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WELCOME & INTRODUCTION S. Vincent Rajkumar, MD Mayo Clinic, Rochester Heather Cooper Ortner President & CEO, International Myeloma Foundation

THANK YOU

Update on IMWG Projects

47 IMWG Consensus Statements/Guidelines 20032026 33 different first authors 27 different last authors 21 IMWG research projects 18 different first authors

Upcoming IMWG Guidelines for 2026-2027

IMWG IMS Revised Response Criteria IMWG Guideline on Newly Diagnosed Myeloma IMWG Guideline on Dose and Schedule of Myeloma Drugs IMWG Guideline on Smoldering Myeloma IMWG Guideline of Inclusion Exclusion Criteria for Clinical Trials

IMWG Working Committees • • • • • •

Bone Disease Committee (Terpos/Hillengass) Immunotherapy Committee (Martin/Lin) Mass Spectrometry Committee (Murray) SMM Committee (Mateos/Kumar) MRD Committee (Paiva/Munshi) QOL/PRO Committee (Zweegman/Sidana)

IMWG Website imwg.org imwg.net imwg.info imwg.online imwg.ai

SESSION 1: NEWLY DIAGNOSED MULTIPLE MYELOMA Session Chairs: Sagar Lonial, MD, FACP Philippe Moreau, MD

HOW DO WE IMPROVE ON STANDARD QUADRUPLETS FOR INITIAL THERAPY – TRIALS & CHALLENGES? Francesca Gay, MD PhD University of Torino, Italy

How do we Improve on Standard Quadruplets for Initial Therapy: Trials and Challenges

Francesca Gay, MD PhD University of Torino, Italy

Outcome with standard quadruplets

Estimated PFS

DVRd plus ASCT (PERSEUS): 205 months (17.1 years) DVRd no ASCT (CEPHEUS): 100 months (8.3 years) DVRd, daratumumab, bortezomib, lenalidomide, and dexamethasone; f/u, follow-up; ITT, intent-to-treat; PFS, progression-free survival; TE, transplant-eligible; TIE, transplant-ineligible; VRd, bortezomib, lenalidomide, and dexamethasone. 12 Sonneveld, P et al, EMN 2025

Outcome with standard quadruplets TRANSPLANT ELIGIBLE

TRANSPLANT NON ELIGIBLE

DVRd

IsaVRd

IsaKRd

DVRd

IsaVRd

Median FU

48 months

16 months

59 months

60 months

24 months

MRD neg (105 )

75% overall

66% after ASCT

79% after light consol

63% after induction

61% overall

76% @60months

53% @18months

1-year sust MRD (10-5)

65% overall

49% overall

47% overall

PFS

84% @4year

88% @3year

66% After light consol NA

59% @72months

63% @60months

85% @24months

CONTINOUS TREATMENT (NO treatment FREE INTERVAL)

Sonneveld, P et al, NEJM 2024,Moreau P etal ASCO 2025, Mai E et al JCO 2025, Gay F et al, Nat Medicine 2026, Perrot A et la NEJM 2025 Facon T et al NEJM 2024 and ASCO 2024; Usmani S et al, Nature medicine 2025, updated ASCO 2026, Leleu X nat medicine 2025, Orlowski R, et al Blood132026.

How to improve? • Improve efficacy: implement novel highly effective therapies in first line • Personalized approach: implement static and dynamic prognostic factors • Avoid unnecessary treatment • Improve on safety

Improve efficacy: novel immunetherapies • Which one? • For all? • When? • For how long?

Aim for CURE: high rate of sustained MRD negativity with fix duration of Therapy 15

Immunetherapies: Bispecifics TE (1) INDUCTION

MAINTENANCE

Raab, M etal; ASH 2024; Zamagni E et al, ASH 2024

Immunetherapies: Bispecifics TE (1) • Implemented in the context of SoC (quadruplet+ASCT) in different treatment phases • Challenging the role of ASCT • Single Agent of combinations • Single or double target on PCs • Mainly Fix duration of therapy

Immunetherapies: Bispecifics TNE (2) EMN 37 FITFIX FOR FRAIL trial

MagnetisMM-6

Immunetherapies: Bispecifics NTE (2) • Implemented upfront • Implemented after debulkig • Challenging the role of SoCs • Single Agent of combinations • Fitness adapted approaches

Immunetherapies: CAR-T cells CARTITUDE 6

CARTITUDE-5

• Challenging SoCs • Fix duration • Further consolidation in HR

Immunetherapies: ADC

DREAMM-10

Bela-DRd

Added to SoCs or challenging SoCs mainly with continous therapy

Improve efficacy: novel immunetherapies • Which one? Most trials are now comparing Immuneth vs SoC • For all? Most trials are now comparing Immuneth vs SoC regarless of baseline features • When? Most trials are now comparing Immuneth vs SoC at different specific timepoints • For how long? Some trials are exploring fix duration th/MRD driven We can find different effective approaches Unlikely one size fits all Can we align sub-analyses to increase comparability? How to draw conclusions on optimal approach? 22

Risk definition in Myeloma

Align risk evaluation to increase comparability

Rees MJ, D'Agostino M, Leypoldt LB et al Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies. Am Soc Clin Oncol Educ Book. 2024 Jun; 44(3). Avet-Loiseau H, et al. J Clin Oncol.

Minimal Residual Disease Adapted Strategy MIDAS = MInimal residual Disease Adapted Strategy Induction

MRD evaluation

Risk-adapted consolidation and maintenance

Standard risk (MRD <10-5)

R IsaKRD x 6 (28d cycles)

Stem cell collection after cycle 3 (G-CSF+/- plerixafor)

IsaKRD x 6

Lenalidomide

Arm A

ASCT + IsaKRD x 2

Lenalidomide

Arm B

ASCT + IsaKRD x 2

Isa - Iberdomide

Arm C

Tandem ASCT

Isa - Iberdomide

(3 years)

1:1

(3 years)

MRD

High risk (MRD >10-5)

1:1

(3 years)

Arm D

Perrot A et al IMS 2024; Perrot et al Blood 2025; Perrot A et al, ASCO 2025; Perrot A et al; NEJM 2025 MRD measurable residual disease; R: Lenalidomide; d: dexamethasone; K: Carfilzomib; Isa: Isatuximab,

Minimal Residual Disease Adapted Strategy High-post induction MRD negativity with 6 cycles of Isatuximab-KRd

Induction

Different Rates of MRD negativity in patients with different cromosomal abnormalities

Post-induction MRDnegativity rates 100% 80% 60%

IsaKRD x 6 (28d cycles)

66% 50%

ITT

40% 20% 0%

Stem cell collection after cycle 3 (G-CSF+/- plerixafor)

63% 47%

Perrot A et al IMS 2024; Perrot et al Blood 2025 MRD measurable residual disease; R: Lenalidomide; d: dexamethasone; K: Carfilzomib; Isa: Isatuximab,

MRD Kinetics: impact of biology on early time points Effect of t(11;14) on the rate of MRD negativity in the overall population

Disease biology impact, not only for high-risk challenges in implementing MRD in the treatment algorithm - the choice of the timepoint ? - MRD and biology? Same for all? Gay F nature medicine

Ongoing trials UKMRA Myeloma XVII iFIT

Explore MRD driven approaches and immunetherapies

Conclusions Some questions: • Immunetherapies: from diagnosis? Anti-CD38-PI-IMID-Dex

• For all and which one? can patient/disease profile determine the choice?

Anti-CD38-PI-IMIDDex

• Immuneth at a specific timepoints?

LEN or Anti CD38-Len maintenance

MRD

MEL200-ASCT

• For how long?

SINGLE VERSUS DOUBLET MAINTENANCE: WHAT'S THE CURRENT STANDARD OF CARE? Shaji Kumar, MD Mayo Clinic, Rochester

Single vs Doublet Maintenance: What’s the current standard of care? Shaji Kumar, M.D. Mark and Judy Mullins Professor of Hematological Malignancies Mayo Clinic

Scottsdale, Arizona

Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

Rochester, Minnesota

Jacksonville, Florida

Concept of consolidation and maintenance Maintenance

Tumor Load

Induction Consolidation

Observation

Ideal - Continued eradication of residual clone At least - Suppression of residual clone

Time from diagnosis Control

?Cure

SCT Eligible SCT Ineligible

Diagnosis & Risk Stratification

Myeloma Treatment Paradigm

Tumor Burden

Induction

Consolidation

Maintenance

Induction followed by continuous therapy

Maintenance vs. consolidation Maintenance

Consolidation • High Intensity • Short duration • Goal is to deepen response

• Low intensity • Long duration • Goal is to prolong/maintain response Ideal Maintenance:

• Easy to administer, preferably an oral therapy (or self administered SQ) • Well tolerated and minimally toxic: prolonged treatment: Quality of life • No long-term deleterious effects • Should prolong overall survival, not just progression free survival

Lenalidomide maintenance Len

McCarthy et al, JCO 2017

Placebo

Daratumumab Maintenance

Philip Moreau et al

Lenalidomide in transplant ineligible MM

Facon et al, Blood 2018

Dual Maintenance – Dara-Len in PERSEUS

Sonneveld et al, NEJM

Dual Maintenance – Dara-Len in MAIA

Facon et al, Lancet Oncol 2021; 22: 1582–96

Do we know DR is better than R? HD7

DRAMMATIC

What about high-risk MM? Exploring dual maintenance S1211

E1A11

Progression-Free Survival (%)

100

Median (95% CI) PFS: VRd=34·4 (30·1-NE) months KRd=34·6 (28·8-37·8) months

0 0

25 26

13 14

3 0

Time from Randomization (Months) KRd VRd

545 542

401 377

252 243

187 183

Numbers at Risk 127 83 59 114 73 43

38 31

Kumar et al, Lancet Oncology; Usmani et al, Lancet Hematology

Impact of dual maintenance – FORTE trial

Gay et al, ASH

Disease risk vs. response depth 100

Patients (%)

P<0.001

pos.MRD-High Risk

pos.MRD-Stdard Risk neg.MRD-High Risk neg.MRD-Stdard Risk

0 0

4 21 5 25

0 3 1 4

Time since MRD assessment N at risk pos.MRD-High Risk pos.MRD-Stdard Risk neg.MRD-High Risk neg.MRD-Stdard Risk

Avet Loiseau et al, ASH 2017

28 82 18 56

19 73 17 54

11 59 14 48

5 42 12 43

PERSEUS: Sustained MRD Negativity ≥CR by Subgroups

Moreau et al ASCO 2025

Importance of continued maintenance

Costa et al, ASH 2021

Current standard of care • Minimum lenalidomide maintenance – at least 2 years – Duration remains a question – ENDURANCE second randomization awaited

• Increasingly lenalidomide + anti-CD38 being adopted – Following quad induction and ASCT or continued triplet or quad in TIE pts

• Dual maintenance recommended for all high-risk patients – PI with IMiD or anti-CD38 with IMiD ? Prefer former

• Continued dual maintenance important for HR MM

SCT SCT Eligible Ineligible

Changing face of pre-maintenance disease Induction

Consolidation

Maintenance

Induction followed by continuous therapy

Tumor Burden

Trial

Regimen

MRD @ end of consolidation (10-5)

CASSIOPEIA

Dara-VTd

64%

PERSEUS

Dara-VRd

75%

HD7

Isa-VRd

66%

ISKIA

Isa-KRd

75%

Cure in MM

Stop Rx

Monitoring Phase – 5 years

Treatment phase Year 1

Year 2

Year 3

Serological Complete response Marrow MRD negative at 106 (NGF or NGS) Functional Imaging Negative

Negative if performed

Future technology

Negative if performed

Year 4

Year 5

Potential Cure

So, what are the questions for future? • Does everyone need maintenance? – Increasingly fewer patients as we can get deep MRD with induction – Disease risk – baseline and dynamic will determine this

• Should it be one or two drugs? – Likely with anti-CD38 + Len based on Ph 3 trials – with T-cell direction therapy likely one drug will be sufficient

• How long should it be? – Will depend on the MRD negativity achievement and disease risk – Duration should be balanced with toxicity, cost and long-term risk

MajesTEC-4: randomized phase 3 trial

Participants with NDMM who have received 4-6 cycles of a 3 or 4 drug-induction that includes a PI and/or an IMiD and a single or tandem ASCT with or without consolidation stratified by: • consolidation use: yes/no • ≥CR vs <CR • anti-CD38 vs non‑anti-CD38 antibody-based induction/consolidation

Study Treatment (28d cycle; 26 cycles)* Enrollment (for 2 years or until PD, death, intolerable toxicity,

Follow-up

(until death, consent withdrawal, loss of follow up, EOS)

consent withdrawal, EOS)

Arm A (N=500) Tec – Len

1:1 Randomization

Screening

(max 28d before randomization; 36 mo accrual period)

Arm B (N=500) Len

Arm C (N=500) Tec

Study will continue until approximately 380 deaths have been observed in the pooled Tec-Len (Arm A) and Len (Arm B) arms and approximately 380 deaths have also been observed in the pooled Tec (Arm C) and Len (Arm B) arms.

EOT Visit

Follow Up

Study End

FU for response until PD or next line. FU post-PD for survival, SST, 2 nd primary malignancy Q16W until EOS

* Participants in Arm A (Tec-Len) who achieve a CR or better after 1 year of treatment (13 cycles) will discontinue teclistamab but continue lenalidomide for the second year (cycles 14-26)

MRD assessment

 At study entry and at 6 & 24 months after C1D1  Time of suspected CR or sCR • For participants with suspected CR or sCR, additional samples at 12,18,30,36,48, & 60 months post C1D1

ASCT, autologous stem cell transplant; EOT, end of treatment; IMiD, immunomodulatory agent; Len, lenalidomide; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; NGF, next generation flow cytometry; CR, complete response; PD, progression disease; EOS, end of study; Tec, teclistamab

https://clinicaltrials.gov/ct2/show/NCT05243797

kumar.shaji@mayo.edu

THANK YOU

PANEL DISCUSSION Panelists: Katja Weisel, MD Hamburg-Eppendorf, Germany Saad Usmani, MD Memorial Sloan Kettering Cancer Center

SESSION 2: RELAPSED MYELOMA – PART I Session Chairs: Philippe Moreau, MD S. Vincent Rajkumar, MD

FIRST RELAPSE: CAR T VERSUS BISPECIFICS Noopur Raje, MD Massachusetts General Hospital

First Relpase: CAR T cells Versus Bispecifics Noopur Raje, MD Director, Center for Multiple Myeloma Mass General Brigham Cancer Institute Professor of Medicine Harvard Medical School

Relapse MM • With QUADs used upfront, patients at first relapse are triple class exposed at the least. • Median time to relapse predicted to be 17 years in standard risk patients on a QUAD • Early relapse post a QUAD are therefore genomically or biologically high risk

FDA-Approved Autologous CAR T Therapy for R/R MM

Initial approvals: patients with R/R MM after ≥4 prior LOT, including an IMiD, PI, and an anti-CD38 mAb. Expanded indications granted (April 2024): ide-cel after ≥2 prior LOT including an IMiD, PI, and an anti-CD38 mAb (KarMMa-3) and cilta-cel after ≥1 prior LOT including a PI and an IMiD and refractory to len (CARTITUDE4).

Berdeja. Lancet. 2021;398:314. Ciltacabtagene autoleucel PI. Idecabtagene vicleucel PI. Image created from BioRender.com

CARTITUDE-4: Cilta-cel vs DPd/PVd After 1-3 Lines Trial design

Baseline characteristics Median age

61.5 yrs

Median time since diagnosis

3 yrs

Median prior therapies

N=2

Triple-class refractoriness

14.4%

Daratumumab refractoriness

23.1%

High-risk cytogenetics

59.4%

Phase 3 CARTITUDE-4 compared cilta-cel vs SOC in R/R patients MM after 1-3 prior lines

Jesús San-Miguel et al. N Engl J Med 2023; 389:335-347

CARTITUDE-4: Response and PFS ORR

PFS by treatment and number of prior lines

Phase 3 CARTITUDE-4 compared cilta-cel vs SOC in R/R patients MM after 1-3 prior lines

Jesús San-Miguel et al. N Engl J Med 2023; 389:335-347

CARTITUDE-4: OS

• Median OS was not reached

– Overall MRD negativity, a secondary endpoint, was also higher in patients randomized to cilta-cel vs SOC (62.0% vs 18.5%)

OS in the ITT population, 33.6 months median follow-up 100

30-month OS

76.4

Alive, %

– Cilta-cel also showed an OS benefit over SOC, with HR, 0.55 (95% CI, 0.39– 0.79; P=0.0009)1,a

Cilta-cel SOC

63.8

40 20 0

HR (95% CI), 0.55 (0.39–0.79); P=0.0009b,c 0

24 27 Months

Data cut-off date: May 1, 2024. bLog-rank test. P value, 0.0009, crossed the prespecified boundary of 0.0108 as implemented by the Kim-DeMets spending function with parameter=2. cHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable.

cilta-cel, ciltacabtagene autoleucel; CR, complete response; HR, hazard ratio; ITT, intent-to-treat; MRD, minimal residual disease; OS, overall survival; SOC, standard of care. 1. Mateos MV, et al. Presented at IMS; September 25–28, 2024; Rio de Janeiro, Brazil. Oral #1437.

BCMA-directed BsAbs for RRMM: Registrational trials TRIAL

KEY ELIGIBILITY

ELRANATAMAB1–4 MagnetisMM-3 Phase 2

MM refractory to ≥1 of each of the following: PI, IMiD, anti-CD38 mAb

TECLISTAMAB5–10 MajesTEC-1 Phase 2

MM with ≥3 prior LoT including PI, IMiD, anti-CD38 mAb

LINVOSELTAMAB11 LINKER-MM1 Phase 1/2

MM with ≥3 prior LoT including PI, IMiD, anti-CD38 mAb

COHORTS BCMA-Naïve BCMA-Exposed (ADC and/or CAR T)

BCMA-Naïve BCMA-Exposed (ADC and/or CAR T)

BCMA-Naïve or BCMA-Exposed (ADC only)

THERAPY

PRIMARY ENDPOINT

Elranatamab monotherapy

IMWG ORR by BICR

Teclistamab monotherapy

IMWG ORR by IRC

Linvoseltamab monotherapy

IMWG ORR by IRC*

Linvoseltamab is not approved by the EMA *Primary endpoint for Phase 2 of trial. ADC, antibody-drug conjugate; BCMA, B-cell maturation antigen; BICR, blinded independent committee review; BsAb, bispecific antibody; CAR T, chimeric antigen receptor T-cell; CD, cluster of differentiation; EMA, European Medicines Agency; IMiD, immunomodulatory drug; IMWG, International Myeloma Working Group; IRC, independent review committee; LoT, lines of therapy; mAb, monoclonal antibody; MM, multiple myeloma; ORR, overall response rate; PI, proteasome inhibitor. 1. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04649359. Accessed 21 August 2024. 2. ELREXFIO™ (elranatamab-bcmm) [prescribing information]. New York, NY. Pfizer Inc; August 2023. 3. ELREXFIO® (elranatamab) Summary of Product Characteristics. Bruxelles Belgium: Pfizer Europe; 2024. 4. ELREXFIO® (elranatamab). Sao Paulo, Brazil: Pfizer Brazil; 2024. 5. Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04557098. Accessed 21 August 2024. 6. Moreau P et al. N Engl J Med. 2022;387:495–505. 7. TECVAYLI® (teclistamab-cqyv) [prescribing information]. Horsham, PA. Janssen Biotech, Inc; February 2024. 8. TECVAYLI® (teclistamab) Summary of Product Characteristics. Beerse Belgium: Janssen-Cilag International; 2024. 9. TECVAYLI™ (teclistamab) Sao Paulo, Brazil: Janssen-Cilag Farmacêutica Ltda; 2024. 10. Touzeau C et al. ASCO 2022. Abstract 8013 (poster presentation). 11. Bumma N et al. J Clin Oncol. 2024;42:2702–2712.

TecDara vs DPd/DVd in early relapse 1-3L (MajesTEC-3)) This study builds on the synergy between two key agents

Teclistamab plus Daratumumab compared against standard triplets — DPd or DVd — in patients with 1-3 prior lines of therapy

Cohort Prior exposure anti-CD38

Tec/Dara (n=291)

DPd/DVd (n=296)

15 (5.2%)

16 (5.4%)

Only about 5% of subjects had prior anti-CD38 exposure 1. MV Mateos et al. MajesTEC-3. ASH 2025 LBA-6

Tec-Dara vs DPd/DVd in early relapse 1-3L (MajesTEC-3) ORR and MRD Negativity

Progression Free Survival Tec-Dara vs DPd/DVd ≥CR: 82% vs 23%

Tec-Dara clearly outperformed DPd/DVd across all response depths...

Tec-Dara vs DPd/DVd MRD-neg: 58% vs 17%

1. MV Mateos et al. MajesTEC-3. ASH 2025 LBA-6

Toxicity

CRS 60.1% (G1/2: 44.2%/15.9%) ICANS 1.1% Infections Over Time

Randomized phase III studies of anti-BCMA bispecific antibody in progress in relapsed myeloma MagnetisMM-5

LINKER-MM3

Elranatamab

R 555 patients

Elranatamab Daratumumab

CERVINO

Etentami g

Linvoseltamab

R ~300 patients

Elotuzumab Pomalidomide Dexamethasone

R 380 patients

Daratumumab Pomalidomide Dexamethasone

Carfilzomib Dexamethason e Elotuzumab Pomalidomide Dexamethason e Selinexor Bortezomib Dexamethason e

Primary endpoint: PFS

Primary endpoint: PFS and ORR

1-4 prior lines of therapy, including lenalidomide and PI

≥ 2 prior lines of therapy, including lenalidomide, PI, and anti-CD38 antibody

Prior anti-CD38 allowed if > 6 months

Prior anti-CD38 antibody allowed Patients in the EU and the UK must have had 2-4 prior lines of therapy, including an anti-CD38 antibody

This slide includes information of product or indication that are not approved in Japan.

