD3 bispecific) combined with pomalidomide-dexamethasone in BCMA-naïve patients with median 2 prior lines of therapy.

Discussion Points:

• Efficacy and safety results
• Positioning in treatment paradigm
• Use before BCMA BsAbs?

Sonrotoclax + Dexamethasone in t(11;14) R/R MM

Phase 1/2 study of sonrotoclax (next-generation BCL2 inhibitor) plus dexamethasone as an all-oral regimen in patients with t(11;14) R/R MM (median 3 prior lines, ~75% triple-exposed).

Discussion Points:

• Efficacy including response rate and PFS
• Safety profile
• Future of BCL2 inhibitors in t(11;14) myeloma in the era of BsAbs and CAR T

RedirecTT-1

Phase 2 trial combining teclistamab + talquetamab in 90 heavily pretreated patients with R/R extraosseous extramedullary disease (84% triple-class refractory, 36% penta-refractory, 20% prior BCMA CAR T).

Discussion Points:

• Response rate and durability in difficult-to-treat population
• Safety concerns with dual bispecific combination
• Off-label use considerations

4. CAR T-CELL THERAPY TOXICITIES

CAR T Immune-Related Adverse Events (UPenn Study - Ho et al)

Large cohort study of 198 patients (125 cilta-cel, 73 ide-cel) examining all adverse events other than CRS, ICANS, IEC-HS, and IECAHT.

Discussion Points:

• Landscape of CAR T IRAEs: incidence, types, and timing
• Risk factors identified for CirAEs
• Mechanism of toxicities and role of CD4+ CAR T-cells
• Clinical implications: Should prophylactic corticosteroids be used? What ALC threshold? Optimal dose/duration? Prospective studies needed?

In this episode of Blood Cancer Talks, hosts Eddie, Ashwin, and Raj welcome two distinguished experts to explore the cutting-edge field of circulating tumor DNA (ctDNA) in B-cell lymphomas. Dr. David Russler-Germain, a lymphoma clinician from Siteman Cancer Centre at Washington University in St. Louis, returns as a familiar voice to the podcast audience. Joining him is Dr. Ash Alizadeh, the Moghadam Family Professor of Medicine, Oncology, and Hematology at Stanford University and leader of the Cancer Genomics Program at Stanford Cancer Institute. Dr. Alizadeh has been instrumental in advancing our understanding of lymphomagenesis and lymphoma genetics over the past two decades, pioneering multiple ctDNA techniques that are revolutionizing cancer care. Together, they discuss the transformative potential of ctDNA technology in B-cell lymphomas, particularly DLBCL, covering everything from the technical evolution of biomarker detection to groundbreaking clinical data that may reshape how we monitor and treat these aggressive cancers.

Key Discussion Topics

1. Genetic Heterogeneity in B-Cell Lymphomas

Complex genetic landscape of DLBCL

Implications for treatment strategies

Need for personalized approaches

2. Clinical Need for ctDNA in Lymphoma

Why ctDNA is needed in aggressive lymphomas:

Curative vs. non-curative treatment settings

Limitations of current PET imaging

Additional prognostic information beyond imaging

Risk stratification capabilities

Potential to avoid overtreatment

Therapy adaptation opportunities

3. Challenges in Lymphoma MRD Assessment

Why lymphoma MRD is more complex than other hematologic malignancies:

Differences from acute leukemias, CLL, and myeloma

Technical challenges specific to lymphoid tumors

Lower circulating tumor burden compared to liquid tumors

4. ClonoSEQ Technology

Mechanism: Immunoglobulin sequencing approach

Advantages: Established platform with regulatory approval

Disadvantages: Limited sensitivity in peripheral blood, requires adequate tumor sample

5. CAPP-Seq Technology

Full Name: Cancer Personalized Profiling by Deep Sequencing

Innovation: Developed ~10 years ago by Dr. Alizadeh's group

Mechanism: Targeted sequencing of cancer-specific mutations

Advantages: High sensitivity, personalized approach

6. PhasED-Seq Technology

Evolution: Next-generation advancement of CAPP-Seq

Key Improvements: Enhanced sensitivity and specificity

Technical Advances: Phased variant detection

Clinical Data Highlights

1. Remission Assessment by ctDNA in LBCL on 5 prospective studies of frontline anthracycline-based chemo-immunotherapy: https://pubmed.ncbi.nlm.nih.gov/40802906/

2. Prospective validation of end of treatment ctDNA-MRD by PhasED-Seq in DLBCL patients from HOVON-902 clinical trial: https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7000

3. Korean data on prognostic utility of ctDNA: https://ashpublications.org/blood/article/142/Supplement%201/69/501573

In this episode of Blood Cancer Talks, we have Dr. Adrian Minson from the Peter MacCallum Cancer Centre to discuss the latest developments in lymphoma presented at the recent EHA and ICML meetings in June 2025. The episode focuses primarily on the emerging role of bispecific antibodies in various combinations and treatment settings for diffuse large B-cell lymphoma (DLBCL).

