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Immune Effector Therapies �for Multiple Myeloma

Joselle Madonna Cook MBBS�Consultant hematologist�Division of Hematology�Myeloma Amyloid and Dysproteinemia �Mayo Clinic Rochester MN

#INDY2025

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1. Sequencing

Holding therapy

Bridging therapy

Apheresis + manufacturing�(6 to 8 weeks)

Administered during the manufacturing period to safely “bridge” to CAR T

Administered BEFORE apheresis

GOAL to control disease without �jeopardizing CART therapy�

AVOID ALKYLATORS, BENDAMUSTINE, POLYCHEMOTHERAPY, TCE

Ideally CAR-T therapy before BsAB:

- TCEs cause lymphopenia via T-cell trafficking^¶

- Prolonged TCE exposure leads to T-cell dysfunction/exhaustion^#

-Pre-CART TCE use increases CAR-T manufacturing failure risk ^*

# Verkleij, Christie P M et al. Clinical cancer research vol. 30,14 (2024): 3006-3022. *Ferreri CJ et al RWE of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood Cancer J. 2023 Aug 9;13(1):117. ¶Costa, L.J., et al. IMWG immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia (2025). https://doi.org/10.1038/s41375-024-02482-6

Consider BsAB before CAR-T if:

-Rapid pace of disease

-Frailty considerations

ALKYLAOTRS �POLYCHEMOTHERAPY, TCEs �OK

Ferreri CJ et al 2003 BCJ

CAR-T

LD�Chemo

Induces lymphopenia to create an optimal cytokine milieu that favors CAR T-cell expansion and persistence

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Sequential BCMA targeting (BCMA 🡺 BCMA TCE) �Still an option, but LESS EFFECTIVE

Outcomes of Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma with Prior Exposure to BCMA-Directed Therapy: A Multicenter Study from the U.S. Multiple Myeloma Immunotherapy Consortium Dima et al Blood 2024; 144 (Supplement 1): 897.

Outcomes with Teclistamab� by TYPE of BCMA-DT

Reference: MajesTEC-1, ORR 63% , CR 39.4%

Response with Teclistamab�Prior BCMA-DT vs None

Timing of Teclistamab post-BCMA-DT may important. Ideally at least 6 months to Teclistamab from prior BCMA exposure�

Patients who responded to Tec had a numerically longer median time from last BCMA-DT exposure to Tec initiation compared to non-responders: 10.5 vs 7.5 months, p=0.48

Outcomes of Teclistamab after Prior Exposure to BCMA-Directed Therapy

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2. Bridging

Can T-cell engagers (TCE) be used for bridging?

BCMA-directed TCEs prior to BCMA-CAR-T may reduce CART efficacy
GPRC5D-targeted TCEs offer an alternative, targeting BCMA-low/null clones
Talquetamab : approved after 4LOT, ORR 70% mDOR 10 mo (MONUMENTAL-1)
Opportunity for real word Dual targeting

ASH 2024:�Retrospective study, 4 US academic centers in US Multiple Myeloma Immunotherapy Consortium �

Binod Dhakal On behalf of US Multiple Myeloma Immunotherapy Consortium Blood 2024; 144 (Supplement 1): 931, Chari et. al NEJM 2022

N=77 with RRMM to commercial CART, bridged with Talquetamab

12 Preapheresis
65 Post apheresis

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Talquetamab for Bridging

Binod Dhakal On behalf of US Multiple Myeloma Immunotherapy Consortium Blood 2024; 144 (Supplement 1): 931.