Grosicki S, et al., ASCO 2022; Weisel K et al., IMS 2023; Costa LJ et al., IMS 2024

Sequencing: CAR-T Cell Therapy After BCMA-Targeted Therapy CARTITUDE-2, Cohort C: Cilta-cel Patients with RRMM with previous exposure to PI, IMiD agent, antiCD38 mAb, and a non-cellular BCMA-targeting therapy1 ORR PR

Patients (%)

60% (12/20)

25%

 VGPR 55%

Full cohort (N = 20)

31 %

Full cohort

100

sCR

57% (4/7)

15 %

20% 5%

62% (8/13)

10%

VGPR

Patients progression free and alive (%)

100

Real-world experience of patients with multiple myeloma receiving idecel after a prior BCMA-targeted therapy2

14 %

 VGPR 61%

15%

29 % 14 %

 VGPR 43%

40 20

ADC exposed BsAb exposed (n = 13) (n = 7)

Patients at risk

6 9 PFS (months) 12

Median PFS

PFS, mo (95% CI)

Full cohort (N = 20)

ADC exposed (n = 13)

BsAb exposed (n = 7)

9.1 (1.5-13.2)

9.5 (1.0-15.2)

5.3 (0.6-NE)

1. Cohen et al. Blood. 2023;141(3):219-230. 2. Ferreri CJ et al. Blood Cancer J. 2023;13:117; abstract 766.

Real world data of anti-BCMA bispecific antibody ➞ ciltacel Type of prior BCMA therapy

Time (6 m) since prior BCMA therapy

PFS 16.8 v 6.2 months

Decrease in efficacy of cilta-cel in real world data, with effect related to time from prior therapy Effect of prior bispecific antibody may not be as much compared to CARTITUDE-2 cohort C cohort

Sidana S et al., Blood 2025

Outcomes With Bispecific Antibodies After Prior BCMA-Directed Therapy 100% 10 0

Teclistamab Best ORR With and Without Exposure to ≥1 Lines of BCMA Treatment

Pooled Analysis of Elranatamab Efficacy After Prior 100% 10 BCMA Therapy 0

80% 80

60%

60% 60

40% 40

20%

63%

57%

65%

60%

0% 0

69%

≥ CR

61%

40% 40 20% 20 00%

Best ORR

35%

46%

42%

18%

19%

53%

19%

Magnetis Any BCMA Prior ADC Prior CAR T MM-3 (n (n = (n mDoR, mo: 13.6 (n =NR 123) = 17.1 87) 59) = NE 36) Moreau. NEJM. 2022;387:495. Dima. ASH 2023. Abstr 91. Lesokhin. Nat Med. 2023;29;2259-2267. Nooka. ASCO 2023. Abstr 8008.

Tec-Dara vs CART (Cilta-cel) in early relapse (1-3L) Tec-Dara not only delivered impressive depth of response and PFS — it also improved overall survival...

CARTITUDE-4: PFS

54% reduction in the risk of death compared to DPd/DVd

vs This brings up an important real-world question — if we can achieve durable control with off-the-shelf bispecifics like Tec-Dara, how does that stack up to CAR-T?

ASH 2025: Tec-Dara1

Standard of care: CAR-T (cilta-cel) 2

MajesTEC-3 ORR ~89% ≥CR ~82% MRD-neg ~58% Continuous therapy

CARTITUDE-4 ORR ~85% ≥CR ~70–75% MRD-neg ~60% Fixed, one-time therapy

Strength: immediate availability

Strength: one-and-done

Limitation: chronic infection risk 1. 2.

MV Mateos et al. MajesTEC-3. ASH 2025 LBA-6 S. Jagannah et al. JCO 2025

Limitation: manufacturing delay, acute toxicity

And should our first immunotherapy move be a bispecific?

Questions and Challenges

• ? Access • ? Impact of sequencing: Moving therapies early may impact later therapies • Continuous vs One time • Toxicities • Are there special patient populations for CAR vs Bispecifics

Future for MM • Should the ? be about CARs versus Bispecifics OR • Should the ? be about sequencing CARs/Bispecifics and Dual targeting strategies • The goal should be CURE: TOTAL IMMUNOTHERAPY

Noopur Raje, MD Emy Agyemang, NP Andrew Branagan, MD, PhD Jill Burke, NP Dana Cameron, RN Christina Cioffi, RN Diana Cirstea, MD Kelley Grealish, NP Cynthia Harrington, NP Annemarie Haynes, RN Chelsea Jenkins, NP Bridget Kim, PharmD Matthew Lei, PharmD Julia Lin Alicia Marggraf Kareem Mosaheb Sarah O’Neill, PharmD Mira Oravcova-Mejia Nela Oser Lisete Packer, RN Luvlee Perry Benjamin Puliafito, MD Manal Riadi Meredith Richardson, RN Kat Sanclemente, RN Stephanie Sanford, NP Alexa Santilli, NP MaryAnn Weitz, NP Lexie Wright Andrew Yee, MD

Noopur Raje, MD nraje@mgh.harvard.edu @NoopurRajeMD

DURATION OF BISPECIFIC THERAPY Ajay Nooka, MD, MPH Winship Cancer Institute of Emory University

DURATION OF BISPECIFIC THERAPY

Ajay K. Nooka, MD MPH Professor, Department of Hematology and Medical Oncology Director, Myeloma Program Associate Director of Clinical Research Winship Cancer Institute, Emory University School of Medicine

CONFLICT OF INTEREST DISCLOSURE I hereby declare the following potential conflicts of interest concerning my presentation: Consultancy and Honoraria: AstraZeneca, Blue Earth Diagnostics, Cellectar biosciences, GlaxoSmithKline, Janssen, KITE therapeutics, ONK therapeutics, OPNA, Pfizer, Perceptive informatics LLC, Premier Research Sanofi and Sebia Research Funding (to institution): Aduro Biotech, Amgen, Arch Oncology, Bristol Myers Squibb, Cellectis, Cellectar, Genentech, GlaxoSmithKline, Janssen, OPNA, Karyopharm, Kite Pharma, Merck, Pfizer, Skyline diagnostics and Takeda Discussion of off-label drug use: None

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

PATIENT CASE: MS. TF IS A 57 Y/O BLACK FEMALE WITH GASTROPARESIS, ASTHMA EXACERBATIONS, RELAPSED/REFRACTORY MULTIPLE MYELOMA, ENROLLED ON 64007957MMY1001,TECLISTAMAB 1. Initial diagnosis on 05/29/2009 in San Diego, when her presenting bone marrow biopsy showed 80% cellularity with plasma cells comprising 70% of the marrow cells. FISH and cytogenetics were not available on this specimen, but her presenting labs do reveal that she had symptomatic multiple myeloma per IMWG guidelines 2. She underwent initial induction therapy with RVD followed by ASCT1 on 12/31/2009. She remained on observation post transplant, unfortunately progressed and underwent ASCT2 on 06/27/2012, again unmaintained post transplant. 3. At progression, she was on daratumumab, pomalidomide, and dexamethasone (DPd), started on 04/26/2016. Daratumumab monthly treatment started on 11/11/2016, she moved to Atlanta, and we assumed her care and resumed DPd regimen. She had evidence of progression in 2021 and was enrolled on 64007957MMY1001,Teclistamab Priming dose #1 Teclistamab 4/9/21 C1/D1 Full dose Teclistamab C1D1 [1500mcg/kg] = 4/14/21. Tolerated well; no s/sx of CRS/ neurotoxicity 4/28/21-5/4/21 admission for G2 intolerable GI symptoms. 5/13/21-5/16/21, admission for FTT 6/9/21-6/18/21, admission for FTT, G-J tube placed on 6/14/21 7/5/21-7/9/21, admission for blocked feeding tube, tube exchanged 10/2021: hospitalization for line associated infection 12/15/21: Covid +, treatment held until, required hospitalization Repriming Dose 3/18/22, Held dose on 4/8/22 due grade 2 URI; improved to grade 1. 2nd repriming dose 4/14/22), main dose 5/5/22 *Admitted 5/20/22-6/1/22 for PNA. Admission complicated by allergic reaction with unknown trigger requiring ICU transfer and intubation. Discharged is stable condition requiring supplemental O2. Resumed treatment 6/9/22. *Admission 7/21/22 for worsening hypoxic failure, suspected PNA . CT Chest showed worsening bilateral ground-glass opacification. CT maxillofacial showed multifocal odontogenic disease. Discharged on clindamycin. *Admitted 9/16/2022 for planned re-challenge w/ IVIG infusion (significant history of reaction requiring intubation in past). Pt tolerated infusion well without issues. C.diff testing repeated prior to admission and positive, pt is symptomatic; reaction to IVIG, despite giving over 10 hours outpatient. Patient requires hospitalization for IVIG, must be given over 12+ hours. Repriming dose 2/26/23 (no complications) Completed fecal transplant for re-current C-diff on 3/14/23, came off study 08/09/2023 (all together received 12 full doses) WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

SEROLOGICAL RESPONSE AND MRD

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

EFFICACY AND SAFETY OF BISPECIFIC ANTIBODIES IN MYELOMA Target

Agents

Trial

ORR, %

mDOR, mo

mPFS, mo

Teclistamab

MajesTEC-1

Elranatamab

MagnetisMM-3

NR (2y: 67%)

Linvoseltamab

LINKER-MM1

29.4

NR (1yr: 70%)

GPRC5d-directed

Talquetamab

MonumenTAL-1

74*

10*

Target

Agents

Trial

Teclistamab

Multiple Myeloma

BCMA-directed

BCMA-directed GPRC5D-directed

Any Grade Infections, %

Grade ≥3 Infections, %

MajesTEC-1

Elranatamab

MagnetisMM-3

Linvoseltamab

LINKER-MM1

Talquetamab

MonumenTAL-1

59*

20* *Talquetamab dose 0.4 mg/kg weekly

mDOR: median duration of response; ORR: objective response rate; mPFS: median progression-free survival; NR: not reached.

Lesokhin AM, et al. Nat Med. 2023;29(9):2259-2267. Moreau P, et al. NEJM. 2022;387(6):495-505. Garfall AL, et al. ASCO 2024. Abstr 7540. Chari A, et al. Lancet Haematol. 2025;12: e269-e281. Rasche L, et al. EHA 2024. Abstr P915. Bumma N, et al. J Clin Oncol. 2024;42(22):2702-2712.

DOSING SCHEDULE HETEROGENEITY Linvoseltamab IV dosing schedule

Teclistamab SC dosing schedule SUD

SUD1

SUD 2

0.06 mg/kg

0.3 mg/kg

96 h hospitalization

Weeks 2-4

Weeks 5-23

Week 24+

1.5 mg/kg q w

1.5 mg/kg q 2w (phase 1) 1.5 mg/kg q 2w (phase 2)

48 h hospitalization

≥PR ≥4 cycles ≥CR ≥6 months

Weeks 1-2 SUD Week 1: 5 mg

Week 2: 25 mg

5 mg

25 mg

24 h hospitalization

Elranatamab SC dosing schedule SUD

SUD1

12 mg

SUD 2

Weeks 2-4

76 mg qw

Weeks 5-23

76 mg qw

Week 24+

76 mg q2w

32 mg

72 h hospitalization

≥6 cycles & ≥PR for ≥2 months: q2w

Weeks 3-14

Weeks 16-23

Week 24+

50 mg qwa

50 mg q2w

200 mg qw

200 mg q2w

VGPR: q4w <VGPR: q2w

Talquetamab SC dosing schedule SUD

Weeks 2-4

Weeks 16-23

Week 24+

SUD1: 0.01 mg/kg

SUD 2: 0.06 mg/kg

0.4 mg/kg q w

0.4 mg/kg q 2w

SUD1: 0.01 mg/kg

SUD 2: 0.06 mg/kg

SUD 3: 0.4 mg/kg Target: 0.8 mg/kg q 2w

0.8 mg/kg q 2w

0.8 mg/kg q 4w

0.06 mg/kg

0.3 mg/kg

96 h hospitalization

48 h hospitalization

New-Onset Grade ≥3 Infections Over Time in the q2w Cohort Talquetamab

Patients with new-onset grade ≥3 infections, % (95% CI)

Teclistamab 30 20 10 0

≤3 (N=165)

Total RP2D >6 to ≤9 >3 to ≤6 (n=99) (n=113)

>12 to ≤15 >18 to ≤21 >9 to ≤12 >15 to ≤18 >21 to ≤24 (n=71) (n=54) (n=84) Time, mo (n=66) (n=44)

>24 (n=19)

Talquetamab

Weight Loss in Patients With Oral AEs in the qw/q2w Cohorts

RATIONALE FOR FIXED DURATION OF THERAPY

1. Continuous exposure to T-cell engaging bsAb can lead to T-cell exhaustion 2. Continuous exposure to T-cell engaging bsAb may be driver for relapse 3. Continuous exposure to T-cell engaging bsAb leads to increased infectionrelated morbidity and mortality 4. Fixed-duration treatment would lower therapeutic burden and, improve patients QOL 5. Fixed-duration reduces financial impact on patients and payers. WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

REAL-WORLD TREATMENT PATTERNS FOR TECLISTAMAB AND TALQUETAMAB IN MULTIPLE MYELOMA (MM): EXPERIENCE FROM 609 PATIENTS

Chunara F, Lugo C, Osinski K, Shah MR, Shah N, Kent J, Mohyuddin GR, Radhakrishnan SV, Kaur G, Chakraborty R, Banerjee R, Rasche L, Schinke C, D'Souza A, Szabo A, Mohan M. Blood Cancer J. 2025 Apr 8;15(1):61

A PHASE 2, SINGLE-ARM, NON-INFERIORITY STUDY OF LIMITED-DURATION TECLISTAMAB FOR RELAPSED AND REFRACTORY MULTIPLE MYELOMA (LIMITEC)

The primary end point was freedom from teclistamab failure 6 months after enrollment.

Beatrice Razzo,Connor Grady,Sandra Susanibar-Adaniya,Adam Waxman,Dan T. Vogl,Adam D. Cohen,Edward A. Stadtmauer,Wei-Ting Hwang,Alfred L. Garfall, A Phase 2, Single-Arm, NonInferiority Study of Limited-Duration Teclistamab for Relapsed and Refractory Multiple Myeloma (LimiTec), Blood, 2023

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center 87

A PHASE 2, SINGLE-ARM, NON-INFERIORITY STUDY OF LIMITED-DURATION TECLISTAMAB FOR RELAPSED AND REFRACTORY MULTIPLE MYELOMA (LIMITEC

50 pts - median age 73 yrs (range 43-92); 21 male; 25 White, 14 Black, 4 Hispanic), Median follow-up of 12.8 months • Median prior lines of therapy was 4 (range 2-13) with 95% triple-class and 44% penta-drug refractory. 0/43 (23%) had ≥1 prior BCMA-directed therapies (4 bela-maf, 2 cilta-cel, 6 idecel). • Median time from first full Tec dose to enrollment was 7.3m (range 5.7-9.5). • Response to Tec at enrollment was VGPR in 72% and ≥CR in 28% • Estimated FFP at 6m post-enrollment is 77% (95% CI 64-92) and at 12m is 73% (95% CI 6090). • Discontinuation of Tec after 6-9m yielded outcomes comparable to historical expectations with continuous therapy with estimated median FFS of 73% at 12m post-discontinuation in a cohort with 23% prior BCMA-DT. • Early instances of PD (<6m after Tec discontinuation) that were evaluable exhibited BCMA loss and were thus unlikely due to Tec discontinuation. WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

SUSTAINED REMISSION FOLLOWING FINITE DURATION BISPECIFIC ANTIBODY THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY MYELOMA

Multi-institutional retrospective study to investigate the outcomes of patients, who discontinued bsAb for reasons other than disease progression or death, with at least 3 months’ remission after drug discontinuation • 23 patients met the inclusion criteria. Median age was 68 years [range, 28–92], high-risk cytogenetic abnormalities were present in 10/23 patients • Patients had received a median of 4 lines of therapy prior to bsAb [range, 3–9], including 17 patients with prior autologous transplants (six of whom had had two prior autografts) and two patients with prior allogeneic transplants. At a median follow-up of 15.5 months from bsAb discontinuation (range, 3–32.3) • 19/23 patients [82.6%] are alive and progression-free, with estimated Progression-Free Survival (PFS) at 6, 12, and 18 months of 90.5% (95% CI, 78.8–100), 84.0% (95% CI, 68.7–100), and 70.0% (95% CI, 46.4–100), Chakraborty, R., Cheruvalath, H., Patwari, A. et al. Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma. Blood Cancer J. 14, respectively. 137 (2024). WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

PFS AND SWIMMER PLOT FOR OUTCOMES IN ALL 23 PATIENTS WHO DISCONTINUED BISPECIFIC ANTIBODIES

Chakraborty, R., Cheruvalath, H., Patwari, A. et al. Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma. Blood Cancer J. 14, 137 (2024).

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center

MMRC HORIZON ONE: A PHASE II RANDOMIZED ADAPTIVE PLATFORM TRIAL EVALUATING NOVEL THERAPIES IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

NCI Designated Comprehensive Cancer Center 91

Myeloma Team Sagar Lonial Jonathan L. Kaufman Lawrence H. Boise Madhav Dhodapkar Nisha Joseph Craig Hofmeister Vikas Gupta Nishi Shah Richa Parikh Donald Harvey Mala Shanmugam Shannon Matulis Benjamin Barwick Manoj Bhasin Joel Andrews Rosie Pruitt Rachael Morffi Charise Gleason

WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY

Clinical Research team Pauline Newlands Bryan Burton Adam Burgess Shawn Reece Patrick Mazzeo

Research labs Boise lab Lonial lab Shanmugam lab Bhasin lab Gupta lab

Myeloma Patients

NCI Designated Comprehensive Cancer Center

PANEL DISCUSSION Panelists: Paula Rodriguez Otero, MD Clinica Universidad de Navarra, Spain Luciano J. Costa, MD University of Alabama at Birmingham

SESSION 3: RELAPSED MYELOMA – PART II Session Chairs: Jesus San Miguel, MD, PhD & Nikhil Munshi, MD

ROLE AND OPTIMAL USE OF BELANTAMAB Evangelos Terpos, MD, PhD National and Kapodistrian University of Athens, Greece

Role and Optimal Use of Belantamab

Evangelos Terpos, MD, PhD

Professor of Hematology, Director of Stem Cell Transplantation Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

Disclosures

Company name

Research support

GSK, J&J, Sanofi

BMS, Lilly, Pfizer, Swixx, Menarini/Stemline Amgen, Antengene, AOP, EUSA Pharma, Forus,Takeda

Consultant

Advisory board

Other (honoraria)

X X

EHA/EMN 2025 Guidelines: Second Line Therapy

Dimopoulos MA, Terpos E, et al. Nat Rev Clin Oncol 2025; 22(9): 680-700

BELAMAF: Antibody-Drug Conjugate - Mechanism of Action

Offidani M, et al. Drug Des Devel Ther 2021;15:2401-2415.

Belantamab Mafodotin: Randomized Clinical Trials in RRMM DREAMM-7 (NCT04246047)1

•

Daratumumab 16 mg/kg IV cycles 1-3; qw and cycles 4-8; q3w + bortezomib + Treatment until disease progression, death, dexamethaso ne

Belantamab mafodotin monotherapy 2.5 mg/kg IV q3w

• •

Daratumuma b monotherapy

• •

16 mg/kg IV q4w

•

RRMM with ≥1 prior LOT ≥1 prior line of MM therapy including lenalidomide Documented PD during or after their most recent therapy No prior treatment with an anti-BCMA agent or pomalidomide Not refractory or intolerant to bortezomib

BPd

Belantamab mafodotin 2.5 mg/kg IV q3w + bortezomib + dexamethasone

PVd

•

N=302

Cycle 9+

1:1 randomization

•

BVd

•

RRMM with ≥1 prior LOT PD during or after their most recent therapy No prior treatment with an anti-BCMA agent Not refractory or intolerant to daratumumab or bortezomib No ongoing grade ≥2 peripheral neuropathy or neuropathic pain

Cycles 1-8

DVd

•

1:1 randomization

N=494

DREAMM-8 (NCT04484623)2 Belantamab mafodotin 2.5 mg/kg IV (cycle 1) then 1.9 mg/kg IV q4w from cycle 2 onward + pomalidomide + dexamethasone Bortezomib 1.3 mg/m2 SC on days 1, 4, 8, and 11 of cycles 1-8 then days 1 and 8 (21-day cycles) + pomalidomide + dexamethasone

unacceptable toxicity, or withdrawal of consent

Treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent

Primary endpoint: PFS

33% len refractory, almost none anti-CD38 refractory

80% len refractory, 23% anti-CD38 refractory

>50% received the treatment as second line therapy 1. Hungria V, et al. N Engl J Med 2024;391:393-407. 2. Dimopoulos MA, et al. N Engl J Med 2024;391:408-421.

Belantamab Mafodotin: Clinical trials (PFS) DREAMM-7 12 months

26% of patients in the BVd arm (vs 44% in the DVd arm) received anti-myeloma therapy a after progression 1

18 months 78%

1.0

69%

0.8

Median 36.6 months

Median 13.4 months

0.6 53%

0.4

0.2

BVd

18 months

Patients alive and progression free, %

1.0

DREAMM-8

43%

0.8

63% (95% CI, 54–70)

Median 32.6 months

0.6

0.4

Median 12.5 months

0.2

BPd

DVd

PVd

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Time since randomization (months)

Number at risk (number of events) BVd

243 230 211 200 (0) (6) (17) (25)

183 (32)

171 (39)

158 (46)

150 (51)

140 (59)

131 (63)

127 122 118 110 94 72 41 25 11 (67) (69) (71) (78) (81) (86) (88) (89) (90)

6 2 (91) (91)

0 (91)

DVd

251 230 205 183 (0) (9) (29) (47)

155 (71)

141 (81)

124 107 99 91 80 73 67 61 52 33 19 11 2 1 1 0 (97) (113) (119) (124) (133) (138) (144) (148) (151) (154) (154) (156) (158) (158) (158) (158)

PFS

DVd (N = 251)

Median follow-up, months

28.2

Events, n (%)

91 (37)

158 (63)

36.6 (28.4–NR)

13.4 (11.1–17.5)

Median PFS (95% CI),c months P value

0.0

Number at risk (number of events)

18 20 22 24 26 28 30 Time since randomization (months)

BPd

155 143 135 130 125 122 117 113 111 109 107 101 97 94 86 85 84 81 79 76 75 73 67 63 60 59 58 54 52 47 42 36 34 28 28 22 16 11 10 7 5 1 0 0 0 0 0 0 0 (0) (5) (10) (15) (19) (21) (26) (28) (30) (32) (34) (38) (41) (42) (47) (47) (48) (50) (52) (53) (54) (56) (58) (59) (61) (61) (62) (63) (63) (64) (64) (64) (64) (66) (66) (66) (66) (67) (67) (68) (68) (68) (68) (68) (68) (68) (68) (68) (68)

PVd

147 138 123 111 102 96 92 84 76 69 59 56 54 52 49 47 43 42 40 37 33 31 30 30 28 27 25 23 21 18 17 14 13 12 11 8 7 5 3 2 2 2 2 1 1 1 1 1 0 (0) (4) (14) (23) (27) (33) (37) (45) (49) (52) (60) (63) (63) (65) (68) (70) (71) (71) (73) (76) (79) (80) (81) (81) (82) (82) (83) (84) (85) (86) (87) (87) (87) (87) (87) (88) (88) (88) (89) (89) (89) (89) (89) (89) (89) (89) (89) (89) (89)

Adapted with permission from Dimopoulos MA, et al. EHA 2025; Milan, Italy. Poster PF728.