Key Clinical Trials Discussed

1. POLARGO Trial - Polatuzumab + R-GemOx vs R-GemOx in R/R DLBCL

2. SUNMO Trial - Mosunetuzumab + Polatuzumab vs R-GemOx in R/R DLBCL

3. STARGLO Trial - Glofitamab + GemOx vs R-GemOx in R/R DLBCL (2-Year Update)

4. EPCORE NHL-5 & NHL-7 - Epcoritamab Combinations in Frontline DLBCL

5. EPCOR-RICE - Epcoritamab + R-ICE in Transplant-Eligible R/R DLBCL

6. LOTIS-7 Trial - Loncastuximab + Glofitamab in R/R DLBCL

7. Additional Studies Mentioned:

R-Pola-Glo Frail Study

DLBCL Classification

In this episode, we discuss the management of follicular lymphoma with Dr. Gilles Salles from Memorial Sloan Kettering Cancer Center. Here are the articles we discussed: 

1. Relevance of Bone Marrow Biopsy in Follicular Lymphoma: https://pubmed.ncbi.nlm.nih.gov/35787017/

2. TROG 99.03 (RCT of Systemic Therapy after Involved-Field Radiotherapy in Patients with Early-Stage Follicular Lymphoma): https://pubmed.ncbi.nlm.nih.gov/29975623/

3. Long-term follow-up results of RCT comparing early rituximab monotherapy versus watchful waiting for advanced stage, asymptomatic, low tumor burden follicular lymphoma: https://pubmed.ncbi.nlm.nih.gov/40306831/

4. RELEVANCE RCT: Lenalidomide plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma: https://ascopubs.org/doi/10.1200/JCO.22.00843

5. GALLIUM RCT: Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL. https://pubmed.ncbi.nlm.nih.gov/37404773/

https://pubmed.ncbi.nlm.nih.gov/28976863/

6. Long-term follow-up of mosunetuzumab in relapsed/refractory FL: 

https://pubmed.ncbi.nlm.nih.gov/39447094/

7. Epcoritamab in relapsed/refractory FL: https://pubmed.ncbi.nlm.nih.gov/38889737/

8. Phase 3 inMIND RCT: Tafasitamab plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: https://ashpublications.org/blood/article/144/Supplement%202/LBA-1/534319

9. Long term follow-up results from the Phase 3 PRIMA trial of rituximab maintenance in Follicular Lymphoma: https://ascopubs.org/doi/10.1200/JCO.19.01073

In this episode, we dissect the phase 3 MIDAS trial in newly diagnosed transplant-eligible multiple myeloma with Dr. Meera Mohan. 
https://pubmed.ncbi.nlm.nih.gov/39841461/
https://pubmed.ncbi.nlm.nih.gov/40459097/

In this episode, we took a deep dive intro the landscape of menin inhibitors in AML with Dr. Eytan Stein from MSKCC. Here are the key trials and studies we discussed: 

• ELN 2022 AML Classification https://ashpublications.org/blood/article/140/12/1345/485817/Diagnosis-and-management-of-AML-in-adults-2022
• Predictors of outcomes in adults with AML and KMT2A rearrangements: https://www.nature.com/articles/s41408-021-00557-6
• DOT1L inhibitor https://ashpublications.org/blood/article/131/24/2661/37193/The-DOT1L-inhibitor-pinometostat-reduces-H3K79
• AUGMENT 101: https://ascopubs.org/doi/10.1200/JCO.24.00826
• Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study: https://ashpublications.org/blood/article/doi/10.1182/blood.2025028357/537139/Menin-inhibition-with-revumenib-for-NPM1-mutated
• KOMET-001: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00386-3/abstract
• SAVE trial: https://ashpublications.org/blood/article/144/Supplement%201/216/530724/Phase-I-II-Study-of-the-All-Oral-Combination-of
• KOMET-007: https://library.ehaweb.org/eha/2025/eha2025-congress/4159213/harry.erba.ziftomenib.combined.with.intensive.induction.chemotherapy.2872B329.in.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2882%2Aot_id%3D31560%2Amarker%3D5843%2Afeatured%3D19595
• MEN1 mutations: https://www.nature.com/articles/s41586-023-05755-9