N=77 • Median Follow up • after Talquetamab 7.5 mo •After CART 4.9 mo

Prior BCMA 10 (13%) • EMD 33(43%) • CART: Idecel 15, Ciltacel 50 • Talq dose: 0.8q2W 59(77%), 0.4q2W 18 (23%)�

TALQ N=77

CART N=65

Median time on Talquetamab 26 days (IQR 10-57)�Median time from last Talquetamab dose to CAR-T infusion 25 days (IQR 19-35)

RESPONSES DEEPENED AFTER TALQUETAMAB BRIDGING TO CART

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Key Toxicities & Incidence

✅ CRS: 68% (No Grade 3/4)

�✅ ICANS: 10% (Grade 3/4: 2.5%)

�✅ Skin Toxicities: 42% (No Grade 3/4)

�✅ Nail Toxicities: 25% (No Grade 3/4)

�✅ Oral Toxicities: 56% (Grade 3/4: 1.2%)

�✅ Weight Loss: 12% (Grade 3/4: 2.5%)

Resolution of Toxicities

✔60% (40/67) had complete resolution of Talq-related toxicities

�

Binod Dhakal On behalf of US Multiple Myeloma Immunotherapy Consortium Blood 2024; 144 (Supplement 1): 931.

✅ Talquetamab:

SAFE AND EFFECTIVE BRIDGING OPTION to CART

No Delays in transition to CART

Talquetamab for Bridging

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3. CILTA-CEL OR IDE-CEL: Which BCMA CAR product to choose?

Munshi NC, et al. NEJM. 2021.; Martin T, et al. Blood. 2021. Lin Y, et al. JCO 2023

ASH2024: U.S. Multiple Myeloma Immunotherapy Consortium�Multicenter Retrospective study, N=641�Ide-cel N=686; Cilta-cel N=255

Favors Cilta-cel

Favors Ide-cel

20.07

6.8

Comparative Safety and Efficacy of Ciltacabtagene Autoleucel and Idecabtagene Vicleucel CAR T-Cell Therapies in Relapsed or Refractory Multiple Myeloma. Blood 2024; 144 (Supplement 1)

Odds show CILTA-CEL treated patients more likely to experience:

Infections �Delayed neurotoxicity�Severe CRS

≥ CR

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So which CAR-T product to choose?

Cilta-cel affords superior survival outcomes* sensitivity analysis: PFS and OS Restricted to ≥ March 2022

IT DEPENDS…

🔹 Cilta-cel delivers deeper responses

🔹 Cilta-cel affords superior survival outcomes

🔻Toxicity profile shapes CAR-T choice�

Cilta-cel: More Infections, delayed neurotoxicity, severe CRS��Consider Ide-cel in: Older, frailer patients, those at higher risk for neurotoxicity?

Comparative Safety and Efficacy of Ciltacabtagene Autoleucel and Idecabtagene Vicleucel CAR T-Cell Therapies in Relapsed or Refractory Multiple Myeloma. Blood 2024; 144 (Supplement 1)

Non-relapse mortality was slightly higher among patients treated with Cilta-cel HR=1.24, 95% CI=0.67, 2.30, but not significant p=0.49

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4. CAN PROPHYLACTIC TOCILIZUMAB DECREASE INCIDENCE OF CRS? �

No additional tocilizumab or steroids given for CRS

Kowalski et al ASH 2024 ; Tocilizumab Prophylaxis for Patients with Relapsed or Refractory Multiple Myeloma Treated with Teclistamab,Elranatamab or Talquetamab,Blood, Volume 144, Supplement 1, 2024 ASH 2024

Median age 67 (40-84), 21% >75 years

Black 24% , White 76%

YES…�BUT NEED MORE LONG TERM DATA

Grade 3+ heme toxicities-�neutropenia 53% median onset 13 days, anemia 47%, thrombocytopenia 35%

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5. Later complications of BCMA CAR-T

Immune Effector Cell Associated Hematotoxicity (ICAHT)

Cytopenias associated with immune therapies eg CART
Increases morbidity- infection risk, growth factor, transfusions

Use of Tocilizumab , More LOT, lower baseline Platelet count �increased risk

STEM CELL BOOST RAPIDLY IMPROVED RECOVERY

Boost: Previously collected cells intended for a 2^nd ASCT
27% (22/82) received a stem cell boost
Median time to boost was 52 (29-270) days from CAR-T

*** p< 0.001, ** p<0.01, * p<0.05

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Immune effect cell colitis

Protracted diarrhea (>G3) occurring after BCMA CART
Cause unclear…

Eradiation of the BCMA+ long lived IgA plasma cells?
These modulate gut immunity and microbiome
Autoimmune type phenomenon�

Fairly infrequent, but can be fatal due to enterocolitis/perforation

Incidence:1.2% (14/1287) �Idecel 0.2%, 2.2% ciltacel
Death due to enterocolitis 36%

3 cases of T-cell LPD excluded*

5. Later complications of BCMA CAR-T

Blood Cancer J. 14, 180 (2024). https://doi.org/10.1038/s41408-024-01167-8

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Presentation�Time after CART: 92.2 days (2.2-210) • Days after CRS resolution: 85 (2-205)�Nonbloody diarrhea (>G3): 87% • Radiographic enteritis/colitis: 43% �Time to resolution: 113 days (76-188)�

Consider if unexplained diarrhea > 1 month after CART

Rule out infectious colitis, including CMV
Endoscopy and Biopsy to r/o enteral T-Cell Lymphoproliferative disorder

Re-refer to CAR-T treatment center

ID and GI collaboration
Test for CAR presence on enteral biopsies

Early irAE management

Minimize Systemic steroids
Early biologics: Infliximab, vedolizumab
Consider Cyclophosphamide

RECOMMENDATIONS FOR HEMATOLOGISTS

Blood Cancer J. 14, 180 (2024). https://doi.org/10.1038/s41408-024-01167-8

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6. Managing the AEs of GPRC5D BsAb

Palmar

keratoderma

MONUMENTAL 1 Onychomadesis 54%*

Onychoclasis 54%

Nail dystrophy 63%

N. Narayan etal , JAAD Case Reports 2023 Vol. 31 Pages 66-68 , Mansilla-Polo Journal der Deutschen Dermatologischen Gesellschaft, 22: 1282-1286. Faiman et al Blood 2024; 144 (Supplement 1): 3786.Satisfaction and Experiences with Talquetamab: Results from Qualitative Patient and Physician Research, Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab A. Chari, et al Clinical Lymphoma Myeloma and Leukemia 2024 Vol. 24 Issue 10 Pages 665-693.e14

ASH 2024: ORAL RELATED AEs IMPACT QUALITY OF LIFE THE MOST

Dysgeusia
Ageusia
Hypogeusia
Xerostomia
Dysphagia
Oral mucositis

psoriasiform�ecchymotic rash

Palmar desquamation

Most prevalent
Occur fastest

Rashes 35-39% on MONUMENTAL 1

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Managing the AEs of GPRC5D BsAb

ASH 2024 Schinke et al

Less frequent dosing �(0.8 mg/kg Q4W) for patients with good responses.

Dosing adjustments typically occurred after 3 cycles �(range: 2–6 months)
Depending on patient response and toxicity management

Ppx dexamethasone and Nystatin tid
Icepack/cheek wraps tid
Ppx zinc and B-complex to delay toxicities
Dry Mouth: Biotene, lozenges, saliva alternatives

Oral Symptoms

Moisturizers, ammonium lactate, urea-based creams
Topical steroids
Avoid hot showers
low potency topical steroids
DERM CONSULT IF PERSISTENT OR HIGH GRADE TOX , ESPECIALLY IF > CYCLE 2

Skin

Vit E cuticle oil, Ammonium lactate cream, Urea Based treatment
Low dose steroids for peeling around nails
Cotton gloves with Aquafor overnight

Nail

Recommendations:

Real-world Experience With Talquetamab Clinical Management in Relapsed Refractory Multiple Myeloma (RRMM): A Qualitative Study of US Healthcare Providers Schinke et al P-401 �Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab A. Chari, et al Clinical Lymphoma Myeloma and Leukemia 2024 Vol. 24 Issue 10 Pages 665-693.e14

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Emerging therapies in focus

Bispecific combinations (TRIMM, TRIMM-2, REDIRECTT)
Upfront CART –CARTITUDE 2
New BCMA CART constructs with less toxicity –ANITOCEL
GPRC5D CART- ARLO-CEL
ALLO-CART
Tri-specifics

JNJ-79635322 (BCMA, GPRC5D, and CD3)
ISB2001 CD3,BCMA, CD38

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Thank you

Photo credit:https://www.mskcc.org/timeline/car-t-timeline-progress