BVd (N = 243)

HRd (95% CI)

41% (95% CI, 32–50)

0.41 (0.31–0.53)

PFSe

BPd (N = 155)

PVd (N = 147)

Median follow-up, months2

28.01

Events, n (%)2

68 (44)

89 (61)

Median PFS (95% CI), months2 HR (95% CI)f,2

32.6 (21.1–NR)

12.5 (9.1–17.6)

0.49 (0.35–0.68)

< 0.001

Any anti-myeloma therapy includes treatment with steroids, IMiDs, PIs, monoclonal antibodies, chemotherapy, ADCs, other therapies, BiTEs, stem cell transplant, and engineered T-/NK-cell therapy; 1 b DREAMM-7 results from the primary analysis (data cutoff, October 2, 2023); 1 c CIs were estimated using the Brookmeyer Crowley method; 1 d HRs and corresponding 95% CIs were estimated using a stratified Cox proportional hazards model, with treatment as the only explanatory variable; 1 e DREAMM-8 results from the post-hoc analysis (data cutoff, October 7, 2024) and based on the ITT population; 2 f The treatment effect (HR and corresponding 95% CIs) was estimated using a stratified Cox proportional hazards model. 2 aBCMA, BCMA-directed CAR T-cell therapy; ADC, antibody-drug conjugate; BCMA, B-cell maturation antigen; BiTE, bispecific T-cell engager; BPd, belantamab mafodotin, pomalidomide, and dexamethasone; BVd, belantamab mafodotin, bortezomib, and dexamethasone; CAR, chimeric antigen T-cell; DREAMM, Driving Excellence in Approaches to Multiple Myeloma; DVd, daratumumab, bortezomib, and dexamethasone; HR, hazard ratio; IMiD, immunomodulatory drug; NK, natural killer; NR, not reached; PFS, progression-free survival; PI, proteasome inhibitor; PVd, pomalidomide, bortezomib, and dexamethasone; SoC, standard of care. a

1. Hungria V, et al. NEJM 2024;391(5):393-407. 2. Dimopoulos MA, et al. EHA 2025; Poster PF728.

Belantamab Mafodotin: Clinical trials (OS) DREAMM-7

Median OS was not reached. Predicted median OS based on modeling is 84 months with BVd and 51 months with DVd.e

Hungria V, et al. ASH 2024. Oral 772.

DREAMM-8

Interim OS

BPd (N=155)

PVd (N=147)

49 (32)

56 (38)

Median OS (95% CI), months

NR (33.0-NR)

NR (25.2-NR)

HR (95% CI)b

0.77 (0.53-1.14)

Events, n (%)

Dimopoulos MA, et al. N Engl J Med. 2024;391(5):408-421.

Belantamab Mafodotin at first relapse & Len refractory DREAMM-7

PFS Events, n (%) PFS, median (95% CI), monthsa HR (95% CI) 24-month survival (95% CI), %

Hungria V, et al. IMS 2025. Poster PA-494.

DREAMM-8

BVd (n=21) DVd (n=27) 9 (43) 19 (70) 35.7 (17.513.5 (6.6NE) 26.3) 0.39 (0.17-0.88) 67 (41-84)

35 (17-53)

PFS

BPd (N=66)

PVd (N=53)

Events, n (%)

23 (35)

30 (57)

PFS, median (95% Cl), monthsa

NR (21.1NR)

13.1 (9.119.8)

HR (95% CI)b

0.43 (0.25-0.75)

Beksac M, et al. ASH 2024. Poster 4731.

PFS Benefit With BVd vs DVd Was Maintained in Patients With High-Risk Cytogenetics High Risk 1.0

Events, n (%) PFS, median (95% CI), mob

0.8

18 months

0.6

BVd (N=67) 26 (39) 33.2 (20.3-NR)

DVd (N=69) 48 (70) 10.5 (7.6-13.4)

0.4

Median 10.5 months

0.2

35%

1.0

Events, n (%) PFS, median (95% CI), mob

0.8

18 months

0.6

Median 15.3 months

0.4

67 64 69 62

60 55

59 45

Median 36.6 months

45%

DVd

0.0 7

No. at risk

BVd DVd

0.44 (0.32-0.60)

BVd

0.0 5

HRc (95% CI)

69%

DVd 3

DVd (N=175) 106 (61) 15.3 (11.8-20.1)

0.2

BVd

0 1

BVd (N=175) 65 (37) 36.6 (28.4-NR)

PFSa

0.31 (0.18-0.52)

Median 33.2 months

67 %

Standard Risk

HRc (95% CI)

PFS probability

PFS

54 38

50 36

45 29

43 22

15 17 19 21 23 25 27 Time since randomization, months 39 21

37 20

36 17

33 15

29 13

28 11

25 11

0 1 No. at risk

19 10

13 7

9 5

3 0

2 0

0 0

BVd DVd

15 17 19 21 23 25 27 29 Time since randomization, months

175 165 150 140 128 120 112 107 101 175 161 143 131 111 101 91 81 74

94 68

91 61

89 56

89 52

82 48

69 40

53 22

28 12

16 6

8 2

4 1

2 1

0 0

Mateos MV, et al. Presented at the European Hematology Association 2024 Hybrid Congress. Poster P938. Reprinted with permission by the author.

BVd, belantamab mafodotin, bortezomib, and dexamethasone; DVd, daratumumab, bortezomib, and dexamethasone ; HR, hazard ratio; ITT, intention to treat; NR, not reached; PFS, progression-free survival; R-ISS, Revised International Staging System. a Two patients in the ITT population were randomized, not treated, rescreened, and rerandomized. They are counted as 4 unique patients in this output. b CIs were estimated using the Brookmeyer-Crowley method. 95% CIs were not adjusted for multiplicity and cannot be used for hypothesis testing. c HRs were estimated using a Cox proportional hazards model stratified by the number of lines of prior therapy (1 vs 2 or 3 vs ≥4), prior bortezomib, and R-ISS stage at screening (I vs II/III), with a covariate of treatment.

Mateos MV, et al. EHA 2024:P938 (poster presentation)

DREAMM-8: MRD Negativity and Sustained MRD Negativity MRD Negativity (43/67)

36%

(9/25)

27.7% (43/155) 95% CI, 20.9-35.5 BPd PVd

6.1% (9/147)

95% CI, 2.8-11.3

≥CR + MRD-negativity rate, % b

Patients in the ITT population receiving BPd vs PVd were >4 times more likely to achieve ≥CR + MRD negativity

ITT

Patients with ≥CR-based MRD negativity

Patients with ≥CRa

64.2%

Series1

ITT

Sustained MRD Negativityc 55.8% (24/43)

44.4% (4/9)

15.5% (24/155) 95% CI, 10.2-22.2

Series1

BPd PVd

2.7% (4/147)

95% CI, 0.7-6.8

Sustained (≥12 months) MRD-negativity rate,b %

Patients in the ITT population receiving BPd vs PVd were >5 times more likely to achieve MRD negativity sustained for ≥12 months

BPd, belantamab mafodotin, pomalidomide, and dexamethasone; CR, complete response; ITT, intention to treat; MRD, minimal residual disease; PVd, pomalidomide, bortezomib, and dexamethasone. a Patients with ≥CR refers to patients who achieved MRD negativity based on a ≥CR. b MRD negativity was assessed by next-generation sequencing (at 10 −5 threshold) during confirmed ≥CR according to the International Myeloma Working Group and independent review committee–assessed response. c Sustained MRD negativity is ≥CR-based MRD negativity sustained for ≥12 months; otherwise, MRD negativity is not sustained. A 1-month window is considered as per data collection.

PRESENTED BY:

Dr. Meletios A. Dimopoulos

DREAMM-8: PFS and PFS2 in Patients With or Without Sustained MRD Negativity PFS

PFS2 24 Months

24 Months

100%

(95% CI, 100%-100%)

0.8

1.0 Proportion alive and progression free

Proportion alive and progression free

1.0

(95% CI, 100%-100%)

44%

0.6

(95% CI, 35%-54%)

0.4 0.2 0.0

28%

(95% CI, 20%-37%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

(95% CI, 100%-100%)

0.6

42%

(95% CI, 33%-51%)

0.4 0.2 0.0

No. at risk Time since randomization, months (No. of events) BPd with sustained 24 24 24 24 24 24 24 24 24 24 24 24 23 23 23 23 22 22 21 19 15 11 7 4 3 1 0 MRD negativity (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (1) (1) (1) (1) (1) (1) (1) BPd without 131 111 101 93 87 83 73 62 60 55 51 47 41 40 38 36 33 29 25 22 17 13 10 7 4 1 0 sustained MRD (0) (10) (19) (26) (30) (34) (41) (47) (48) (52) (54) (58) (62) (63) (65) (66) (66) (68) (69) (70) (71) (72) (72) (72) (72) (72) (72) negativity 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 2 2 1 0 0 0 0 0 0 PVd with sustained MRD negativity (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) PVd without sustained MRD 143 119 98 88 72 55 50 45 39 36 29 27 25 23 21 18 18 17 15 12 11 10 6 4 3 2 1 negativity (0) (14) (27) (37) (49) (60) (63) (68) (71) (73) (79) (81) (83) (85) (87) (89) (89) (89) (91) (92) (92) (92) (93) (93) (93) (93) (93)

BPd

100%

(95% CI, 100%-100%)

0.8

21%

(95% CI, 14%-28%)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Time since randomization, months 25 (0)

24 (0)

23 (0)

4 (0)

BPd

Sustained MRD negativityb (n=24)

Without sustained MRD negativityc (n=131)

Sustained MRD negativityb (n=4)

Without sustained MRD negativityc (n=143)

Events, n (%)

1 (4)

72 (55)

93 (65)

21 (1)

19 (1)

15 (2)

13 (2)

10 (2)

5 (2)

3 (2)

2 (2)

0 (2)

4 (0)

3 (0)

2 (0)

1 (0)

0 (0)

143 121 99 89 74 60 52 47 42 38 31 27 26 24 22 19 18 18 16 13 11 10 9 5 3 2 1 (0) (16) (35) (45) (59) (72) (80) (85) (90) (93) (100) (104) (105) (107) (109) (111) (112) (112) (114) (115) (116) (116) (117) (117) (117) (117) (117)

PVd

PFSa

22 (0)

130 114 105 96 88 84 75 64 62 57 54 50 45 43 39 38 35 31 27 23 18 14 12 9 5 2 0 (0) (9) (17) (26) (32) (36) (43) (51) (53) (57) (59) (63) (68) (70) (74) (75) (75) (77) (78) (79) (80) (81) (81) (81) (81) (81) (81)

PVd

PFS2a

Sustained MRD negativityb (n=25)

Without sustained MRD negativityc (n=130)

Sustained MRD negativityb (n=4)

Without sustained MRD negativityc (n=143)

Events, n (%)

2 (8)

81 (62)

117 (82)

BPd, belantamab mafodotin, pomalidomide, and dexamethasone; CR, complete response; MRD, minimal residual disease; NR, not reached; PFS, progression-free survival; PFS2, progression-free survival on subsequent line of therapy; PVd, pomalidomide, bortezomib, and dexamethasone; VGPR, very good partial response. PFS, median (95% CI), NR (NR-NR) 20.2 (13.9-24.0) NR (NR-NR) 9.3 (7.4-11.9) PFS, median (95% CI), NR (NR-NR) 21.1 (15.0-28.4) NR (NR-NR) (8.6-16.0) a Data cutoff: July 7, 2025. Median follow-up: 35.8 months. b Sustained MRD negativity10.2 is ≥CR-based MRD negativity sustained for ≥12 months; otherwise, MRD negativity is not sustained. A 1-month window is months months considered as per data collection. c Patients who had ≤VGPR were assumed to be without sustained MRD negativity.

PRESENTED BY:

Dr. Meletios A. Dimopoulos

Belantamab Mafodotin: Clinical trials (Safety) Eye-related side effects (ERSEs) Most common ocular adverse reactions, n (%)

Any ocular adverse reaction

DREAMM-7 BVd1,2,a (n=242) 191 (79)

DREAMM-8 BPd3,4,b (n=155)

Blurred vision Dry eye Photophobia Eye irritation

160 (66) 123 (51) 114 (47) 103 (43)

133 (89) 119 (79) 91 (61) 66 (44) 75 (50)

Foreign-body sensation in eye

106 (44)

91 (61)

Eye pain Cataract

77 (32) 49 (20)

49 (33) 40 (27)

Corneal epithelial microcysts

34 (23)

Punctate keratitis Reduced visual acuity

NR NR

34 (23) 34 (23)

Events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Events reported in ≥20% of patients (safety population). a Data cutoff, October 2, 2023. b Data cutoff, January 29, 2024.

 In DREAMM-7 and DREAMM-8, ocular events were mainly corneal examination findings1-4  The most common ocular adverse reactions included blurred vision and dry eye1-4  Grade ≥3 blurred vision and dry eye were reported in 22% (53/242) and 7% (17/242) of patients in DREAMM-7 and in 17% (26/150) and 8% (12/150) of patients in DREAMM-8, respectively1,3  Although ocular adverse reactions were common with belantamab mafodotin, most patients experienced mild to moderate symptoms1,3  Of those with ocular adverse reactions, 57% (109/191) of patients in DREAMM-7 and 51% (68/133) of patients in DREAMM-8 experienced grade 1/2 events  Ocular events were managed with dose modifications and few patients discontinued treatment Dose reductions Dose delays/ interruptions Discontinued

BVd1,2 44%

BPd4 59%

78%

83%

 Ocular events were generally resolvable with adequate follow-up2,4  No new safety signals were observed when compared with previous analyses5-7

1. Hungria V, et al. N Engl J Med. 2024;391:393-407. 2. Hungria V, et al. IMS 2024. Poster P-396. 3. Dimopoulos MA, et al. N Engl J Med. 2024;391:408-421. 4. Trudel S, et al. ASCO 2024. Oral LBA105; 5. Nooka AK, et al. Cancer. 2023;129:3746-3760.΄6. Lonial S, et al. Lancet Oncol. 2020;21:207-221. 7. Lonial S, et al. Cancer. 2021;127:4198-4212.

Belantamab Mafodotin: Clinical trials Dose extension manages ERSEs & maintains efficacy DREAMM-7

DREAMM-8

AR, adverse reaction; BCVA, best-corrected visual acuity; PR, partial response. a Only the belantamab mafodotin treatment period was considered in these post hoc analyses. b Only patients with 20/25 or better in ≥1 eye at baseline are considered. c Mean of days between doses for each patient per interval is used. d Graph is truncated at 30 months because data beyond 30 months represented low number of patients on treatment (>30 to ≤33 months, n= 42; >33 to ≤36 months, n=20; >36 to ≤39 months, n=8; >39 to ≤42 months, n=3).

AR, adverse reaction; belamaf, belantamab mafodotin; BCVA, best-corrected visual acuity. a Only the belamaf treatment period was considered in these post hoc analyses. b First 2 years of treatment shown due to limited patients at risk beyond this time point. c Mean of days between doses for each patient per interval is used. d Only patients with 20/25 or better in either or both eyes at baseline are considered. e Only patients receiving ≥6 months of treatment included in analysis to exclude early discontinuations (eg, rapid PD).

Mateos MV, et al. Blood Adv. 2025 Nov 25;9(22):5708-5719

Recommendations for the management of Ocular Events (ophthalmology evaluation before the first 4 belamaf doses) Eye examination findings per KVA scale

Recommended dose modifications

Grade 1

Corneal examination finding(s) Mild superficial punctate keratopathy* • Change in BCVA† Decline from baseline of one line on Snellen Visual Acuity •

Continue according to belamaf prescribing information; ophthalmic evaluation may be planned to confirm ocular event(s) do not worsen

Grade 2

Corneal examination finding(s) Moderate superficial punctate keratopathy‡ • Change in BCVA† Decline from baseline of two or three lines • (and Snellen Visual Acuity not worse than 20/200)

Use Q8W dosing and maintain at new dose interval, provided recovery to Grade 1; if dose interval exceeds 12 weeks, reduce belamaf dose

Grade 3

Corneal examination finding(s) Severe superficial punctate keratopathy§ • Change in BCVA† Decline from baseline by more than three lines • (and Snellen Visual Acuity not worse than 20/200)

Reduce belamaf dose AND extend dose interval to at least 12 weeks and maintain at new dose interval, provided recovery to Grade 1; if dose interval exceeds 16 weeks, further reduce belamaf dose

Grade 4

Corneal examination finding(s) Corneal epithelial defect¶ • Change in BCVA† Snellen Visual Acuity worse than 20/200 •

Consider treatment discontinuation until Grade 1; if continuing treatment with belamaf is being considered, reduce belamaf dose AND extend dose interval to at least 12 weeks and maintain at new dose interval Terpos E, et al. Am J Hematol 2025;100(10):1839-1850

Recommendations for the management of Ocular Events (after the 4th cycle) The Vision-Related Anamnestic tool • Patients are requested to answer the following questions: • If the patient replies ‘No’ to all of the below questions, this is considered ‘none of the time’ and treatment is continued • If the patient’s reply is ‘Yes’ to any of the below questions, then the patient is requested to specify if the symptoms lasted for:  4–<8 hours (minimal)  8–<12 hours (moderate)  12–<16 hours (substantial)  ≥16 hours (severe) Q1 During the last 24 hours, did you ever feel that your eyes were sensitive to light? Q2 During the last 24 hours, did your eyes ever feel gritty? Q3 During the last 24 hours, did your eyes ever feel painful or sore? Q4 During the last 24 hours, did you ever experience blurred vision? Q5 During the last 24 hours, did you ever experience poor vision? Q6 During the last 24 hours, did you ever experience problems in reading due to problems with your eyes? Q7 During the last 24 hours, did you ever experience problems in driving due to problems with your eyes? Q8 During the last 24 hours, did you ever find it difficult to work with a computer or a smartphone due to problems with your eyes? Q9 During the last 24 hours, did you ever find it difficult to watch TV due to problems with your eyes?

Terpos E, et al. Am J Hematol 2025;100(10):1839-1850

Belantamab Goes at First Line - BelaRd: Study design

Part 1 – Dose finding

• Intermediate/frail per IMWG frailty score • Adequate organ system function • eGFR ≥30 mL/min/1.73 m 2

Part 2 – Dose expansion R a n d o m i z a ti o n 1 : 1 3 0 p a ti e n t s

R a n d o m i z a ti o n 1 : 1 : 1 3 6 p a ti e n t s

Key inclusion criteria • Documented MM • Ineligible for high-dose chemotherapy with ASCT • ECOG PS 0–2

Belamaf

Group A – Ophthalmologist (n=15)

Cohort 1/2/3: 2.5/1.9/1.4 mg/kg Q8W

Belamaf 1.9 mg/kg Q8W plus Rd Dose modifications based on KVA scale as assessed by the Ophthalmologist

Lenalidomide: 25 mg/d PO, days 1– 21 of every 28-day cycle Dexamethasone: 40 mg/day PO or IV, days 1, 8, 15, 22 of every 28-day cycle* U n ti l P D o r unacceptable toxicity

Permitted dose (mg/kg) modifications Cohort 1

Cohort 2

Cohort 3

Dose +1

2.5 Q4W

1.9 Q4W

1.4 Q4W

• BelaRd safety and tolerability • Belamaf RP2D

Starting dose

2.5 Q8W

1.9 Q8W

1.4 Q8W

Secondary endpoints

Dose -1

2.5 Q12W

1.9 Q12W

1.4 Q12W

Primary endpoints

• • • •

111

BelaRd efficacy Corneal AE management PK profile Ocular AEs by OSDI

Group B – Hematologist (n=15)

Belamaf RP2D 1.9 mg/kg

Belamaf 1.9 mg/kg Q8W plus Rd Dose modifications based on the VRA tool as assessed by the Hematologist and grade 3 KVA events as assessed by ophthalmologist U n ti l P D o r u n a c c e p t a b l e toxicit y

Primary endpoints

• BelaRd efficacy (ORR per IMWG) • BelaRd safety (AEs / SAEs / Gr³ 2 ocular toxicity per KVA scale)

Secondary endpoints

• BelaRd efficacy • Ocular AE incidence and management

*For participants ≥75 years, 20 mg/day on days 1, 8, 15, 22 of every 28-day cycle. AE, adverse event; ASCT, autologous stem cell transplantation; belamaf, belantamab mafodotin; BelaRd, belamaf plus lenalidomide and dexamethasone; ECOG PS, Eastern Cooperative Oncology Group Performance Status; eGFR, estimated glomerular filtration rate; IMWG, international myeloma working group; IV, intravenously; KVA, Keratopathy Visual Acuity; MM, multiple myeloma; OSDI, Ocular Surface Disease Index; PD, progressive disease; PK, pharmacokinetic; PO, per os; Q4/8/12W, once every four/eight/twelve weeks; RP2D, recommended phase 2 dose; SAE, serious adverse events.

Terpos E, et al. Blood. 2026 Apr 2;147(14):1574-1583

Vision-Related Anamnestic tool assessments Part 2 Group A – Ophthalmologist Ocular assessment (1.9 mg/kg)

Group B – Haematologist Ocular assessment (1.9 mg/kg)

Assessments (cycles) with Gr≥3 OAE without ‘substantial’ time VRA findings / Total number of assessments

10/300 (3.3)

2/251 (0.8)

Dosing cycles with Gr≥3 OAE without ‘substantial’ time VRA findings / Total number of dosing cycles (cases where ophthalmologists interrupted hematologist-driven dosing)

N.A.

0/121 (0.0)

*Assessments from patients who never drove are excluded from both the numerator and the denominator

No drug administration defined by hematologist ocular assessment was interrupted by ophthalmologist for grade 3 ocular adverse events Data are n (%) assessments. Gr, grade; OAE, ocular adverse events; VRA, Vision-Related Anamnestic

Terpos E, et al. Blood. 2026 Apr 2;147(14):1574-1583

Vision-Related Anamnestic tool assessments Part 1

Part 2

Cohort 1 (2.5 mg/)

Cohort 2 (1.9 mg/kg)

Cohort 3 (1.4 mg/kg)

Group A – Ophthalmologist Ocular assessment (1.9 mg/kg)

Group B – Haematologist Ocular assessment (1.9 mg/kg)

Assessments at which patients stopped driving mainly due to eyesight issues/ total number of assessments*

4/414 (1.0)

18/350 (5.2)

0/266 (0.0)

0/228 (0.0)

1/155 (0.6)

Assessments at which patients stopped reading mainly due to eyesight issues/ total number of assessments

3/414 (0.7)

2/434 (0.5)

3/333 (0.9)

1/304 (0.3)

1/254 (0.4)

*Assessments from patients who never drove are excluded from both the numerator and the denominator

Stop driving or reading was reported in 0% - 0.6 % of monthly ophthalmologist assessments Data are n (%) assessments. Gr, grade; OAE, ocular adverse events; VRA, Vision-Related Anamnestic

Terpos E, et al. Blood. 2026 Apr 2;147(14):1574-1583

BelaRd Updated Results

MRD Negativity Rate, n(%) of all patients MRD Negativity Rate, n(%) of evaluable patients

Overall, 1.9mg/kg (Part I & II), (N=42)

Cohort 2, 1.9mg/kg (Part I), (N=12)

Group A+B, 1.9mg/kg (Part II), (N=30)

21 (50.0)

6 (50.0)

15 (50.0)

1.9 (0.9-3.8)

1.1 (1.0-4.0)

12.8 (2.8-28.3)

10 (1.1-26.0)

21/22 (95%)

Time to PR or better 1.1 (0.9-4.0) (months), median (range) Time to best response 11.8 (1.0-28.3) (months), median (range) Overall Response Rate

Participants (%)

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Progression Free Survival (PFS)

18 (42.9%)

5 (41.7%)

4 (9.5%)

1 (8.3%)

15 (35.7%)

5 (41.7%)

13 (43.3%) 3 (10.0%) 10 (33.3%)

3 (10%) 4 (9.5%) 1 (8.3%) Overall, 1.9mg/kg Cohort 2, 1.9mg/kg Group A+B, (Part I & II), (N=42) (Part I), (N=12) 1.9mg/kg (Part II), PR VGPR CR sCR (N=30)

For 1.9 mg/kg cohort 18 months PFS- 82.9% (95% CI 67.5-91.5) 24 months PFS- 77.2% (95% CI 60.6-87.5)

Projected Progression Free Survival Overall (2.5/1.9/1.4 mg/kg) Distribution

Predicted mPFS, months

95% LCL

Exponential Weibull Log-logistic Log-normal Gamma

86.7 96.5 105.7 115.5 93.1

54.4 48.4 50.2 50.5 48.8

1.9 mg/kg

95% UCL

Predicted mPFS, months

95% LCL

95% UCL

137.7 183.3 224.1 257.7 165.2

83.7 87.6 94.2 101.8 84.5

46.2 38.0 38.7 38.1 38.2

151.3 189.0 232.1 263.9 167.0

• Predicted mPFS for the combined cohorts ranged from 86.7 to 115.5 months. • Predicted mPFS for the 1.9 mg/kg cohort ranged from 83.7 to 101.8 months.