In this episode, we discuss the recent proceedings at the FDA ODAC meeting on AQUILA trial in smoldering myeloma and STRAGLO in R/R DLBCL, and provide an update to our audience on some of the clinically relevant data presented from those trials, along with insights from the panelists. Here is the link to the webpage with FDA briefing documents and slides: 

https://www.fda.gov/advisory-committees/advisory-committee-calendar/may-20-21-2025-meeting-oncologic-drugs-advisory-committee-05202025#event-materials

Here is the youtube link for FDA proceedings: 

https://www.youtube.com/watch?v=5ecyDbK9ezc

In this episode, we discussed the management of systemic mastocytosis with Dr. Daniel DeAngelo from the Dana Farber Cancer Institute. Here are the key studies we discussed:

• Midostaurin https://www.nejm.org/doi/10.1056/NEJMoa1513098?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
• Avapritinib
• EXLPORER study: https://www.nature.com/articles/s41591-021-01538-9
• PATHFINDER study: https://www.nature.com/articles/s41591-021-01539-8
• Bezuclastinib: APEX trial: https://ashpublications.org/blood/article/144/Supplement%201/659/530240/Apex-Part-1-Updated-Assessment-of-Bezuclastinib
• HSCT for Advanced SM: https://ascopubs.org/doi/10.1200/JCO.2014.55.2018

In this episode, we explore the emerging entity of CAR Transgenic T-cell Lymphoproliferative Neoplasms (CTTLN), a rare but important complication of CAR T-cell therapy. Dr. Piers Blombery from Peter MacCallum Cancer Center joins us to dissect two cases from the CARTITUDE-4 trial where patients developed T-cell lymphomas expressing the chimeric antigen receptor following cilta-cel treatment for multiple myeloma. As a bonus, we also briefly discussed Dr. Blombery’s paper on menin inhibitors in UBTF tandem duplicated AML. Here are the papers we discussed: 

1. CTTLN cases from CARTITUDE-4: https://pubmed.ncbi.nlm.nih.gov/39938094/

2. CTTLN case from MSKCC with insertional mutagenesis: https://pubmed.ncbi.nlm.nih.gov/39908432/

3. Other CTTLN cases in myeloma:
https://pubmed.ncbi.nlm.nih.gov/38865661/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8417502/

4. Response and resistance to menin inhibitors in UBTF tandem duplication AML: https://pubmed.ncbi.nlm.nih.gov/38924737/

In this episode, we delve into the key clinically relevant abstracts in leukemia and myeloid neoplasms with Dr. Jayastu Senapati from the MD Anderson Cancer Center. Here are the links to the abstracts we discussed: 

Older AML: Ven+HMA vs 7+3

Abstract 450: https://ash.confex.com/ash/2024/webprogram/Paper210320.html

Abstract 971: https://ash.confex.com/ash/2024/webprogram/Paper202801.html

Abstract 969: https://ash.confex.com/ash/2024/webprogram/Paper199267.html

Venetoclax resistance mechanisms

https://pubmed.ncbi.nlm.nih.gov/39478230/

FLAG-GO vs FLAG-IDA 

https://ashpublications.org/blood/article/144/Supplement%201/1513/532742/Gemtuzumab-Ozogamicin-Added-to-Fludarabine

 CPX-351: 

Abstract 55: https://ash.confex.com/ash/2024/webprogram/Paper207094.html

Abstract 60: https://ash.confex.com/ash/2024/webprogram/Paper200413.html

Menin Inhibitors 

Abstract 211 https://ash.confex.com/ash/2024/webprogram/Paper194384.html

Abstract 212 https://ash.confex.com/ash/2024/webprogram/Paper207106.html

Abstract 213 https://ash.confex.com/ash/2024/webprogram/Paper194827.html

Abstracts 214 https://ash.confex.com/ash/2024/webprogram/Paper198218.html

Abstract 215 https://ash.confex.com/ash/2024/webprogram/Paper198218.html

Abstract 216 https://ash.confex.com/ash/2024/webprogram/Paper204375.html

FLT3 inhibitors
Abstract 221: https://ash.confex.com/ash/2024/webprogram/Paper201595.html

MDS

 Abstract 349: https://ash.confex.com/ash/2024/webprogram/Paper194510.html

ATRA in MDS:  

https://ash.confex.com/ash/2024/webprogram/Paper200433.html