GEM-BELA-VRd: Belantamab in Induction and maintenance NDMM TE after 2y maint. With BR: study design

PFS

PFS at 36m was 78%

OS at 36m was 82%

Gonzalez V. Presented at: 22nd International Myeloma Society Annual Meeting; 2025 Sep 17-20; Toronto (ON), Canada. Oral OA 48

What is the Future? Development of Belantamab (BCMAb), the unconjugated mAb: BCMA Efficacy, Simple Delivery, and Clean Safety Profile Belantamab (GSK2857914)1

ADCC/ADCP

BCMA

Effector cell

BCMA

Malignant plasma cell

Fc receptor

Effector cell–mediated lysis/phagocytosis

• • • •

Median of 4.5 (3-18) prior lines of therapy and 94% were triple class exposed 1 Limited numbers, however, time on treatment exceeding 20 months and ongoing No DLTs or TRAEs leading to discontinuation of BCMAb were reported The most frequently reported TRAEs were infusion-related reactions and hematologic AEs

Promising Activity and Clinical Development Potential: BCMA Targeting Agent

No DLTs identified

Meaningful Responses in Late Line Triple Class Exposed

Combinable Profile

Conclusions Belamaf IS BACK with two very efficacious combinations that are going to be widely used (BelaVd and BelaPd) as they become the new standards of care for patients with relapsed/refractory myeloma after one prior line of therapy (FDA has approved only BelaVd after two prior lines of therapy). Bela combinations are efficacious both in len refractory patients and in dara exposed patients (BelaPd). EHA guidelines suggest that they are preferred in this populations (len and dara refractory) along with cilta-cel Occular problems are mainly of grade 1 or 2 and are almost always reversible with up to 8 weeks. Ocular AEs are easily managed with treatment delays and reduction of dose; THIS DOES NOT AFFECT EFFICACY

Thank you

UPCOMING TRISPECIFICS AND NEW CART OPTIONS Niels van de Donk, MD, PhD Vrije Universiteit Amsterdam

IMWG Summit, JUNE 2026, STOCKHOLM

Upcoming Trispecifics and New CART Options Niels van de Donk Professor of Hematology Department of Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Netherlands Niels van de Donk MD PhD

Disclosures • Advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Galapagos, Kite Pharma, Merck, Pfizer, AbbVie, and Servier, all paid to institution. • Research funding from Janssen Pharmaceutical, Amgen, Celgene, Novartis, Cellectis, and Bristol-Myers Squibb

Bispecifics: Why need to improve? ELRANATAMAB mPFS: 17.2 months

TALQUETAMAB: 0.8 mg/kg mPFS: 11.2

TECLISTAMAB mPFS: 15.1 months

-Not everyone responds to BsAb treatment (high tumor burden, extramedullary plasmacytomas, poor T cell fitness) -Patients with deep response can still develop relapse Martin ASH 2024; Tomasson Hemasphere 2024; Chari Lancet Haem 2025

Resistance to BsAbs

Van De Donk et al. Lancet Haem 2024

Niels van de Donk MD PhD

Substantial heterogeneity in BCMA and GPRC5D expression among patients and within the tumor

O’Neill et al. ASH 2025

Antigen escape during BCMA BsAb treatment • BCMA antigen escape • Biallelic deletions • Monoallelic deletion coupled with an extracellular domain mutation interfering with target binding

Lee Nature Med 2023; Truger Blood Adv 2021; Lee Blood 2025; Lee ASH 2025

Antigen escape during GPRC5D BsAb therapy • GPRC5D antigen escape • Biallelic deletions • Monoallelic deletion plus mutation • Hypermethylation-driven epigenetic silencing

GPRC5D mutations mediate resistance to GPRC5Dtargeting therapies by impairing trafficking of GPRC5D to the cell membrane, or by preventing stable binding of the drug to GPRC5D

Lee Nature Med 2023; Lee ASH 2025; Lee Nature Med 2026; Derrien Nat Cancer 1536; Han ASH 2023; Mouhieddine ASH 2024

Dual targeting to address tumor heterogeneity and prevent antigen escape

Van De Donk….Einsele. Blood 2026

Resistance to BsAbs

Van De Donk et al. Lancet Haem 2024

Dual-targeting -TEC+TAL -TsAb

Niels van de Donk MD PhD

Combination of two BsAbs or TsAb ?

--JNJ-5322 (ramantamig) mediates higher lysis versus the combination of 2 monotargeting antibodies (enhanced avidity-based binding of the two tumor-associated antigen binders; superior immune synapse?) O’Neill……van De Donk. ASH 2025

Several TsAbs in development Ramantamig BCMAxGPRC5DxCD3

ISB2001 BCMAxCD38xCD3

MBS314 BCMAxGPRC5DxCD3

IBI3003 BCMAxGPRC5DxCD3 Van De Donk et al. Blood 2026

JNJ-79635322: trispecific antibody  ramantamig

Ramantamig (JNJ-79635322): trispecific antibody

Trispecific antibody prevents tumor progression in MM mouse model

Pillarisetti Blood 2025; Pillarisetti ASH 2023

Ramantamig: Trilogy-1

Van de Donk ASCO 2025; Krishnan ASH 2025

Ramantamig

Across all RP2D patients (n=37): MRD-negativity rate of 100.0% at 10–5 (n=10/10) and 10–6 (n=7/7)

N=37 -Median 4 prior regimens, -27 naive to BCMA/GPRC5D, 9 exposed -Median follow-up: 17 months Van de Donk ASCO 2025; Krishnan ASH 2025

Ramantamig: side effect profile

Krishnan et al. ASH 2025

Selected ongoing studies • TRILOGY-4: ramantamig vs teclistamab in at least 3 prior lines including CD38/IMiD/PI • TRILOGY-5: ramantamig vs teclistamab in 1-3 prior lines including CD38 and LEN • EMN30/TAURUS; MajesTEC-5; TRILOGY-6 (combination strategies!): NDMM

ISB 2001-101: BCMAxCD38xCD3 TsAb

Tuned BCMA>CD38>CD3 binding affinity and distal positioning of the CD38 vs CD3 binders drive potent tumor killing while minimizing CD38-related off-tumor adverse events

Best Overall Response

Percentage of Patients

100 80 60

ORR 74% CR/sCR 28% ≥ VGPR 50%

sCR:17% CR:11%

CR/sCR 30% ≥ VGPR 64%

sCR:18% CR:12%

40 VGPR:32%

VGPR:34%

20 0

35 patients treated across all dose levels Median prior lines: 6 Prior BCMA: 46% (11% CART, 20% BsAb, 20% ADC) Median follow-up: 6.3 months

ORR 79%

•

Safety:

• No DLTs observed across full dose escalation up to 2700 ug/kg PR:14%

PR:15%

DL1 to 9 N=35

DL3 to 9 N=33

8 out of 10 patients with ≥CR were MRD evaluable. 75% (6/8) were MRD negative by NGS or NGF (10⁻⁵)

• Mild CRS and injection site reactions; 1 patient with ICANS. • Infections: 74% (grade ≥3: 29%)

•

Next Steps:

• Dose –expansion part 2 is ongoing to establish RP2D and best dosing schedule for further development

Quach ASH 2024; Lichtman ASCO 12025; Carretero-Iglesia Nature Cancer 2024

CAR T-cell therapy TRISPECIFICS

/Durable

Simplify manufacturing / reduce treatment delays

Earlier e.g., CARTITUDE-4/5/6

Improved safety profile BCMA: Anito-cel

Novel targets GPRC5D: Arlo-cel

New strategies to improve access/speed In vivo CAR T: KLN-1010/ESOT01 Allogeneic CAR T: CB-011

Dual targeting e.g., AZD0120, BMS-986453

CAR T-cell therapy: cilta-cel

•

Jagannath JCO 2025

CARTITUDE-1: 33% of patients remained alive and progression-free ≥5 years after cilta-cel • Enriched with patients with low tumor burden • Higher E:T ratio • Fitter T-cell phenotype

Earlier e.g., CARTITUDE-4/5/6

Cilta-cel

•

How to improve? • Earlier (Fitter T-cells) • • •

Jagannath JCO 2025

Effective bridging therapy (also mitigates delayed neurotoxicity) Avoid agents with negative impact on T-cell function / antigen prior to CAR T-cell therap

CARTITUDE-1: 33% of patients remained alive and progression-free ≥5 years after cilta-cel • Enriched with patients with low tumor burden • Higher E:T ratio • Fitter T-cell phenotype

Improved safety profile BCMA: Anito-cel

Anito-cel in patients with ≥3 prior LOTs (iMMagine-1)

-Anito-cel demonstrated deep, durable responses in 4L+ RRMM -Anito-cel has a manageable safety profile, including no delayed or non-ICANS neurotoxicities and no immune effector cell-associated enterocolitis, which may be related to the use of a specific CAR construct, which allows for quick release of CAR T cells from their BCMA target, potentially conferring tumor killing without prolonged inflammation -Anito-cel is currently undergoing investigation in the iMMagine-3 phase 3 trial in patients with 1-3 prior LOTs in RRMM Patel ASH 2025; Hart ASH 2025; Kuipers BioDrugs 2026

Novel targets GPRC5D: Arlo-cel

Arlo-cel in patients with 1-3 prior LOTs (CC9526-MM-001)

-Arlo-cel led to a high response rate that was deepened over time in patients with 1-3 prior LOTs -QUINTESSENTIAL-2: randomized phase 3 trial with arlo-cel (target dose 75x106 CAR T cells) in patients with 1-3 prior LOTs and prior lenalidomide exposure

Bal IMS 2025; Bal EMN 2026

Dual targeting e.g., AZD0120, BMS986453

AZD0120 (BCMA/CD19 CAR T) in patients with ≥3 prior LOTs (DURGA-1)

-AZD0120 resulted in early and deep responses in patients with ≥3 prior LOTs - DURGA-4 phase 3 trial is ongoing in patients with 1-3 prior LOTs in RRMM Richard ASH 2025; van de Donk Blood 2026

New strategies to improve access/speed In vivo CAR T: KLN-1010/ESO-T01

KLN-1010: Off-the-shelf in vivo BCMA CAR T-cell generation

KLN-1010 uses T-cell-targeted lentiviral particles to generate BCMA CAR T-cells in vivo, aiming to simplify delivery vs ex vivo CAR T-cells

-Robust CAR T-cell persistence in the absence of lymphodepletion

• inMMyCAR Phase 1 (NCT07075185): RRMM ≥3 prior lines (PI, IMiD, anti-CD38); ECOG 0–1 • Initial patients (n=18): DL1 2×10 ⁷ IU/kg (n=3); DL-1 6×10 ⁶ IU/kg (n=8); DL-2 4×10 ⁶ IU/kg (n=7)

Harrison ASH 2025; Ho ASCO 2026; Xu Lancet 2025; An Nature Med 2026

-100% MRD-negative responses -Manageable safety profile; No delayed neurotoxicity; all CRS cases were grade 1-2; no IRR following dexamethasone premedication implementation

Conclusions • Novel strategies are improving efficacy/safety of T-cell immunotherapy • Dual-targeting approaches • Earlier stages of disease • Novel CAR T-cell generation techniques • Combination strategies

AMMSTERDAM MYELOMA GROUP CONNECTING SCIENCE WITH CARE

Sonja Zweegman

Niels van de Donk

Kaz Groen

Jurgen Wegman

Ilse Kuipers

Niels van de Donk

HEMATOLOGISTS

Maaike de Ruijter

Isabelle Dekker

NURSE PRACTITIONERS

Maria Themeli

Richard Groen

Sonja Zweegman Tuna Mutis

SCIENTIFIC STAFF

Sandy Kruyswijk Jolijn Chrystine Ogenia Diana Nacy Schellingerhout

Isa Rosel

Merel vd Maas

Sylvi Kaspers

Patty Bosman

Tanja Roosma

Rabia Asik

CLINICAL TRIAL TEAM; RESEARCH NURSES & STUDY COÖRDINATORS

OVERCOMING EXTRAMEDULLARY DISEASE Prof. Dr. Hermann Einsele, MD, PhD University Hospital Würzburg, Germany

June 10th, 2026 Stockholm

Overcoming Extramedullary Disease Prof. Dr. Hermann Einsele

Department of Internal Medic II

Disclosures: Consulting or Advisory Role BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis Research Funding BMS/Celgene, Janssen, Amgen, GSK, Sanofi Honoraria

BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis

Travel Support BMS/Celgene, Janssen, Amgen, Takeda, Novartis, Sanofi

Extramedullary disease (EMD) lesions are a sign of aggressive disease Clonal Plasma Cell Growth outside of bone marrow microenvironment MM cells

The primary site of multiple myeloma

Bone Marrow (BM) Skin

EMD can develop in multiple sites

EMD

Liver MM cells acquire the ability to grow independently of the BM

Spleen Rare Manifestations: CNS, PCL

It needs to be distinguished from paramedullary disease (PMD), which does not reflect the aggressive biology of true EMD.

152

Extra-medullary disease •

EMD is an aggressive form of MM

•

Depending on methods of assessment (imaging), the prevelance is • 6-10 % at diagnosis 1,2,3,4 • 10-30 % in relapsed refractory MM 1,2,3,4 • EMD prevalence increased from 2005 to 2014 (6.5→23.7%) due to sensitive screening and longer survival5

•

Biology distinct from medullary myeloma : • Different phenotype (CD56 ↓ , increased cell cycling), immature/ plasmablastic morphology (bcl2/bclx ↑↑) • Higher incidence of adverse cytogenetics (TP53 and DIS3 mutations, MYC rearrangements, t(14;16), t(14;20), 1q abnormalities, KRAS/NRAS, BRAF mutations) • High LDH (increased proliferation)

Zamagni E et al Blood 2011 Wale A et al Haematologica 2016 3 Moreau P et al J Clin Oncol 2017 4 Kraeber-Bodéré F et al Blood 2025 5 Kastritis, E. IMS Belgrade 2026 6 Gagelmann et al Haematologica (2018) 1 2

EMD: Impact of Tumor Biology and Tumor Microenvironment  Disease progression is characterized by the aberrant activation of intracellular signaling pathways and the secretion of proangiogenic cytokines.

Roccaro A M, et al. Cell reports 2015 Bhutani M, et al. Leukemia 2020 Yao, et al. Clin. Epigenetics 2018 Bansal R, et al. Blood Cancer J. 2021 Bianchi G, et al. Blood cancer discovery 2021 Merz M, et al. Blood advances 2023 Notarfranchi L, et al. Haematologica. 2024 Martello M ,et al. Blood cancer journal 2024 Lutz R, et al. Science immunology 2025 Anilkumar S A, et al. Blood cancer discovery 2026

EMD exhibits higher resistance to traditional anti-MM agents Prognostic Impact of EMD in NDMM for anti-CD38 therapy CASIOPET study (substudy of CASIOPEIA) N=268 (D-VTd, n=137; VTd, n=131) with assessable baseline PET;

Kraeber-Bodere F et al Haematologica 20

CD38 Expression on PCs in BM and EMD Sites A direct 56-marker profiling of matched BM and EMD disease explains why EMD patients show worse outcomes in the era of current therapies Mean BM CD38 expression

Mean EMD CD38 expression

P value

MM#1

1874

198

< 0.0001

MM#2

824

119

< 0.0001

MM#3

740

246

< 0.0001

MM#4

878

382

< 0.0001

MM#5

665

328

< 0.0001

CD38 is a PCs surface marker There is a reduced expression of CD38 in EMD samples Resistance to anti-CD38 therapies

Saltarella I, et al. Cells 2020 Jelinek T, et al. Leukemia 2024 Notarfranchi L, et al. Haematologica. 2024 Desantis V, et al. J Hematol Oncol 2025

EMD

EMD represents a clinically aggressive phenotype, frequently associated with high-risk cytogenetic aberrations, reduced treatment susceptibility and a significantly poorer prognosis.

Resistance to modern Immunotherapies in EMD (BisAb and CAR-T) Trial • Ide-cel: ORR 59 % vs. 75 % (Hansen et al.) • Teclistamab: ORR ~35 vs 70 % • Talquetamab: ORR ~40 vs 80 % • Cilta-cel: PFS lower in EMD

Targeting BCMA and GPRC5D in EMD

Kumar, S. et al., Am J Hematol. 2026

Tomo-seq:

Highly heterogenous Expression of BCMA and GPRC5D on EMD

 Dual BCMA/ GPRC5D-targeting or novel targets more uniformly expressed on EMD to improve efficacy of CART/BsAb-Therapy in EMD

John et al., Blood 2024

RedirecTT-1: Dual Targeting of EMD with Talquetamab and Teclistamab

Kumar et al NEJM (2026)

Phase 1 trial: BCMA/GPRC5D Dual targeting CAR-T in 12 pts with true EMD

20 of Hematology & Oncology (2025) Yao et al. Journal

Novel Targets: CAR T Cells CARAMBA-1: SLAMF7-directed CAR T Cells

• no interference from soluble SLAMF7 CARAMBA-1 is a First-in-Human Phase I/IIa trial of SLAMF7 CAR-T therapy

CD38

• Sustained high level expression on MM/EMD,

SLAMF7

SLAMF7 is a strong CAR-T target in MM

bone marrow extramed. lesion

Dose escalation is ongoing

• Safety: favorable safety signal, no DLTs • Efficacy: SLAMF7 CAR-T engraftment, responses in heavily pretreated MM • But: SLAMF7 Expression on activated T Cells / CAR-T Cell fratricide  2 generation SLAMF7 CAR-T Cells based-edited for SLAMF7 deletion nd

Sophia Danhof

Karl Petri

Focal Infiltration of Immune Cells in EMD Lesions (Spatial Transcriptomics)

• EMD lesions are infiltrated by immune cells that are anatomically confined to distinct niches. • T cells found in the vicinity of PCs showed signs of T cell dysfunction.

John, Helal et al, Blood 2024 (in press) John M,, Rasche L. et al., Blood. 2024 Aug 20

EMD TME vs MMBM: Diverse subsets of T and NK cells : CD8+ T cells are less cytotoxic and often exhausted Proportion of exhausted T cells by FCM

Extramedullary lesions: ↓E: T ratio, ↓CD4 cells (MHCT↓) ↑regulatory NK cells, ↑T cells with an exhausted phenotype vs bone marrow infiltrating T cells Low cytotoxicity score in EMM

High exhaustion score in EMM

Correlation of exhaustion and cytotoxicity scores in EMM

Sithara et al., BCD

Immune desertification in EMD niche

T-cell exclusion drives immune desertification and limits CAR-T and BiTE therapy efficacy (Spatial Proteomics/ MACSima Imaging) Desantis V, et al. J Hematol Oncol 2025

CXCR4-theranostics protocol (Würzburg) Dreher et al., Clin Nucl Med 2024.

Aplasia

CXCR4 G-protein-coupled receptor Ligand SDF-1/CXCL12 Highly uniformely expressed on MM

[68Ga]-PentixaFor PET

Dosimetry ([ Lu]-PentixaTher) 177

Therapy ([ Y]-PentixaTher) 90

Stem Cell Transplantation

Engraftment

177

Lu-CXCR4 theranostics to eradicate large EMD lesions

F-FDG PET/CT

D +142

D +31

D +97

D +12

D + 81

A huge EMD lesion (7 kg tumor) was successfully eradicated using CXCR4theranostics

 Additional T-cell based therapy is required for long-term tumor control

TRIUMMpH Trial: TRansplant and ImmUnotherapy for Multiple Myeloma with High Risk features N= 222

Patient Selection • Newly diagnosed transplant-eligible multiple myeloma patients with ≥ 1 high-risk feature - del(17p) - t(4;14) - t(14;16) - Gain/amp(1q) - Extramedullary disease - ISS stage III - Age 18-70 years, ECOG 0-2 •

MRD testing

Dara-VRd at least 16 weeks but no less than 24 weeks

R a n d o m i z e

Leukapheresis

HDM / ASCT

Arm 1 (n=74)

Arm 2 (n=74)

Arm 3 (n=74)

Stem cell mobilization and collection

MRD testing

Cilta-cel

Tal-Dara Maintenance

Cilta-cel

Tal-Dara Maintenance

Dara VRd X2 Cycles

Tal-Dara Maintenance

60-120 days

57-180 days

MRD testing

Primary Endpoint PFS

1 year

Alternative debulking option: Melflufen: ORR 22% EMD (vs 32% non-EMD)

2 years

Mezigdomide (CELMOD) is active in EMD (Anti-MM activity, ↑T cell fitness, improving T cell migration?)

Next Generation Genetic Engineering: Base/Prime Editing TRUCKS, the fourth-generation CAR-T Cells Transgenic proteins released by chimeric antigen receptor (CAR) T Cells upon activation impacting TME !

Karl Petri

Michael Hudecek

Abken, H. et al., Adv Cell Gene Ther. 2020

Enhanced CAR-T Cell Therapy for Lymphoma after previous failure improving expansion and persistence Three-Month Response (all patients and by lymphoma subtype)

Responses in patients with NHL resistant to CD19-CART cell therapy

huCART19-IL18 Expansion and Persistence According to Dose Level

Shorter manufacturing time Humanized CD19 CAR Local IL-18 production

3/4 patients evaluable showed CAR-T Cell persistence > 2 yrs Median DOR: 9.6 mo. Svoboda, J. et al., NEJM 2025

Conclusions: Extramedullary Multiple Myeloma •

Represents a clinically aggressive disease, frequently associated with high risk cytogenetic aberrations, reduced treatment susceptibility and poor prognosis

•

Reduced and very heterogenous expression of target antigens (CD38, BCMA, GPRC5D)

•

↓Infiltration of immune effector cells in EMD - often exhausted immune cells

•

T cell exclusion to MM cells (↑ distance of MM cells to T cells; ↓ distance from MM cells to M2) when compared to BM MM cells

New strategies: •

Novel drugs (Mezigdomide, Selinexor, Melflufen)

•

Dual Targeting (RedirecTT-1, Dual targeting CAR T cells)

•

Novel Targets (SLAMF7)

•

Optimized Debulking (TRIUMMpH trial, local irradication including theranostics with CXCR4-targeting)

•

Novel CAR constructs (e.g. TRUCKS) to improve immune cell infiltration, epitope spreading

Thanks to Medizinische Klink/Poliklinik II, Würzburg M. Topp M. Hudecek T. Bumm S. Danhof

Cima Universidad de Navarra J. San Miguel B. Paiva F. Prosper P. Rodriguez-Otero

Myeloma Research Rotterdam P. Sonneveld T. Cupedo A. Broijl

L. Rasche G. Stuhler J. Waldschmidt

Hospital Clínic Barcelona J. Bladé

Amsterdam UMC N. van de Donk

A. Beilhack J. Mersi

M. Kortüm

Wilhelminen Cancer Research Institute, Wien H. Ludwig Università di Bologna E. Zamagni M. Cavo P. Zinzani Università di Torino F. Gay R. Mina CHU Lille S. Manier CHU de Nantes P. Moreau

M. Boccadoro

T. Facon C. Touzeau

Hôpital Saint-Antoine, Sorbonne Université, Paris M. Mohty

L. Rosinol

Memorial Sloan-Kettering Cancer Center, NYC S. Usmani F. Maura M. Merz Dana-Farber Cancer Institute, Boston N. Munshi K. Anderson S. Treon C. Mitsiades UCSF Health T. Martin

A. Chari

Fred Hutchinson Cancer Research Center, Seattle M. Dhodapkar University of Calgary N. Bahlis P. Neri H. Lee Princess Margaret Cancer, Toronto K. Stewart S. Trudel

S. Zweegman

Patients and family members

Funding Agencies

Thank you for your kind attention!

Clinical Trial Updates and Future Designs: Moving Immunotherapy Options to Frontline Settings Cyrille Touzeau Nantes, France

175

T-cell redirecting immunotherapies in transplant ineligible NDMM

BispAbs in TI NDMM Majestec-7 : safety run in (n=26, median follow-up 13.8 months)

C Touzeau et al. ASCO 2024

BispAbs in TI NDMM MagnetisMM-6 : safety run in (n=37, median follow-up 7.9 months)

Elra + Dara + Len

H Quach et al. ASCO 2025

BispAbs in TI NDMM IFM 2022-01 : Tec + dara (n=37, median follow-up 10.3 months)

Infections : 65%, 14% grade 3-4

S Manier et al. ASH 2025

New trials in TI NDMM : incorporation of TCR

MajesTEC-7: Phase 3 Design

New trials in TI NDMM : incorporation of TCR

MagnetisMM-6

New trials in TI NDMM : incorporation of TCR IFM/PETHEMA Philae trial (M25-586): elderly unfit patients Sponsor Abbvie - Collaboration IFM/PETHEMA Phase 3 randomized trial Response-adapted strategy

Newly dg MM Age ≥ 18 yo Transplant Ineligible ECOG 0-2 Unfit

Study Endpoints : • Dual Primary: PFS & MRDneg CR rate • Key Secondary: OS, 12m sustained MRDneg CR, Response rates ≥CR and ≥ VGPR • Other Secondary: ORR, EFS, PFS2, Safety and Tolerability, PROs

Ph2 start feb 2026

Response-directed discontinuation of etenta -

At least 24 cycles of etenta MRD neg CR, sustained MRD >12 months Continuation of dara

CART in TI NDMM CAR-T are also evaluated in frontline, vs SOC

CARTITUDE-5

T-cell redirecting immunotherapies in transplant eligible NDMM

Improving quad with Bispab in TE NDMM Majestec-5 : Tec D(V)R in TE NDMM

100% of evaluable patients achieved MRD negativity (10-5) after 3 cycles MRD negativity rates after DVRD transplant DVRD in PERSEUS : 57.5% (P Rodriguez Otero ASCO 2024)

Raab et al. ASH 2024

Improving quad with Bispab in TE NDMM Immunoplant study : linvoseltamab in NDMM with suboptimal response (MRD+) after >4 cycles of triplet/quadruplet induction

Kazandjian et al. ASH 2025

Improving maintenance with Bispab in TE NDMM Majestec-3 : Tec+-len as post transplant maintenance

100% of evaluable patients achieved MRD negativity (10-5) after 6 or 12 months MRD negativity rates (10-5)at 1yr in PERSEUS : 65% (P. Rodriguez Otero ASCO 2024)

Zamagni et al. ASH 2024

Replacing ASCT with Bispabs Study design

Population

- NDMM - Transplant eligible

N=824

Arm A

Dara-VRD x 4 (28-day cycle)

R1 1:1*

PBSC Harvest after cycle 4 (G-CSF+- plerixafor)

Arm B

Dara-VRD x 4 (28-day cycle)

* stratification : Cytogenetic, site

PI : C Touzeau and A Perrot

ASCT

Objectives

Dara-VRD x2

- Primary :

Arm C

Dara Len 2 yrs

- R1 : MRD (10-5) pré R2 - R2 : PFS

- Secondary:

Sustained MRD OS Safety QoL Rework

R2 1:1** Elra-Len 6 cycles

Arm D

Elra 2yrs

- Exploratory:

genomic, immuno, PET, Mass spec, CTCs)

** stratification : R1, MRD

272 patients screened (april 13)

Replacing ASCT with Bispabs FASTER Trial

enrolment ongoing

PI :

Replacing ASCT with CART CARTITUDE-6

enrolment completed

PI : P Sonneveld

Improving quad+transplant with Bispabs

enrolment almost completed

PI : L Costa

Improving quad+transplant with Bispabs

PI : Marc Raab, Leo Rasche

Improving maintenance EMN30

PIs : E zamagni, N Von de Donk

MagnetisMM-7

Improving maintenance

PI : C Touzeau

May, 13 : 126 patients/176 enrolled

CONCLUSION T-cell redirecting immunotherapies will certainly become standard of care in NDMM in the very next years Improving outcomes (undetectable MRD, PFS, OS… and potentially the goal of CURE)

HOPE

Allowing fixed-duration (2 to 3 years?) treatment, while current SOC (until PD) is theorically >6-7 years The end of high-dose chemo/transplant, and therefore the disappearence of « TE » and « TI » in future guidelines

CONCERN

Safety (infections, late neurotoxicity), quality of life (GPRC5D related events), cost and availability

Thank you for your attention

INFECTION PREVENTION WITH CART BISPECIFICS Surbhi Sidana Stanford University

Infection Prevention with CAR-T and Bispecific Antibodies in Multiple Myeloma Surbhi Sidana, MD Associate Professor Stanford University June 9, 2026

COI Disclosures

•

Research Funding: BMS, Janssen, Kite, Novartis, Kelonia

•

Advisory Board/Consulting: BMS, Janssen, Sanofi, Takeda, Regeneron, Abbvie, Pfizer, BiolineRx, Legend, Kite, Arcellx, Genentech, Cell Centric, Caribou

Cytopenias and Infection Risk Baseline and therapy related immunodeficiency Pre-existing poor marrow reserve Inflammation: T cell activation, cytokine production Potential expansion of CHIP clones Depletion of normal B cells and plasma cells Short-term impact of lymphodepletion (CAR-T) 1. Baird et al. Blood Adv 5:143-155, 2021; 2. Hamilton et al. ASH 2023. Blood 142:360, 2023; 3. Hill et al. Blood 131:121-130, 2018; 4. Jain et al. Blood 141:2460-2469, 2023; 5. Lancman et al. Blood Cancer Discov 2:423-433, 2021; 6.Logue et al. Blood Adv 6:6109-6119, 2022

Types of infection Common: • Bacterial • Respiratory viral infections Less common • Fungal infection • Opportunistic infections (PJP) • Viral reactivations (Hep B, C, CMV, adenovirus, etc)

1. Baird et al. Blood Adv 5:143-155, 2021; 2. Hamilton et al. ASH 2023. Blood 142:360, 2023; 3. Hill et al. Blood 131:121-130, 2018; 4. Jain et al. Blood 141:2460-2469, 2023; 5. Lancman et al. Blood Cancer Discov 2:423-433, 2021; 6.Logue et al. Blood Adv 6:6109-6119, 2022

Risk of Severe Neutropenia with CAR-T Grade ≥ 3 Neutropenia occurs in almost all patients and prolonged beyond 1 month in 30-40% of patients

96%

89%

95%

90% 70%

41%

40%

Ide-cel (KarMMa)

Ide-cel (KarMMa-3)

Neutropenia G ≥3

30%

Cilta-cel (CART-1)

26%

Cilta-cel (CART-4)

30%

Arlo-cel

Neutropenia G ≥3 beyond 1 month

Risk of Infections with CAR-T Grade 3 or 4 infections in 20-25%, grade 5 infections in 4-5% Highest risk in first year post CAR-T

24%

22%

2% Ide-cel (KarMMa)

24%

20%

4% Ide-cel (KarMMA3)

4% Cilta-cel (CART-1)

Infections Gr 3 or 4

19%

4% Cilta-cel (CAR-4)

Arlo-cel

Grade 5

Risk of Infections with CAR-T Grade 3 or 4 infections in 20-25%, grade 5 infections in 4-5% Highest risk in first year post CAR-T

24%

22%

2% Ide-cel (KarMMa)

24%

20%

RWE with Cilta-cel

19%

Total NRM Infection NRM

Ide-cel (KarMMA3)

Cilta-cel (CART-1)

Infections Gr 3 or 4

Grade 5

Cilta-cel (CAR-4)

Arlo-cel 0-6 months 6-12 months >12 months

63/761 (8%) 35 (5% infection related NRM rate), half of NRMs 28 5 2

Cytopenias and infections with BsAb • Hypogammaglobulinemia occurs in most patients treated with BsAbs • Severe infections: 50% with BCMA BsAb, less common with GPRC5D BsAb • Grade ≥ 3 infections twice as common with BsAb than CAR-T Grade ≥ 3 neutropenia and hypogammaglobulinemia

64%

76%

75%

Teclistamab

Neutropenia G ≥3

49%

71% 32%

Elranatamab

Talquetamab q2W

Hypogammaglobulinemia

1. Moreau et al. N Engl J Med 387:495-505, 2022; 2.Lesokhin et al. Nature Medicine 29:2259-2267, 2023; 3. Chari et al. NEJM 387:2232-2244, 2022

Cytopenias and infections with BsAb • Hypogammaglobulinemia occurs in most patients treated with BsAbs • Severe infections: 50% with BCMA BsAb, less common with GPRC5D BsAb • Grade 3/4 infections twice as common with BsAb than CAR-T Infections

Grade ≥ 3 neutropenia and hypogammaglobulinemia

64%

Teclistamab

Neutropenia G ≥3

76%

75% 49%

71% 32%

Elranatamab

Talquetamab q2W

Hypogammaglobulinemia

70% 45%

46%

Teclistamab

Elranatamab

Infections (All)

34% 7% Talquetamab Q2W Infections G 3/4

1. Moreau et al. N Engl J Med 387:495-505, 2022; 2.Lesokhin et al. Nature Medicine 29:2259-2267, 2023; 3. Chari et al. NEJM 387:2232-2244, 2022

BCMA vs GPRC5D Expression: Implications for Depletion of B cells and Normal Plasma Cells

1. Jelinek et a. Blood 147:1070-1082, 2026;

Infections with Teclistamab on MajesTEC-1

Nooka et al. Cancer 2023. DOI:doi: 10.1002/cncr.35107.

Infections: Early vs Late Line Teclistamab Any grade infection

Grade 3 or 4

Grade 5

MajesTEC-1 (Tec ≥ 3 prior lines)

76%

45%

10%*

MajesTEC-3 (Tec+dara 1-3 prior lines)

97%

54%

MajesTEC-9 (Tec 1-3 prior lines)

83%

42%

5.5%

Infection incidence decreased in all studies after month 6 • Monthly dosing • Less cytopenias • Less disease burden (MM associated immune dysfunction) *Treatment emergent infectious deaths, including related and unrelated unless clearly specified to be after progression and subsequent therapy

1. Moreau et al NEJM 387:495-505, 2022; 2. Costa et a. NEJM 394:739-752, 2026; 3. Touzeau et a NEJM 2026

Infections: Leading cause of NRM with both CAR-T and Bispecific Antibodies BCMA CAR-T

• 5% NRM due to infections in trials and RWE • 2 out of 4 NRM events with CAR-T are infections

BCMA BsAb

• 5% NRM due to infections in trials and RWE • Infections: 3 of 4 NRM events with BCMA BsAb

1. Munshi et al. N Engl J Med 384:705-716, 2021; 2. Rodriguez-Otero et al NEJM 388:1002-1014, 2023. ; 3.Berdeja et al. Lancet 398:314-324, 2021; 4. San-Miguel et al NEJM 389:335-347, 2023; 5. . Sidana et al. Blood. 2025;145(1):85-97; 6. Sidana et al Blood 146:167-177, 2025; 7. Moreau et al. N Engl J Med 387:495-505, 2022; 8.Lesokhin et al. Nature Medicine 29:2259-2267, 2023.

IVIG for Infection Prevention  Associated with decreased risk of infections

 In one study, 90% reduction in

grade 3-5 infections in patients treated with BCMA BsAb (N=37)

 Should be considered for all

patients with IgG < 400 mg/dL

1. Lancman et al. Blood Cancer Discov. 2023;4(6):440-451; 2. Raje et al. Blood Cancer J 13:116, 2023.

IMWG Infection Prevention Guidelines

2022 Evolving, now consistent use of IVIG and other prophylaxis for last 2-3 years

Infection Prevention    

Do not initiate CAR-T/BsAb in setting of active infection Baseline screening: Hepatitis B, Hepatitis C, HIV in all Other screening based on risk (Quantiferon) Opportunistic viral infection screening less clear (eg. CMV)

Antimicrobial Prophylaxis: All patients VZV and HSV Pneumocystis jirovecii

Drug

Duration

Acyclovir or valacyclovir Trimethoprimsulfamethoxazole (or alternatives)

CAR T: 12-18 months after infusion, at least until CD4 count > 200/μL BsAb: During treatment and until one month after treatment discontinuation

Infection Prevention Antimicrobial Prophylaxis: Select Patients Prophylaxis

Drug

Indication

Hepatitis B reactivation

Entecavir

History of HBV infection/known exposure

Antibacterial

Levofloxacin

Prolonged severe neutropenia (ANC < 0.5 x 109/L)

Antifungal

Fluconazole or posaconazole

Prolonged severe neutropenia (ANC < 0.5) Prolonged steroid therapy

Infection Prevention Prophylaxis

Drug

Indication

IVIG

• Serum IgG ≤ 400 mg/dL vs al • Monitor serum IgG levels q4 weeks

G-CSF Growth Factors TPO agonist

Vaccinations

• Consider if ANC < 1.0; esp. if < 0.5 • Active neutropenic infection • Caution with active/high-risk of CRS • Prolonged severe thrombocytopenia

Influenza • Influenza and COVID vaccines COVID-19 Repeat COVID vaccine post CAR-T Age-appropriate • • Limited data: post CAR-T childhood vaccines vaccines

MajesTEC-9: Teclistamab in 1-3 pLOT • IVIG use was recommended in the tec arm. • Majority, but not all, received IGRT (IVIG/SCIG) • Half the patients (8/16) with G5 infections had IgG <400 mg/dL or 4 g/L around fatal infection • Almost all deaths from infections were within 6 months

Touzeau et a NEJM 2026

Retrospective Study: Amsterdam UMC • N=80 Teclistamab • Median 5 prior LOT • Median PFS: 18 months

Febe ..van den Donk et al. IMS 2025

Retrospective Study: Amsterdam UMC • N=80 Teclistamab • Median 5 prior LOT • Median PFS: 18 months

Febe ..van den Donk et al. IMS 2025

Retrospective Study: Amsterdam UMC • N=80 Teclistamab • Median 5 prior LOT • Median PFS: 18 months

Febe ..van den Donk et al. IMS 2025

Teclistamab: IVIG Breakthrough Infections

Febe ..van den Donk et al. IMS 2025

IVIG Use: Practical Points  Strong case for prophylactic use regardless of IgG level in first 6 months of BCMA BsAB  BCMA CAR-T: Prophylactic use vs pre-emptive based on levels  GPRC5D BsAb: Prophylactic use vs pre-emptive based on levels

IGRT Figure: Rejeski K, Banerjee R, Hill JA: Blood, 2026

Opportunistic Viral Infections: TEC-9

All grades

Grades 3 or 4

31 (10.7)

14 (4.8)

CMV

22 (7.6)

11 (3.8)

Herpes

6 (2.1)

3 (1.0)

13 (4.5)

4 (1.4)

Viral

Fungal

Summary  Grade 3/4 infections 2x with BCMA BsAb vs CAR-T (45% vs 20%), both in late and early line use

 Infection risk highest in first 6 months  Infections are leading cause of NRM  IVIG is effective, but breakthrough infections occur, often with suboptimal IgG levels

 Other factors that impact infection risk: lymphopenia, neutropenia, disease related immune dysfunction

Discussion with Audience  Infection related mortality despite IVIG ppx - what else should we be doing?

 Should all patients receive IVIG monthly regardless of IgG levels?  For how long? 6 months or longer?  Should it differ for CAR-T vs BsAb and by target (BCMA vs not)  Duration of antimicrobial prophylaxis: CD4 driven or time dependent  CMV monitoring? 

Vaccinations?

UPDATE ON CELMODS Paul G. Richardson, MD Dana-Farber Cancer Institute

2026 IMWG Summit Session 4: New Treatment Updates and Supportive Care Stockholm, Sweden June 9, 2026

Update on The Role of CELMoD Agents in Relapsed/Refractory and Newly Diagnosed Multiple Myeloma Disclosures of relevant conflicts of interest:

Paul G. Richardson, MD

• Service RJ on Corman advisory committees/consulting: Professor of Medicine • Celgene/BMS, GSK, Karyopharm, Harvard Medical School Oncopeptides, Regeneron, Sanofi

Clinical Program Leader, Director of Clinical Research Jerome Lipper Multiple Myeloma Center • Research grants: Dana-Farber Cancer Institute • Karyopharm, Oncopeptides Boston, Massachusetts, USA

Treatment of MM in 2026: multiple therapies approved or under investigation Backbone/standard-of-care agents

Additional RRMM/recent approvals

Emerging therapies for RRMM**

IMiDs

PIs

mAbs

HDACis

ADCs

Targeted therapies

CAR T cell therapies

BiTEs® / bispecifics

CELMoDs®

Lenalidomide

Bortezomib*

Daratumumab (CD38)

Panobinostat‡

Belantamab mafodotin‡

Selinexor

Idecabtagene vicleucel

Teclistamab (BCMAxCD3)

Etentamig (ABBV-383)† (BCMAxCD3)

Iberdomide†

Pomalidomide

Carfilzomib

Isatuximab (CD38)

Vorinostat†,#

AZD0305†

Melflufen‡

Ciltacabtagene autoleucel

Elranatamab (BCMAxCD3)

Alnuctamab†# (BCMAxCD3)

Mezigdomide†

Thalidomide

Ixazomib

Elotuzumab (SLAMF7)

Belantamab†

Venetoclax†,#

CAR T cell therapies

Lisaftoclax†

Arlocabtagene Linvoseltamab (BCMAxCD3) autoleucel†

Marizomib†,#

Strategies for managing MM, including doublet, triplet, and quadruplet combination both upfront *Also approved in combination with liposomal doxorubicinregimens (Doxil®). **Under investigation. Sonrotoclax† † Not currently approved in RRMM. ‡FDA approval withdrawn. deprioritized. and in relapse,#Development as well as treatment ® ADCs, antibody–drug conjugates; BCMA, B-cell maturation BiTEs , bispecific T-cell sequencing, areantigen; rapidly evolving in the engagers; CAR, chimeric antigen receptor; CELMoDs®, cereblon E3 ligasetherapeutic modulators; CHMP, context of this expanding Committee for Medicinal Products for Human Use; COMy, Controversies in multiple myeloma; armamentarium EMA, European Medicines Agency; FcRH5, Fc receptor-homolog 5; FDA, Food and Drug Administration; GPRC5D, G protein-coupled receptor family C group 5 member D; ICIs, immune checkpoint inhibitors; IMiDs®, immunomodulatory drugs; mAbs, monoclonal antibodies; PIs, proteasome inhibitors; RRMM, relapsed/refractory multiple myeloma.

Forimtamig† Talquetamab (GPRC5DxCD3) (GPRC5DxCD3) Cevostamab† (FcRH5xCD3)

Others Cemsidomide, Inobrodib†

Anitocabtagene autoleucel†

CAR NK cell therapies†

Durcabtagene autoleucel†

ICIs, Immunocytokines†,#

Adapted from Richardson PG. 5th Oxford Myeloma Workshop, January 30–31, 2025, Oxford, UK.

MOA of CELMoDs: iberdomide1 and mezigdomide2 CELMoDs: overview of immunologic effects

/ CELMoDs

CELMoDs: MOA and immune effects

Neural stem cell proliferation

/ CELMoDs

1. Lonial S, et al. Lancet 2022;9(11):e822–32. 2. Richardson PG, et al. N Engl J Med 2023;389(11):1009–22. KegyesHaematol D, et al. Biomarker Res 2025;13(1):105. Figures adapted from: (left) Sato T, et al. Front Cell Dev Biol 2021;9:629326; (right) D’Souza C, et al. Front Immunol 2021;12:632399.

/ CELMoDs

CELMoDs: summary of pharmacodynamics

Enhanced effects seen with anti-MM agents, potential mechanisms of resistance Sensitization/potentiation

Direct immune/antitumor effects

Enhanced/synergistic effects

+N o

ve l

•↑ Cytotoxicity of BCMA-targeted BsAb •↑ Cytokine production •↑ Tumor growth inhibition, synergistic cell killing – alnuctamab, greater enhancement of activity with •↑ T cell activation and proliferation mezigdomide + V±dex mezigdomide vs pom •Potent immunomodulation with mezigdomide + Vd •↑ NK cell cytotoxicity •↑ Alnuctamab antitumor activity in vivo, T-cell •↑ Apoptotic activity vs pom with mezigdomide + V •↓ Exhausted/senescent T and NK cells activation, tumor tissue infiltration or K at 100-fold lower concentration of • Activated innate/adaptive immunity •↑ Adhesion molecules, T-cell-mediated killing mezigdomide vs pom • Modulation of adhesion molecules •↑ Regressions and PFS in vivo with mezigdomide • Near-complete regressions, prolonged survival in •↑ Antigen presentation viaemerging MHC-I Mezi overcomes CRBN mutations post IMiD therapy + GPRC5D-targeted BsAb forimtamig vivo with mezigdomide + Vd vs pom-Vd 2025 •↑ Durable responses, favorable T-cell profile • Mezigdomide interacts with additional moieties outside of the +B sA thalidomide binding domain Is bs +P E3 ligase • May affect the stabilization CD38 priming, enhanced apoptosis of cereblon or the CRL4CRBN Enhanced viability/persistence CUL4A complex •↑ CD38 cell surface expression DDB1 • May result in clinical RBX responses •↑ Viability in IL-2-starved CAR T cells •↑ ADCC / ADCP with subsequent Dara + 1 m • Not seen with pomalidomide Abs •↑ Activation markers HLA-DR, CD69 +CAR T •↑ Apoptosis with mezigdomide + Dara •↑ Effector memory phenotype CAR T cellsWatson E, et al. Blood 2025;146(Supplement CRBN 1):436. •↑ Proliferative CD3+ T cells, effector •↑ Production of IL-2, IL-17a, TNFα antigenIkaros/ memory CD4+ T cells, HLA-DR-expressing Mez specific cytokines by CD8+ and CD4+ CAR T i CD4+ T cell activation Aiolos cells against BCMA-expressing MM cells •↑ Antigen-specific toxicity CKS1B downregulation •↑ Apoptosis, ↓ cell proliferation with mezigdomide + bromodomain-containing protein 4 (BRD4) inhibitor •Potential for activity in gain/amp 1q21 MM Mo CC, et al. Expert Opin Emerg Drugs 2025;30(3):209–19.

Potential resistance mechanisms • CRBN alterations • Monoallelic 3p26 loss • ↓ Expression of COP9 signalosome protein complex • ↑ USP15 expression • Alterations in SREBP lipid synthesis pathway • High baseline EZH2 expression → poorer PFS

Iberdomide: immune cell responses Immunostimulatory effects:1 increased proliferating (Ki-67+) NK and T cells

T-cell subset analysis:1 shift from naïve to activated, effector-memory T cell phenotype with iberdomide, with decrease in naïve T cells and increase in effector-memory T cells

Paired BM sample analysis of iberdomide effects2

Increased effector cell abundance

1. Amatangelo M, et al. Cell Rep Med 2024;5(6):101571. 2. Van Oekelen O, et al. Cell Rep Med 2024;5(6):101684.

Increased activation

Decreased exhaustion

Mezigdomide: immune cell responses Paired BM sample analysis of mezigdomide effects1 Shift towards effector T cell phenotype

Increased activation

2025

Increased activation

Mechanistic rationale for enhanced antitumor immunity

• Mezigdomide and iberdomide significantly decrease induction of monocytic myeloid-derived suppressor cells (mMDSCs) • Significant upregulation of inflammatory response genes in MM cells • Reduced expression of key immunosuppressive mediators IL-10 and MIF • Mechanisms contribute to remodelling tumor microenvironment towards an immune-permissive state Niiyama-Uchibori Y, et al. Blood 2025;146(Supplement 1):7447. Chen, LY et al. Blood 2023;142(Supplement 1):4686.

Decreased exhaustion

CELMoD doublet for later-relapse RRMM

Mezigdomide + dex: Phase 1/2 study, N=178 CC-92480-MM-001 first-in-human phase 1 trial: Mezigdomide + Dex 100

• 77 heavily pretreated RRMM patients • 30% high-risk cytogenetics, 35% EMD • Median 6 prior therapies • 56% triple-class-refractory Dose expansion at RP2D

R esponse, %

Dose escalation

ORR 25% 1 12 12 5

60 40

ORR 41% 2 3 20 16 6 39

Mezigdomide:20updates in RRMM 22

• 101 heavily pretreated RRMM patients • 37% high-risk cytogenetics, 40% EMD • Median 6 prior therapies • 100% triple-class-refractory Efficacy in dose expansion cohort • Median DOR 7.6 months • Median PFS 4.4 months • In patients with prior anti-BCMA therapy, median DOR 6.9 months and median PFS 5.4 months Richardson PG, et al. N Engl J Med 2023;389(11):1009–22.

10 5

ORR 30% 5 18 8 52

ORR 50% 3 30 17 3 37

10 8

Safety in dose escalation/expansion cohorts • Grade 3/4 neutropenia 71%/76%, anemia 38%/36%, thrombocytopenia 24%/28%, febrile neutropenia 9%/15% • Infections 74%/65% (Grade 3/4 40%/35%) • Treatment discontinuation due to AEs NR/6%

sCR CR VGP R PR MR SD PD NE

CELMoD doublet for later-relapse RRMM

Mezigdomide + dex induces responses in patients with EMD Dosing Dose level schedulea 0.1 mg QD 0.2 mg QD 10/14 days × 2 0.3 mg QD 0.6 mg QD 21/28 days

0.8 mg QD

10/14 days × 2

1.0 mg QD

PD PD SD SD

1.0 mg QD

C10

PET scan pretreatment

VGPRa

PRb MR

SD PDc

SD SD PR SD MR SD

On treatment at time of data cut PR

SD PD SD PR VGPR PR VGPR PR (case study) SD

PET scan post-mezigdomide C3D1

VGPR PR

21/28 days

PD SD

1.0 mg dose active in EMD

1 patient in the 21-/28-day 1.0 mg QD cohort had an unconfirmed VGPR as of the data cutoff date. b1 patient in the 21-/28-day 0.8 mg QD cohort had an unconfirmed PR as of the data cutoff date. c 1 patient in the 21-/28-day 0.8 mg QD cohort had an unconfirmed PD as of the data cutoff date. a

1. Richardson PG, et al. J Clin Oncol 2020;38(15_suppl): abstract 8500.

In a subset analysis of CC-92480-001 phase 1/2 trial, Mexi+Dex treatment shows activity in patients with EMD1 C, cycle; CR, complete response; D, day; EMD, extramedullary disease; MR, minimal response; PD, progressive disease; PET, positron emission tomography; PR, partial response, QD, once daily; SD, stable disease; VGPR, very good partial response.

CELMoD doublet for later-relapse RRMM

Mezigdomide + dex induces responses in patients with EMD At start of treatment (study entry)

After 4 months of treatment with Mezi 1.0 mg, D1–21 every 28 days, + Dex

Richardson PG, et al. Blood 2022;140(Supplement 1):1366–8. Richardson PG, et al. N Engl J Med 2023;389(11):1009–22.

CELMoD doublet for later-relapse RRMM

Mezigdomide + dex: real-world experience EAP: 10 patients with RRMM

2025

Best responses

• Median age 71 years N=10 50% 20% 10% • 50% ECOG performance status ≥2 ORR 80% • 40% high-risk cytogenetics Mezi-dex active in high-risk patients 0 10 20 30 40 50 60 70 80 90 100 • 20% EMD 2025 Patients, % • 20% R-ISS stage III • Pharmacodynamic activity seen across doses in peripheral blood

PR VGP R

and tumors of pomalidomide-exposed/refractory patients • Ikaros/Aiolos protein degradation seen in patients with CRBN Median follow-up 7 months; 6-month PFS 58% / OS 60% Median 6 prior lines (range 3–12) defects and with high-risk cytogenetics • Clinical responses seen in patients with CRBN defects and ultra70 high-risk molecular features • 100% prior CD38 mAb (80% refractory) • Tumor burden biomarkers – sFLC, sBCMA – reduced in patients • 100% prior IMiDs (100% refractory) 60 with plasmacytomas with high-risk cytogenetics and those 60PFS • 100% prior PIs (90% refractory) • Aiolos degradation in tumor associated with 50 1):5697. Chow 10% T, et al. Blood 2025;146(Supplement • 40% prior belantamab mafodotin, prior

belantamab mafodotin and teclistamab, 10% prior belantamab mafodotin, teclistamab, and CAR T cells • 70% triple-class refractory, 40% penta-drug refractory

De Novellis D, et al. Blood 2025;146(Supplement 1):7543.

Patients, %

Safety

40 30 20 10 0

40 20 10 G3/4 G3/4 Pneumonia neutropenia thrombocytopenia

Febrile neutropenia

10 CMV reactivation

Invasive aspergillosis

CELMoD triplets for RRMM: mezigdomide–PI regimens

Mezigdomide + Vd or Kd

CC-92480-MM-002 Phase 1/2 Study: Mezigdomide + Vd / Kd 1,2

Mezigdomide + Kd (N=27) • 59.3% high-risk cytogenetics • Median 2 prior therapies • 77.8% R-refractory • 51.9% PI-refractory • 74.1% CD38 mAb-refractory • Median duration of treatment: 12 cycles

4 (14.3) 1 (3.6) 6 (21.4)

60 40

10 (35.7)

100 sCR CR VGPR PR MR SD PD NE

1 (3.6) 5 (17.9) 1 (3.6)

• • • • • • •

Median DOR 10.9 months Median PFS 11.2–13.4 months Grade 3/4 neutropenia 35.7% Grade 3/4 thrombocytopenia 21.4% Grade 3 anemia 14.3% Infections 71.4% (Grade 3/4 17.9%) Grade 3/4 pneumonia 10.7%

1. Oriol A, et al. Clin Lymphoma Myeloma Leukemia 2023;23(Suppl 2):S31. 2. Sandhu A, et al. Blood 2024;144(supplement 1):1025.

ORR

90.9% 384.2% (7.9) 4 (10.5) 3 (27.3)

60 17 (44.7) 6 (54.5)

40 20 0

• • • • • • •

8 (21.1) 1 (2.6) 3 (7.9) 1 (2.6) 1 (2.6)

Mezigdomide + Kd (N=27)

sCR CR VGP R PR MR SD PD NE

1 (9.1) 1 (9.1)

Median DOR 19.4 months Median PFS 16.6 / 20.8 months Grade 3/4 neutropenia 63.3% Grade 3/4 thrombocytopenia 26.5% Grade 3 anemia 6.1% Infections 79.6% (Grade 3/4 32.7%) Grade 3/4 pneumonia 22.4%

100 80

Response, n (%)

ORR 75.0%

Response, n (%)

Mezigdomide + Vd 1.0mg (N=38) / 0.6 mg (N=11) • 53.1% high-risk cytogenetics • Median 1 prior therapy • 63.3% R-refractory • 16.3% PI-refractory • 34.7% CD38 mAb-refractory • Median duration of treatment: 15 cycles

100 Response, n (%)

• 42.9% high-risk cytogenetics • Median 3 prior therapies • 82.1% R-refractory • 50.0% PI-refractory • 50.0% CD38 mAb-refractory • Median duration of treatment: 12.5 cycles

Mezigdomide + Vd (1.0 mg, N=38 / 0.6 mg, N=11)

Mezigdomide + Vd (N=28, dose escalation)

Mezigdomide + Vd (N=28)

60 40 20 0

• • • • • • •

ORR 61.5%

1 (3.7) 3 (11.1) 8 (29.6)

sCR CR VGPR PR MR

11 (40.7) 2 (7.4) 1 1 (3.7) (3.7)

Median DOR 11.9 months Median PFS 11.7–13.8 months Grade 3/4 neutropenia 44.4% Grade 3/4 thrombocytopenia 14.8% Grade 3/4 anemia 14.8% Infections 70.4% (Grade 3/4 33.3%) Grade 3/4 pneumonia 3.7%

Phase 3 studies of CELMoD triplets in RRMM:

combination with SOC mAbs or PIs

Study

Treatment

SUCCESSOR-1 (NCT05519085)1

~810 patients 1–3 prior lines

Stage 1: Mezi + Vd Determine recommended Mezi dose

Stage 2

SUCCESSOR-2 (NCT05552976)2

~525 patients ≥1 prior line

Stage 1: Mezi + Kd Determine recommended Mezi dose

Stage 2

Mezi + Vd Pom-Vd Mezi + Kd Kd

Primary endpoint: PFS

Primary completion: Jan 2027

Primary endpoint: PFS

Primary completion: Mar 2026

Iber 1.0 mg + Dara-dex EXCALIBER-RRMM (NCT04975997)3

Stage 1 ~200 patients 1–2 prior lines

Iber 1.3 mg + Dara-dex Iber 1.6 mg + Dara-dex

Stage 2 ~664 patients 1–2 prior lines

Dara-Vd 1. Richardson PG, et al. Clin Lymphoma Myeloma Leuk 2023;23(Supplement 1):S495–6, abstract MM-372. 2. Richardson PG, et al. J Clin Oncol 2023;41(16_suppl):abstract TPS8070. 3. Lonial S, et al. Future Oncol 2025;21(14):1761–9.

Iber + Dara-dex Dara-Vd

Primary endpoint: PFS Primary completion: Nov 2027

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Stage 1, dose optimization: n = 235

N = 606

Stage 2, efficacy and safety: n = 372

Median PFS

Hazard ratio

0.9

18.0 months

HR 0.48

0.8

8.3 months

(95% CI, 0.36–0.63) P < 0.0001

1.0

Probability of PFS

Total confirmatory analysis by ITT in 479 patients

0.7 0.6 0.5 0.4

MeziKd

0.3 0.2

Median follow-up: 10.6 months

0.1 0 No. at risk MeziKd Kd

288 191

250 134

197 90

133 59

81 31

15 18 Time (months) 47 15

27 8

19 3

11 1

6 0

2 0

0 0

In anti-CD38 mAb- and R-exposed patients who had received ≥1 prior LOT (range 1–9), MeziKd significantly reduced risk of progression or death by 52% Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506.

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Subgroup analysis of PFS in confirmatory analysis group by ITT, n = 479 Subgroup

Favors MeziKd Favors Kd

HR (95% CI)

Age, years

Subgroup

Favors MeziKd Favors Kd

HR (95% CI)

Prior LOTs

< 65

181

0.52 (0.34–0.80)

65 to < 75

178

0.43 (0.27–0.67)

≥ 75

120

0.52 (0.29–0.94)

≤2

253

0.54 (0.37– 0.80)

226

0.44 (0.30– 0.64)

Yes

411

0.48 (0.36– 0.64)

0.50 (0.23– 1.08)

Yes

363

0.50 (0.36– 0.67)

116

0.40 (0.21– 0.76)

Baseline ISS disease stage I

245

0.42 (0.28–0.64)

146

0.51 (0.31–0.84)

III

0.60 (0.34–1.05)

High risk

136

0.49 (0.30–0.80)

Standard risk

280

0.51 (0.35–0.74)

Cytogenetic risk groups

Soft-tissue plasmacytomas Yes

118

0.34 (0.21–0.54)

361

0.58 (0.42–0.82)

Yes

0.33 (0.16–0.67)

434

Extra-medullary plasmacytomas 0.51 (0.38–0.69) 0.01

0.1

Refractory to anti-CD38 mAbs

Refractory to LEN

Refractory to anti-CD38 mAbs and LEN Yes

326 0.01

0.1

No 153 PFS survival benefit with MeziKd superior across all prespecified subgroups

Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506.

Refractory to POM

0.47 (0.34– 0.65) 0.48 (0.28– 0.82)

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd OS: Key secondary endpoint in confirmatory analysis group by ITT, n = 479 1.0 0.9 Probability of OS

0.8 0.7

MeziKd

0.6 0.5

No. of events

0.4

62/288 (21.5%)

0.3

51/191 (26.7%)

0.2

No. at risk MeziKd Kd

HR 0.79

(95% CI, 0.54–1.15)

Median follow-up: 10.6 months

0.1 0

Hazard ratio

288 191

273 175

244 157

180 118

122 84

15 18 Time (months) 79 44

45 31

35 24

25 12

12 5

5 0

0 0

Planned futility analysis demonstrates a positive OS trend favoring MeziKd with no cross-over of the curves Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506.

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Treatment response, n = 479 100

Patients (%)

80 70 60 50 40 30

sCR CR VGPR PR

ORR 80.2%

25.0

≥CR 26.7%

1.7 33.3

PFS2, n = 479

ORR 53.4%

0.5

8.4

≥CR 8.9%

≥VGPR 60.1%

22.0

≥VGPR 30.9%

20 10 0

20.1

22.5

MeziKd (N = 288)

Kd (N = 191)

Median time to response 1.1 mos 12-month DoR 72%

1.1 mos 54%

Addition of Mezi to Kd deepened response, doubling the rate of ≥VGPR and tripling the rate of ≥CR Superior with MeziKd demonstrates sustained clinical benefit beyond first progression Richardson PG, et al. J ClinPFS2 Oncol 2026;44(16_suppl):LBA7506.

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Most common TEAEs in confirmatory analysis group for safety, n = 474 TEAE, n (%) Any TEAE Hematological Neutropenia Febrile neutropenia Thrombocytopenia Anemia White blood cell count decrease Nonhematological Diarrhea URTI Fatigue Cough Pneumonia Dyspnea Hypertension

MeziKd (N = 288)

Kd (N = 186)

Any grade

Grade 3/4

Any grade

Grade 3/4

286 (99.3)

241 (83.7)

178 (95.7)

105 (56.5)

199 (69.1) 24 (8.3) 174 (60.4) 149 (51.7)

176 (61.1) 23 (8.0) 113 (39.2) 75 (26.0)

32 (17.2) 0 77 (41.4) 66 (35.5)

17 (9.1) 0 42 (22.6) 28 (15.1)

67 (23.3)

54 (18.8)

23 (12.4)

7 (3.8)

112 (38.9) 79 (27.4) 67 (23.3) 66 (22.9) 58 (20.1) 58 (20.1) 31 (10.8)

10 (3.5) 13 (4.5) 9 (3.1) 1 (0.3) 45 (15.6) 11 (3.8) 11 (3.8)

33 (17.7) 31 (16.7) 39 (21.0) 22 (11.8) 21 (11.3) 26 (14.0) 40 (21.5)

1 (0.5) 3 (1.6) 7 (3.8) 0 11 (5.9) 5 (2.7) 17 (9.1)

•

Neutropenia is an on-target reversible AE; only 1 patient discontinued treatment due to neutropenia with MeziKd (none with Kd)

•

A reduction in grade 3/4 hypertension was observed with MeziKd, potentially associated with the lower K dose

•

Grade 3/4 VTE occurred in 2.8% (MeziKd) and 0.5% (Kd) of patients

•

Grade 5 TEAEs were observed in 7.3% (MeziKd) and 4.3% (Kd) of patients –

The majority were in the context of myeloma progression

Neutropenia was the most common grade 3/4 AE and was managed effectively with dose interruptions/modifications and/or G-CSF Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506.

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Summary of infections in confirmatory analysis group for safety, n = 474 MeziKd (N = 288) TEAE, n (%)

Kd (N = 186)

Any grade

Grade 3

Grade 4

Any grade

Grade 3

Grade 4

210 (72.9)

82 (28.5)

16 (5.6)

100 (53.8)

28 (15.1)

1 (0.5)

URTI

79 (27.4)

13 (4.5)

31 (16.7)

3 (1.6)

Pneumonia

58 (20.1)

39 (13.5)

6 (2.1)

21 (11.3)

10 (5.4)

1 (0.5)

Influenza

30 (10.4)

9 (3.1)

18 (9.7)

2 (1.1)

COVID-19

29 (10.1)

5 (1.7)

11 (5.9)

RTI

29 (10.1)

7 (2.4)

8 (4.3)

UTI

26 (9.0)

8 (2.8)

9 (4.8)

1 (0.5)

Nasopharyngiti

17 (5.9)

18 (9.7)

17 (5.9)

6 (2.1)

7 (3.8)

Any infection

s Bronchitis

•

Most infections (68.6% MeziKd; 98.0% Kd) were not associated with grade 3/4 neutropenia

•

Incidence of hypogammaglobulinemia was low

•

–

10.1% (MeziKd) versus 6.5% (Kd)

–

31.6% (MeziKd) versus 21.0% (Kd) of patients received ≥1 dose of IGRT

Incidence of fatal infections was low (2.4% MeziKd; 1.1% Kd)

Infections were mostly well managed following standard clinical practice and supportive care, with low incidence of grade 4 events Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506.

CELMoD triplets for RRMM: mezigdomide–PI regimen

Phase 3 SUCCESSOR-2 trial of mezigdomide + Kd vs Kd Contextualization of clinical benefit seen in SUCCESSOR-2 for anti-CD38 mAb- and R-exposed RRMM patients across multiple settings SUCCESSOR-2 ITT

Median PFS, months

18.0

Median prior LoT, n (range) R refractory, % Anti-CD38 refractory, %

MeziKd

N= 191

N = 288

2 (1–9) 76.9 85.3

2 (1–9) 74.4 86.1

10 11.1

HR: 0.24

8.3 0

Dara-exposed subgroup

HR: 0.49

HR: 0.48

CARTITUDE-43

ITT

KARMMA-32

SELECT1

KPdKPd

13.8 4.4 SRs

N = 52

N = 132

2 (1–2) 100 75

3 (2-4) 73 95

Ide-cel N = 254

3 (2-4) 79 94

10 0

19.3 4.5

DPd/PVd

Cilta-cel

N = 54

N = 51

100 83.3

100 90.5

All patientsa were antiCD38 mAband R-exposed

Trials are not intended for direct comparison. Side-by-side data are presented solely to summarize information. a 77% of patients received prior anti-CD38 mAb in the SELECT trial.

Richardson PG, et al. J Clin Oncol 2026;44(16_suppl):LBA7506. 1. Perrot A, et al. Leuk Lymphoma 2024;65(6):833-842; 2. Ailawadhi S, et al. Blood 2024;144(23):2389-2401; 3. Einsele H, et al. Lancet Oncol 2026;27(2):254-268.

CELMoD triplets for RRMM: mezigdomide–mAb regimens

Mezigdomide + Dara-dex or Elo-dex

CC-92480-MM-002 Phase 1/2 Study: Mezigdomide + Dara-dex / Elo-dex 1

Mezigdomide + Elodex (N=20) • Median 3 prior therapies • 85% prior CD38 mAb

Mezigdomide + Elo-dex (N=20)

Mezigdomide + Dara-dex (N=56)

80 60

ORR 75.0%

2 (3.6) 8 (14.3)

16 (28.6)

2 (3.6) 3 (5.4) 9 (16.1)

0 • • • • •

1. Richardson PG, et al. Blood 2023;142(supplement 1):1013.

DOR / PFS not mature Grade 3/4 neutropenia 53.6% Grade 3/4 thrombocytopenia 7.1% Grade 3/4 anemia 10.7% Grade 3/4 infections 19.6%

100 sCR CR VGPR PR MR SD PD NE

Response, n (%)

100 Response, n (%)

Mezigdomide + Dara-dex (N=56) • Median age 67 years • Median time since diagnosis 8.2 years • Median 2 prior therapies • 82.5% IMiD-refractory • 61.4% PI-refractory • 15.8% prior ASCT • 8.8% prior CD38 mAb

7 (35.0)

60 40 20 0

• • • • •

ORR 45%

1 (5.0) 1 (5.0)

3 (15.0) 6 (30.0) 1 (5.0) 1 (5.0)

DOR / PFS not mature Grade 3/4 neutropenia 40% Grade 3/4 thrombocytopenia 10% Grade 3/4 anemia 20% Grade 3/4 infections 35%

sCR CR VGPR PR MR SD PD NE

CELMoD triplets for later-relapse RRMM: combination with targeted agents

STOMP Arm 12: Mezigdomide + Selinexor-dex

2025

Patient demographics and baseline characteristics

As of Oct 10, 2025, a total of 13 patients have been enrolled • 3 in Cohort 1 seli 40 mg QW/mezi 0.6 mg QD/dex 40 mg QW • 3 in Cohort 2 seli 60 mg QW/mezi 0.6 mg QD/dex 40 mg QW • 7 in Cohort 3 seli 60 mg QW/mezi 1.0 mg QD/dex 40 mg QW Characteristics Age (years), median (range) ≥ 75 years, n (%) Sex (male), n (%) Race, n (%) African American Native Hawaiian or Pacific Islander White ECOG performance status, n (%) 0 1 ISS disease stage, % I II III

Total (N = 13) 66 (42–83) 2 (15) 9 (69) 3 (23) 1 (8) 9 (69) 8 (62) 5 (39) 9 2 2

Characteristics Time since diagnosis (years), median (range)

Total (N = 13) 7.5 (2.7–22.0)

Extramedullary lesions, n (%) Number of prior lines of therapy, median (range)

3 (23) 5 (2–12)

Exposure to at least one IMiD, n (%) Exposure to at least one PI, n (%)

13 (100) 13 (100)

Exposure to at least one anti-CD38 antibody, n (%) Exposure/refractory to T-cell redirecting treatment,† n (%)

13 (100) 3 (23)

Exposure/refractory to belantamab mafodotin, n (%) Exposure/refractory to iberdomide, n (%)

3 (23) 1 (7)

Prior ASCT, n (%) Refractory to at least one IMiD, n (%)

9 (69) 12 (92)

Refractory to at least one PI, n (%) Refractory to at least one anti-CD38 antibody, n (%)

10 (77) 13 (100)

Refractory to last line of treatment, n (%)

12 (92)

Safety • Common treatment-emergent AEs: neutropenia 85%, thrombocytopenia 62%, constipation 54%, leukopenia 54% • Most common Grade 3/4 treatment-emergent AE: neutropenia (54%)

Mo CC, et al. Blood 2025;146(Supplement 1):4010. Mo C, et al. 7th European Myeloma Network Meeting, April 16–18, 2026, Prague, Czechia, poster #P43.

CELMoD triplets for later-relapse RRMM: combination with targeted agents

STOMP Arm 12: Mezigdomide + Selinexor-dex

2025

Cohort 1 40 mg Seli 0.6 mg Mezi 40 mg Dex

Stable Disease

Cohort 2

60 mg Seli 0.6 mg Mezi 40 mg Dex

PR VGPR

Cohort 3

60 mg Seli 1.0 mg Mezi 40 mg Dex

(EOT) Progressive disease (EOT) Death (EOT) Adverse event (EOT) Withdrew consent

C10

C11

C12

C13

C14

C15

ORR: 50% (6/12) – all VGPR or better Mo CC, et al. Blood 2025;146(Supplement 1):4010. Mo C, et al. 7th European Myeloma Network Meeting, April 16–18, 2026, Prague, Czechia, poster #P43.

CELMoD triplets for later-relapse RRMM: combination with targeted agents

STOMP Arm 12: Mezigdomide + Selinexor-dex Mezi-Seli-dex results in CD8+ T cell proliferation and activation CD8+: Functional Markers

Percent change at Week 4 Relative to Baseline

85.8

127.0

-6.0

60.3

18.5

-2.6

0.1

-29.6

26.9

6.0

-3.6

800

250

100

Mezigdomide + Selinexor-dex: potential strategy for overcoming immune exhaustion Use of T cell ‘energizing’ regimen before or after T cell exhausting agents

-50 -100 Ki67

CD38

CD226

HLA-DR

BHLADR

GranzymeTbet B

CD57

PD-1+

Tim3

TIGIT

Increase in median expression of markers related to CD8 expansion (Ki67, CD38) and MHC-II expression (HLA-DR) and decrease in marker of senescence (CD57) were observed across all dose cohorts

Mo CC, et al. Blood 2025;146(Supplement 1):4010. Mo C, et al. 7th European Myeloma Network Meeting, April 16–18, 2026, Prague, Czechia, poster #P43.

2025

CELMoD triplets for later-relapse RRMM: combination with targeted agents

STOMP Arm 12: Mezigdomide + Selinexor-dex Mezi-Seli-dex upregulates T-cell activation-related cytokines and suppresses pro-inflammatory cytokines inversely associated with poor MM prognosis

Median percent change in cytokine levels compared to C1D1 Category

Comparison

C1D1 vs C1D15

C1D1 vs C2D1

Prognostic association with MM Negative Positive and negative reported None % Median Change 100 50 0 -50 -100

IL-10

Granzyme B

IL-2

IL-8_CXCL8

IL-6

MIP-1 beta_CCL4

TNF-alpha

I-TAC_CXCL11

MIP-3 alpha_CCL20

IL-5

IFN gamma

IL-4 IL-23 sCD137_41BB_TNFRSF9 IL-13 Granzyme A

IL-7

IL-17A_CTLA8

IL-1 beta

IL-12 (p70)

sFasL_TNFRSF6

GM-CSF

MIP-1 alpha_CCL3

sFas

Perforin

Fractaline_CX3CL1

IL-21

C1D1 vs C2D15

Cytokine panel testing in primary patient samples indicated increased T-cell activation signaling (IL-21, Perforin) during on (C1D15, C2D15) and off-treatment (C2D1) periods Pro-inflammatory cytokines and IL-8, IL-6, and TNF-alpha decreased modestly with SMd treatment. These cytokines have also been shown to negatively correlate with MM prognosis.1-3

Mo CC, et al. Blood 2025;146(Supplement 1):4010. Mo C, et al. 7th European Myeloma Network Meeting, April 16–18, 2026, Prague, Czechia, poster #P43. 1. Zhang XG, et al. Blood 1989;74:11–13. 2. Herrero AB, et al. Am J Path 2016;186:2171–82. 3. Jourdan M, et al. Eur Cytokine Netw 1999;10:65–70.

2025

CELMoD triplets for later-relapse RRMM: combination with novel targeted agents

Synergistic activity with CELMoDs and EZH2 inhibition Synergistic activity 1

• EZH2 inhibitor tazemetostat and CELMoDs in KMS-11 resistant MM cell line • Higher synergy scores with stronger cereblon binding potency • Combination suppresses IRF4 expression to inhibit MM cell growth Synergistic mechanism2 • Upregulation of apoptotic gene clusters (e.g. FoxO transcription factor) and downregulation of cell cycle gene clusters • Significantly reduced Aiolos/Ikaros binding, increased chromatin accessibility (reduced H3K27me3)

1. Li Y, et al. Haematologica 2026;doi:10.3324/haematol.2025.288024. 2. Huang T-H, et al. Blood 2025;146(Supplement 1):5699.

2025

CELMoD triplets for later-relapse RRMM: combination with novel targeted agents

Mezigdomide-dex + tazemetostat (EZH2 inhibitor) / BMS-986158 (BET inhibitor) / trametinib (MEK inhibitor) CA057-003 (NCT05372354) Phase 1/2 trial in patients with RRMM

Mezi-dex + Tram (N=20) • 15.0% high-risk cytogenetics • Median 4 prior lines • 45.0% prior T-cell redirecting therapy • 90.0% CD38 mAb-refractory • 90.0% triple-class refractory

1 (6.3)

4 (25.0)

3 (18.8) 1 (6.3)

3 (18.8)

4 (25.0)

0 • • • • • • •

sCR CR VGPR PR MR SD PD NE

Median DOR not reached Median PFS 6.7 months Grade 3/4 neutropenia 50.0% Grade 3/4 thrombocytopenia 6.1% Grade 3 anemia 12.5% Infections 68.8% (Grade 3/4 25.0%) Grade 3/4 pneumonia 12.5%

Costa LJ, et al. Blood 2024;144(supplement 1):677.

ORR

100

135.0% (5.0)

6 (30.0)

1 (5.0)

8 (40.0)

Response, n (%)

Mezi-dex + BMS-986158 (N=20) • 30.0% high-risk cytogenetics • Median 5 prior lines • 60.0% prior T-cell redirecting therapy • 85.0% CD38 mAb-refractory • 75.0% triple-class refractory

ORR 50.0%

100 Response, n (%)

• 31.3% high-risk cytogenetics • Median 5 prior lines • 68.8% prior T-cell redirecting therapy • 87.5% CD38 mAb-refractory • 81.3% triple-class refractory

Mezi-dex + BMS-986158 (N=20, dose escalation)

20 0

• • • • • • •

Mezi-dex + Tram (N=20, dose escalation)

sCR CR VGP R PR MR SD PD NE

4 (20.0)

Median DOR not reached Median PFS 4.6 months Grade 3/4 neutropenia 65.0% Grade 3/4 thrombocytopenia 40.0% Grade 3 anemia 35.0% Infections 50.0% (Grade 3/4 15.0%) Grade 3/4 pneumonia 5.0%

100 80

Response, n (%)

Mezi-dex + Taz (N=16, dose escalation)

Mezi-dex + Taz (N=16)

ORR 75.0%

1 (5.0)

8 (40.0)

60 40 20

6 (30.0)

sCR CR VGPR PR MR

5 (25.0)

0 • • • • • • •

Median DOR 6.5 months Median PFS 8.7 months Grade 3/4 neutropenia 80.0% Grade 3/4 thrombocytopenia 15.0% Grade 3/4 anemia 15.0% Infections 85.0% (Grade 3/4 25.0%) Grade 3/4 pneumonia 5.0%

Phase 3 studies of CELMoD triplets in RRMM:

combination with SOC mAbs or PIs

Study

Treatment

SUCCESSOR-1 (NCT05519085)1

~810 patients 1–3 prior lines

Stage 1: Mezi + Vd Determine recommended Mezi dose

Stage 2

SUCCESSOR-2 (NCT05552976)2

~525 patients ≥1 prior line

Stage 1: Mezi + Kd Determine recommended Mezi dose

Stage 2

Mezi + Vd Pom-Vd Mezi + Kd

Iberdomide: updates in RRMMKd

Primary endpoint: PFS

Primary completion: Jan 2027

Primary endpoint: PFS

Primary completion: Mar 2026

Feb 2026: US FDA accepts NDA for iberdomide in RRMM

EXCALIBER-RRMM (NCT04975997)3

• NDA for iberdomide plus Iber 1.0 mg + Dara-dex Dara-dex in RRMM • Also granted Breakthrough Therapy designation Stage 1 Stage 2 Iber 1.3 mg + Dara-dex Iber + Dara-dex • Based on planned analysis of MRD-neg rates in EXCALIBER-RRMM ~200 patients ~664 patients • PDUFA date: August Iber 17, 1.6 2026 mg + Dara-dex Dara-Vd 1–2 prior lines 1–2 prior lines BMS Press Release. See https://www.myeloma.org/news-events/multipleDara-Vd myeloma-news/fda-accepts-new-drug-application-iberdomide-rrmm

1. Richardson PG, et al. Clin Lymphoma Myeloma Leuk 2023;23(Supplement 1):S495–6, abstract MM-372. 2. Richardson PG, et al. J Clin Oncol 2023;41(16_suppl):abstract TPS8070. 3. Lonial S, et al. Future Oncol 2025;21(14):1761–9.

Primary endpoint: PFS Primary completion: Nov 2027

CELMoD triplets and quadruplets for RRMM: combination with mAbs or PIs

Iberdomide + Isa-dex or Dara-Kd

Iberdomide + Isa-dex for functional high-risk RRMM IBIS AMaRC 20-01 study1 29/50 functional high-risk RRMM patients relapsing ≤18 months after first-line therapy • Median age 65 years (range 43–82) • 24% R-ISS III MM25 (Viber-M): Iberdomide + venetoclax + dex • 1 / 2 / ALLG 3 HRCAs in 32% / 16% / 12% (N=50) in t(11;14) RRMM (N=44) 2025 • Median time to IBIS salvage 6.3 months

• Analysis in first 20 patients • Median age 65 yrs Efficacy, follow-up ≥12 months • 75% 1 prior line, 25% 2 prior lines; 75% R exposed (65% R20% CD38 mAb-refractory • ORRrefractory), 69%80%; 25% ≥VGPR • ORR • Of •29 patients, 15 progression-free and alive, 8 alive with PD, Grade ≥3 AEs 55%, including neutropenia 45%, thrombocytopenia 6 died 10%, infections 20% • 9-month 82% Sim S, PFS et al. 51% Blood/ OS 2025;146(Supplement 1):249.

Safety • Grade 3/4 neutropenia 52%, insomnia 8%, infusion-related reaction 2%, upper respiratory tract infection 4% • 2 grade 5 AEs: lung infection, sepsis

2025

Iberdomide + Dara-Kd in RRMM (Phase 2 ReKInDLE study)2 30 RRMM patients after 1–3 prior lines • Median age 63 years (range 44–77); 33% high-risk (IMWG 2025); 16% EMD • Median 1 prior line Iber maintenance post salvage ASCT • 202593% R-refractory; 27% CD38 mAb-exposed; 30% prior K • 15 patients with RRMM undergoing salvage ASCT • 47% prior ASCT • Median age 61 yrs; 66% high-risk cytogenetics

• Median 2 prior lines; 73% triple-class refractory Efficacy

• Post salvage ASCT: 7% CR/MRD-neg, 33% CR/MRD-pos, 13%

VGPR, 33% PR, 14% • ORR 92% (38% ≥CR,SD35% VGPR) • Median follow-up 15.4 months • 8/12 (67%) MRD-neg CR and PET-neg • Best response to iberdomide: 25% CR/MRD-neg, 25% VGPR, 25% • 27PR, patients 25% SDremain on treatment for up to 17 months • Median PFS from start of iberdomide 9.3 months • Grade 3 AEs: 1 neutropenia, 2 maculopapular rash, 3 infections Safety Tijaro Ovalle N, et al. Blood 2025;146(Supplement 1):4048.

• Grade ≥3 hematologic AEs: 50% neutropenia, 10% thrombocytopenia, 3% anemia • 6 (20%) SAEs, including 3 (10%) lung infections

1. Lim S-L, et al. Blood 2025;146(Supplement 1):5841. 2. Landgren O, et al. Blood 2025;146(Supplement 1):251.

Overcoming T-cell exhaustion

Improving CAR T-cell function with CELMoDs In vitro evaluation of impact of mezigdomide and iberdomide

2024

Preclinical benefit of CELMoD-dex on TCE outcome

2024

Immune system reactivation with mezigdomide regimens

• Evaluation of the persistence, proliferation, and activation of healthy donor-derived anti-BCMA CAR T cells in • Immunocompetent response CRBN+ to addition of model CELMoDs mouse • Analysis of immune profiles in 56 patients with RRMM receiving • Dex alone • 40-color shown to moderate T-cell proliferation in response to TCE spectral flow cytometry panels used to investigate dynamics of CAR T-cell phenotypes and proliferation mezigdomide-dexamethasone-based regimens and to give moderate of sustained production • 28 patients • Evaluation had T cellactivity redirecting therapy (TCRT) in last regimen effect ofcytokine CELMoDs on antigen-specific cytokine production and cytotoxic of CAR T cells

• Incremental TCE step-up dosing combined with iberdomide or • TCRT-treated patients had increases in immune cell subsets mezigdomide plus dex was feasible and tolerable related to persistent activation and lower Treg counts Cellular • Pretreatment witheffects iber-dex before TCE gave 100% response rate, • Mezigdomide treatment resulted in increased proliferation levels, highest overall survival, and more favorable T-cell profiling over enhanced CD4+/CD8+ T cell and NK/NKT cell activation, and a shift • Significant decrease in Ikaros and Aiolos in CAR T cells by 24 hoursto an effector memory phenotype, regardless of prior TCRT time Mezigdomide / iberdomide: potentialCAR strategy overcoming immune exhaustion • Persistence Meermeier EW, et al. Blood 1):356. and2024;144(supplement increased viability in IL-2-starved T cells for Kurtova A, et al. HemaSphere 2025;9(S1):PS1674.

CELMoDs and CAR Ts/BsAbs in RRMM

• Median viability 82% vs 45% (p<0.001) after CELMoD treatment Use of T cell ‘energizing’ agents in combination with/after T cell exhausting agents

Enhancing CAR T cells with iberdomide

Activation

Expansion of highly activated CAR T cell

• Analysis of functional effect of iberdomide-dex on CAR T cells in 7 patients population after mezigdomide exposure post–ide-cel and on immune activation tripled in 17 patients with RRMMdoubled previously treated with • Mezigdomide and iberdomide presence of activation•markers HLA-DR and CD69 of mezigdomide started 60–120 days Phase 1 study (NCT06048250) CAR T-cell therapy • CELMoDs during CAR T cell transduction doubled production of effector memory phenotype CAR (median T cells, age potentially post-ide-cel; 6 RRMM patients 81 years, median 5 • Increases in CD4+ T cells, central memory and effector memory T cells, and Tpromoting survival and function prior lines) with peripheral blood immunoprofiling data cell-expressing activation markers in iberdomide-treated samples obtained • Trend towards increased BCMA CAR T cells by C1D8 – % of BCMA for CAR T-cell therapy production CAR T cells associated with achieving CR • Manufactured CAR Tproduction cells had higher proliferation rates and decreased Cytokine and cytotoxicity • Early increases in HLA-DR+/CD38+ T cells/CAR T cells – proportions of exhausted cells associated with inflammation and disease activity in other settings • Ex vivo treatment with production iberdomide enhanced CAR TTNFα cell expansion and • Increased of IL-2, IL-17a, antigen-specific cytokines• by CD8+ and CD4+ CAR T cells against BCMAEarly increases in CD8+ effector memory cells, CTLA-4+ T cells functionality expressing MM cells • Early decreases in suppressive cells (e.g. CD8+ TEMRA) • In patients• with prior CAR T-cell therapy, iberdomide increased T/NK cell 46% increase in antigen-specific toxicity with CELMoDs • Shift from exhausted to activated T-cell phenotype proliferation and promoted shift to an activated effector memory phenotype Aleman A, et al. HemaSphere 2025;9(S1):PF685. Liu LW, et al. J Clin Oncol 2026;44(16_suppl):7540. Aleman A, et al. Blood 2024;144(supplement 1):3259.

ASH 2025: Novel combination studies in RRMM with CELMoDs and CAR Ts/BsAbs

2025

MagnetisMM-30: Elranatamab + iberdomide1

CA057-1040: Elranatamab + mezigdomide4

• 22 patients with RRMM following 2–4 prior lines • Median age 68 yrs, 41% high-risk cytogenetics, 18% EMD • Median 2.5 prior lines; 50% triple-class refractory • Median follow-up 6.1 months • Unconfirmed ORR 91%; 68% ≥VGPR, 46% ≥CR • Grade 3/4 AEs 68%, including neutropenia 59%, anemia 14%, thrombocytopenia 14% • CRS 68% (all Grade 1/2), 9% ICANS • Infections 41% (5% Grade 3/4)

• Phase 1b/2a study (NCT06988488) of elranatamab plus mezigdomide • Phase 1 dose-escalation and phase 2 doseexpansion study, 22 patients in 2 phase 2 arms • Patients with RRMM following 2–4 prior lines of therapy, including an IMiD, a PI, and a CD38 mAb • Primary endpoint: AEs and DLTs • Secondary endpoints: ORR, CR rate, VGPR rate, TTR, DOR, PFS and OS

CADMIUM (Alliance A062102): Ide-cel + iberdomide2 • Randomized Phase 2 study (NCT06179888) of iberdomide maintenance post ide-cel • Patients with RRMM, ≥4 prior lines of therapy • 6–12 patients in part 1 (safety run-in) • 60 patients in part 2, randomized to iberdomide or observation post ide-cel • Primary endpoint: PFS • Secondary endpoints: OS, best response, deepening of response, including MRD-neg CR conversion

CA088-1005: Arlo-cel + mezigdomide3 or iberdomide • Phase 1 study (NCT06121843) of arlo-cel plus novel therapies including mezigdomide and iberdomide • Dose-finding and doseexpansion study, with up to 30 patients in the latter part • Patients with RRMM following ≥3 (dose-finding, n=10 in dose-expansion) and 1–3 (n=20 in doseexpansion) prior lines of therapy • Primary endpoint: AEs and RP2D • Secondary endpoints: preliminary efficacy (ORR, CR rate, VGPR rate) and pharmacokinetics

MELT-MM: Elranatamab + mezigdomide5 • Phase 1/2 study (NCT06645678) of elranatamab plus mezigdomide • 75 patients receiving one of 3 dose levels of mezigdomide • Patients with RRMM ≥2 prior lines of therapy, including R and a PI • 11 patients enrolled to date: 8 at mezi 0.3 mg/kg, 3 at mezi 0.6 mg/kg • Median 4 prior lines • ORR (n=10) 90% (50% CR/sCR) • CRS 55% (all grade 1)

1. Suvannasankha A, et al. Blood 2025;146(Supplement 1):100. 2. Tuchman S, et al. Blood 2025;146(Supplement 1):2289 . 3. Bal S, et al. Blood 2025;146(Supplement 1):5807. 4. Bar N, et al. Blood 2025;146(Supplement 1):8246. 5. Byun JM, et al. Blood 2025;146(Supplement 1):5835.

CELMoD doublets/triplets for NDMM

Iberdomide-dex ± Dara Iber-Dara-dex in 77 elderly/frail

Iber-dex in 18 elderly/frail transplantineligible NDMM patients 1 • Iberdomide 1.6 mg (Days 1–21, 28-day cycles) + weekly dex 40 mg (20 mg if ≥ 75 years) • Median age 79 years, 12 (67%) were frail per modified IMWG criteria • High-risk cytogenetic abnormalities in 5 (28%) patients, EMD in 6 (33%) • ISS stage III in 9 (50%); R-ISS stage III in 5 (28%)

transplant-ineligible NDMM patients • Iberdomide 1.6/1.0 mg (Days 1–21, 28-day cycles) + Dara 1800 mg (standard schedule) + weekly dex 40 mg (20 mg if ≥ 75 years) • Median age 77 years, 51 (69%) were frail per modified IMWG criteria, with 30 being ultra-frail • ISS stage III in 29% • Analyses after first 6 cycles; median follow-up 11.1 months Outcomes Safety ORR 93% • 12-month PFS 80.8% 100 100 ORR 82% • 12-month OS 81.1% Safety 80 80 34% • Median treatment exposure: • Grade 3/4 AEs: CR/ CR/ 20 cycles neutropenia 68%, sCR 60 47% sCR 60 thrombocytopenia 7%, • Common AEs: neutropenia VGPR VGPR anemia 5%, febrile 40 78%, infections 72% 40 49% neutropenia 5% PR PR • Grade 3/4 neutropenia in 12 24% • 20 Infections 48% (17% 20 patients (67%) and Grade ≥3), including 39% 11% infections in 7 patients 10% (9%) respiratory 0 0 (39%) infections Evaluable ... n=73 • Anemia 33% • Rash 23% (3% Grade ≥3) 1. Puig N, et al. HemaSphere 2025;9(S1):PS1784. 2. González-Calle 2):S363–4, • Diarrhea • Thrombocytopenia 28%V, et al. Clin Lymphoma Myeloma Leuk 2025;25(Supplement 17% OA-63. (1% Grade Response, n (%)

Response, n (%)

Iberdomide: updates in NDMM

CELMoD triplets for NDMM

Iberdomide + Dara-dex 75 transplant-ineligible NDMM patients • Iberdomide 1.0, 1.3, 1.6 mg • 25 patients at each dose level • NDMM with no planned or recommended due IDEAL: Efficacy ASCT and safety of to age or comorbidities iberdomide + Dara-Vd in NDMM • Biomarker defined populations: IHC, WGS, RNAseq analyses

• >90% sFLC reductions across all dose levels • ORR 100% • 6 patients proceeded to ASCT • At 3 months post-ASCT, ORR 100% (3 CRs, 2 VGPRs, 1 PR) • 1 patient with documented sCR and MRD-neg at data cutoff • Median PFS not reached

MRD-neg in ≥VGPR patients

Patients, %

Activity

• 44 transplant-eligible/-ineligible NDMM pts receiving Iber-Dara-Vd at RP2D for 12 cycles followed by Iber maintenance for 24 cycles • Median age 65 years; 52.3% high-risk disease • ORR 100% Median follow-up 22.3 • ≥CR 36.4% after induction, 52.3% overall months2 • MRD-negative (10-5) response 29.5% after induction, 47.7% overall • Median follow-up 18.3 months • 44% MRD-neg CR at • 12-month PFS 91%, 18-month PFS 88% • 12-month 80 OS 97%, 18-month OS 94% any time • Common toxicities: neutropenia, rash, PN, diarrhea, infections • Of these patients, 59.1 58.8 Kapoor P, et40 al. J Clin Oncol 2026;44(16_suppl):7514.

43.8

1.0 mg (n=17)

1.3 mg (n=22)

1.6 mg (n=16)

1. Amatangelo M, et al. Blood 2024;144(Supplement 1):1973. 2. Jeyaraju D, et al. Blood 2025;146(Supplement 1):2255.

64% were MRD-neg at 12 months • 57% MRD-neg VGPR at any time • Of these patients, 72% were MRD-neg at

2025

CELMoD triplets for NDMM

KID: Iberdomide as pre-ASCT induction 31 NDMM patients2

Patients and efficacy • Median age 66 years, 42% highrisk cytogenetics • Post-induction ORR 96% • 23 patients proceeded to ASCT • At 3 months post-ASCT, ORR 100% • 26% sCR/CR; all MRD-neg • Median follow-up 12.4 months; median PFS not reached

• Iberdomide 1.0, 1.3, 1.6 mg investigated in phase 1 doseescalation1 – 1.6 mg select for phase 2 • 10 patients on study • Median age 66 years, 40% male • 30% ISS stage II • 40% high-risk cytogenetics (2 t(4;14), 2 1q21 duplication, 1 t(14;16); 1 del17p, 1 TP53mut

Safety (n=31)

Best responses to KID Post-induction, n=24 Post-ASCT, n=19

53 20

4 26

PR VGP R CR

100

Patients (%)

1. Biran N, et al. Blood 2023;142(Supplement 1):2022. 2. Biran N, et al. J Clin Oncol 2025;43(16_suppl):7553.

• Neutropenia 39%, thrombocytopenia 23%, anemia 19% • Pruritus 23%, rash 23% • Grade 3 AEs 26%: neutropenia 26%, thrombocytopenia 6%, rash 6% • No treatment-related deaths

Iberdomide in NDMM

EMN26: Iberdomide as post-ASCT maintenance

2025

120 • ≥PR after PI-IMiD-containing induction, 1/2 ASCT, ± consolidation age 59 years, 54% male NDMM •• Median 31% / 57% / 12% R-ISS stage I / II / III patient •• 21% high-risk cytogenetics 40 patients per dose cohort (0.75, 1.0, 1.3 mg) s1 0.75 mg, n=40 100% 80% 60% 40% 20% 0%

20% 15% 50% 15% Screening

57.5% 7.5% 32.5% 2.5% Through Cycle 6

Iberdomide maintenance sCR after upfront ASCT in MM sCR 1.0 mg, n=40 1.3 mg, n=40 CR • 38 patients with ≥VGPR after triplet/quadruplet induction CR and ASCT 100% • Median VGPR VGPR 100% age 61 years; 15%34% high-risk disease 20% • At day 35% 58% ≥CR,PR 7.5% 80–100 post-ASCT: 100% ≥VGPR, 87% MRD-neg 80% 80% 45% PR 10% • Median 18 cycles of iberdomide received to date 2.5% 60% 60% • 19 patients deepened response to sCR 10% 65% 40% 40% 62.5% • 3 patients converted from MRD-pos to MRD-neg 57.5% 42.5% • MRD-neg 20%rate 85% post cycle 12, 100% post cycle 24 20% • Grade 3/4 neutropenia 12.5% in 19/5 patients 7.5% 5% 2.5% 0% 0% • 11/6 patients Screening discontinued within/after 1 year, including 5/4 due to Through Screening Through neutropenia Cycle 6 Cycle 6

0.75 mg cohort2 •59% improved response depth through cycle 6 •Best response ≥CR 78% •50% MRD-pos to MRD-neg •2-year PFS 92% •Grade ≥3 neutropenia 48%, infections 8%

Wildes T, et al. J Clin Oncol 2026;44(16_suppl):7528. 1.0 mg cohort2

•37% improved response depth through cycle 6 •Best response ≥CR 60% •42% MRD-pos to MRD-neg •2-year PFS 82% •Grade ≥3 neutropenia 58%, infections 18%

1. Gay F, et al. Hemasphere 2024;8(S1):1703–4. 2. van de Donk NWCJ, et al. Blood 2025;146(Supplement 1):101.

sCR CR VGPR PR

1.3 mg cohort2 •38% improved response depth through cycle 6 •Best response ≥CR 70% •53% MRD-pos to MRD-neg •2-year PFS 84% •Grade ≥3 neutropenia 60%, infections 18%

Iberdomide in NDMM: a replacement for lenalidomide? Phase 3 studies EXCALIBER-Maintenance (NCT05827016)

GEM21menos65 (NCT05558319)

MIDAS / IFM 2020-02 (NCT04934475)

Post-ASCT maintenance 3–6 PI+IMiD-based induction cycles ≥PR post-ASCT

Transplant-eligible patients Age ≤65 years ECOG PS ≤2

~120 patients 1:1:1:1 Iber (3 dose levels) or R

~480 patients 1:1:1

791 patients 6 x Isa-KRd

Optimal Iber dose selected ~1096 patients 1:1

Potential benefits of iberdomide vs lenalidomide maintenance MRD-pos (1:1) Isa-RVd RVd Iber-Isa-Vd

GMMG-HD9/DSMM XVIII (NCT06216158) Post-ASCT maintenance Prior treatment in GMMG-HD8/DSMM XIX, ≥PR postASCT ~411 patients 1:1 randomization

MRD-neg (1:1)

ASCT ASCT + Doubl ASCT + 6x • LowASCT rates ofASCT infection in studies toe 2 x Isa2 x IsaIsaKRd KRd dateIsa-RVd RVd ext Iber-Isa-Vd KRd ASCT Rd / Iber-Isa Iber-Isa R 3 yr R 3 yr Iber R • Possibility Isa-R Iber-Isa 3 yr 3 yr ofERI*reduced secondary cancer risk (preclinical dataPrimary endpoint: MRD-neg rate Primary endpoint: PFS Primary endpoint: MRD-neg rate suggestive, confirmatory clinical Primary completion: September Estimated primary completion: Estimated primary completion: 2024 March 2029 April 2027 observation ongoing) Study completion: September 2028 • Sperling *Early rescueAS, intervention: et al.Isa-Iber-d Blood ClinicalTrials.gov, February 23, 2026. Liu Y, et al. Expert Rev Hematol 2024;17(8):445–65. 2022;140(16):1753–63. Perrot A, et al. Blood 2025;146(1):52–61. Perrot A, et al. N Engl J Med 2025;393(5):425–37.

Iber

Iber + Isa

Primary endpoint: MRD-neg at 2 yr Estimated primary completion: December 2028

CELMoD-based quadruplets and maintenance in NDMM

DETERMINATION 2 study design Cohort 1

Target accrual: 720 patients

Maintenance part 2 Maintenance part 1

Standard-risk MRD-neg

Isa-Iber x 36 cycles

Induction Determine cytogenetic risk status, clonality

IsatuximabIberdomide-Vd

x 8 cycles (stem cell collection after 4–6 cycles)

MR D

• Cytogenetic risk status based on FISH/NGS • Clonality based on Adaptive Biotechnologies clonoSEQ® assay

Off study if FISH/NGS or clonotype failure Mo CC, Richardson PG, Jacobus SJ, Wei LJ, Liu Y, et al. DETERMINATION 2 Investigator Meeting; ASH; 2024.

Cohort 2

High-risk and/or MRD-pos/ind

Ineligible patients continue Isa-Iber-V to PD

MR D

MRD-neg

Continue Iber only to PD

MRD-pos/ indeterminate

Continue Isa-Iber to PD

Consolidation

Maintenance

HDM-ASCT

Isa-Iber to PD

Linvoseltamab x 8 cycles

Isa-Iber to PD

Stratification factors: • Cytogenetic risk – high-risk vs standard-risk • MRD status – neg vs pos/indeterminate

Conclusions and next steps/future directions in the evolution of treatment with CELMoDs for RRMM/NDMM CELMoDs: targeted protein degradation, with improved activity vs IMiDs • More potent binding of cereblon and degradation of Ikaros / Aiolos • Greater anti-MM activity, including in IMiD-resistant models • Enhanced immunomodulatory effects, including immune-stimulating properties Integration of CELMoDs into RRMM treatment • Oral agents with ease of real-world application • Integration with standard-of-care partner drugs/drug classes in early-relapse RRMM • Positive findings from SUCCESSOR-2 and EXCALIBER-RRMM Phase 3 trials potentially leading to approvals • SUCCESSOR-1 Phase 3 trial and Phase 2 studies ongoing in RRMM • Encouraging activity in heavily pretreated RRMM – addressing an urgent unmet medical need • Novel combination strategies under investigation in later-relapse RRMM, e.g. with selinexor, tazemetostat, based on synergistic mechanisms of action Integration of CELMoDs with CAR T-cell therapies and bispecific antibodies in RRMM • Immune-‘energizing’/‘reactivating’ agents, potentially enhancing activity of CAR Ts and bispecifics • Utility in combination and in sequence, e.g. as maintenance post CAR T-cell therapy, under ongoing investigation Integration of CELMoDs into NDMM treatment • Ongoing Phase 3 trials of iberdomide in NDMM • Emerging option as maintenance therapy in NDMM; combination regimens also under investigation • Potential replacement for lenalidomide in this setting (with enhanced efficacy and prospect of reduced second cancer risk)

Ongoing MM collaborative model for rapid translation of novel therapeutics from bench to bedside 2003–2026

Thank you!

Pharmaceuticals Academia

Progress and Hope NIH NCI

Philanthropy Advocacy

Courtesy of Phil McCarthy MD

MMRF/C; IMF IMWG; LLS; IMS HealthTree

FDA EMA

20 novel drugs/therapeutic modalities and >36 new FDA-approved drug combos/indications in last 23 years

SPECIAL PRESENTATION: REAL WORLD DATA Session Chairs: Sagar Lonial, MD, FACP S. Vincent Rajkumar, MD

USING REAL WORLD DATA TO IDENTIFY AND ADDRESS PRACTICE GAPS Prateesh Varughese, PharmD Integra Connect

From Observation to Improvement: Using Real-World Data to Improve Quality & Close Care Gaps in Multiple Myeloma Prateesh Varughese PharmD

While many real world assets focused on creating data sets for research purposes, IntegraConnect focused on creating real world data driven quality initiative programs that enabled outcomes improvement – closing gaps in care! Integra Connect Confidential and Proprietary

266

Therapeutic Innovation Is Accelerating and Results are Improving We are living in an era of extraordinary therapeutic innovation — novel therapies are giving patients more options and longer survival than ever before

2003– 2006

2012– 2015

IMiDs & Proteasome Inhibitors

Next-Gen Small Molecules

2015– 2020

2021– 2022

Monoclonal Antibodies

CAR-T Cell Therapy

2022– 2025

2025– 2026

Bispecific Antibodies

CELMoDs & ADCs

Treatment: Survival: 1980–1990

~2 yr

Conventional chemo

2001–2010

~5 yr

IMiDs + PIs introduced

2011–2020

~8.6 yr mAbs + multi-agent combos

2020s+

12+ yr 2+ novel agents in 1L

Key Takeaway: With 20+ FDA-approved agents across 7 mechanistic classes, median overall survival has improved from ~2 years in the 1980s to over 12 years with current multi-agent regimens. Sources: Puertas et al., Cancers 2023; HemOnc.org Global Approvals (May 2026); FDA.gov approved drugs database. Survival data from a 1,001-patient cohort study (1980–2020).

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267

Failure to Rapidly Implement Best Practices Undermines Patient Impact ~86% of myeloma patients receive some or all care in community settings, making community adoption the critical bridge between innovation and patient outcomes

Where Myeloma Care Is Delivered

43.6% Community Only

42.4% Both Settings

14.0% Academic Only

Community Adoption Lags — And Patients Pay the Price

The Patient Impact: Community sites adopt proven therapies more slowly than academic centers. This lag directly translates to real patients waiting years longer to receive guideline-recommended regimens already shown to improve survival.

Ex. 1: Quadruplet Use in Frontline MM Despite guideline support, quadruplet use in community settings rose from<1% to 9.4% by 2022 — meaning >90% of community patients were not receiving a regimen shown to improve outcomes.

Ex. 2: Daratumumab-Based Frontline Regimens Daratumumab-based frontline regimens in community settings grew from2% in 2019 to 29% by 2022 — but 71% of community patients still weren’t receiving a therapy with strong phase 3 survival evidence. Site-of-care data: claims-based study of 3,778 MM patients. Community network adoption data: large U.S. community oncology network (2019–2022).

Integra Connect Confidential and

Solution: Closing this community adoption gap requires a fit-forpurpose real-world data platform to identify where patients aren’t receiving best practices — and drive measurable improvement in outcomes

To Shine A Light On The Gap In Treatment, Trustworthy Real-World Data is Needed Example: Refreshed data in 2024 highlights that even in 2024-2026 (4 years later), we are seeing variability in care <50% for QUAD use in the real world

Across Practices (Network-Wide)

43%

Overall (3,862 pts)

~15%

Lowest Practice

Within a Single Practice

~65%

48%

Highest Practice

Overall (365 pts)

~31%

Lowest Care-Site

~83%

Highest Care-Site

Bottom Line: Innovation is proven. The real challenge is ensuring it reaches every patient, every time, across all sites of care. The focus now must shift from identifying gaps to partnering to close them and improve outcomes.

Real-world data: Large U.S. community oncology network, first-line multiple myeloma patients (Oct 2024 – Mar 2026). Network-wide: 3,862 patients across 31 practices. Single-practice drill-down: 365 patients across 16 care-sites.

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Building a Fit-for-Purpose, Actionable, MM Real-World Dataset

Core dataset requirements and data domains for real-world evidence in multiple myeloma — aligned with the FDA Oncology RWE Program’s emphasis on fit-for-purpose methodology

Settings of Greatest Need Community, IDN, and AMC settings Agnostic to EMRs & Affiliations

Use the data and highlighted gaps to enable quality improvements

National Distribution

Quality Improvement Programs

Nationally distributed with broad geographic representation

Quality Measurement Identify care gaps and drive measurable improvement.

Multi-Level Analysis Data Domains Captured

Support of aggregate population and individual patient levels

Integra Connect Confidential and Proprietary

Demographics

Clinical + Staging

Genetics + MRD

Labs + Renal Function

Treatment + LOT

CAR-T, Bone Marrow Biopsy

Dosing and Events

Transplant

Drug Interruption

AE + Response

271

FIT-FOR-PURPOSE RWD

PATIENT JOURNEY IN MULTIPLE MYELOMA

HIGH-RISK MARKERS

del(17p13) del(13)

POSITIVE

del(1p32)

NEGATIVE

dup(1q21)

NEGATIVE

CRITERIA MET

✓

Del(17p) Positive

✓

Autologous SCT

Partial Resp.

57F

PAYER

WHITE

Medicare/Medicaid

4/12/2018

LOT 2

LOT 3

LOT 4

LOT 5

Bortezomib + Lenalidomide

Lenalidomide (Maintenance)

Bortezomib + Daratumumab

Carfilzomib + Pomalidomide

Bortezomib + Cyclophosphamide

Belantamab Mafodotin

5/2/2018 → 7/19/2018

12/10/18 → 8/22/2019

10/29/19 → 5/13/2020

6/3/2020 → 10/17/21

10/27/21 → 2/2/2022

3/2/2022 → —

78d

255d

197d

501d

98d

M-PR OTE IN

M- PROT EIN

M-P ROTE IN

M-PR OTE IN

M- PROT EIN

2,398 → 44 mg/L

44 → 39 mg/L

948 → 29 mg/L

29 → 561 mg/L

1,040 → 1,150 mg/L

→ Stable

↓97%

↑19×

1,885 → — mg/L

↑11%

Excellent Response

Disease Controlled

Excellent Response

Disease Progression

Refractory

Last Therapy

RESPONSE

Partial Response

Tx Duration

AGE

MAINT

↓98%

Best Response

713_302603612

LOT 1

Total LOTs

5 + Maint

BURDEN

Stable

BURDEN

Unknown

BURDEN

Progression

BURDEN

Refractory

BURDEN

Pending

~4 Years Last Abstract

4/22/2022 TREATMENT TIMELINE

LOT 1

Bort+Len

LOT 2

78d

Bort+Dara

LOT 4

197d

Bort+Cyclo

98d

SCT 9/10/18

2019 M-PROTEIN TREND (mg/L) 2.4k

2020 SCT →

Maintenance

2021

255d

Carf+Pom

LOT 5

501d

Belantamab1.9k — 1k

948 44

2022 LOT 3

1.2k

How Real-World Data Becomes Credible

A dataset built for quality improvement must be designed with clinician trust from the outset

Smoldering MM Example Clinicians at the Table from the Design Phase

Auditable by Researchers and Originating Clinicians

Enriched, Validated, Research-Ready

Trust is not an abstract value — it is built through clinician involvement, transparent methodology, and data that earns confidence through use.

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Where RWD-Driven Quality Initiatives Can Close Care Gaps

Improved Testing

Improve Patient Identification

Optimizing Dosing

Supportive Care

Evaluating Outcomes

Increase testing and effectiveness of biomarker testing

Identify eligible patients for treatment

Determine the minimum effective dose to manage toxicity and ensure effectiveness

Determine optimal supportive care therapy to reduce toxicity and improve duration

Assess outcomes on best practices or treatment approaches (TTD, TTNT, OS)

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274

Quality Initiatives Require Tools for Identifying Variability in Best Practices Four requirements for turning real-world data into actionable quality improvement

Quality Measures Dashboard

1 Clinicians Define What “Good” Looks Like Myeloma specialists — not payers or administrators — set the clinical benchmarks that define guideline-concordant care and meaningful quality thresholds.

2 Honest Baseline of Guideline Concordance Before improvement can begin, practices need a transparent view of where they stand today — surfacing unwarranted variability across providers and sites.

3 Collaborative Review Mechanism

Identifying Practice Variability

Quality dashboards become actionable when clinicians review them together — peer-to-peer discussion turns data into shared accountability and consensus-driven change.

4 Longitudinal Measurement Over Time Refreshable datasets allow practices to track whether interventions are working — measuring change over quarters and years, not just at a single point in time.

When clinicians define the benchmarks and dashboards surface the variability, the foundation is set for measurable outcomes improvement.

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Go From Measuring Behavior to Following Patients Forward and Enable Outcomes Real-time practice intelligence and longitudinal outcomes tracking powered by a research-ready dataset

PRACTICE INTELLIGENCE • Instant Patient Identification • Guideline Concordance • Referral Patterns • Treatment Selection • Practice Variation Monitoring

OUTCOMES INTELLIGENCE

Longitudinal Follow-up

• Time to Next Treatment (TTNT) • Treatment Duration • Real-World PFS • Real-World Overall Survival • Quality Improvement Outcomes

A clinician-curated research-ready dataset unlocks both the ability to track behavior in real time and the power to follow patients forward — evaluating whether guideline-concordant care delivers the outcomes clinical trials promise.

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Outcomes Realized — From Variability to Guideline-Concordant Care Quality initiatives are improving physician behavior and enabling outcomes found in clinical trials

Use of Quad Therapy and CD38 Therapy in First Line Multiple Myeloma

Real World Example from Slide 3

CD38 THERAPY

46%

83%

QUAD THERAPY

Practice 2

QUAD THERAPY

Practice 3

Practices Participating in QI

Practices Not Participating in QI

Practice 1

QUAD THERAPY

CD38 THERAPY

56% 93%

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277

56%

CD38 THERAPY

97%

from 46% baseline

from 77% baseline

↑ +10 pp

↑ +20 pp

QUAD THERAPY

CD38 THERAPY

56%

87%

from 47% baseline

from 77% baseline

↑ +9 pp

↑ +10 pp

QUAD THERAPY

CD38 THERAPY

55%

93%

from 35% baseline

from 68% baseline

↑ +20 pp

↑ +25 pp

Example: PrecisionQ Continuous Quality Improvement Process Real-world data should drive a continuous improvement loop — not just describe what happened, but shape what happens next

Beyond Retrospective Analysis Collect

Insights drive Engagement

Data fuels Insights

10  20% Oncology New Starts from EMR

Practice leaders validate gaps and align on solutions at the Council

EMR access reveals care gaps invisible without curated clinical data

Real-world evidence can and should contribute to broader scientific understanding. But if we stop at observation, we leave too much potential on the table.

Prove

Analyz e

140+ publication s

Highlighting The Gap

Uncover Care gap(s) & QUANT analytics

Is every patient who could benefit from a treatment receiving it? Is it timely, appropriate, and operationally feasible in the setting

Change generates Evidence

Outcomes are measured, published, and shared as proof

Evidence deepens Data

Enabl e

Solutions & RWD driven Gap Closure Programs

Discuss & Share

Published results feed more practices and richer data back in

where they are treated?

The Greater Opportunity

Best Practices & Actions shared with IOC Practice Leaders

Real-world data should move from describing variation to reducing it, from publishing evidence to improving care, and from measuring what happened to shaping what happens next.

Engagement activates Change

Council consensus drives QI programs

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Applying the QI Framework to Bispecifics and CAR-T

The same data-driven approach that moved the needle on Quad and CD38 can address the next adoption gap BsAb and CAR-T New Starts (2022–2026)

Growing Starts, But a Utilization Ceiling BsAb and CAR-T new starts across participating community practices have grown steadily since 2022. Yet real-world utilization among eligible patients is topping out at roughly 25% — far below what clinical trial evidence would support.

Community-Specific Barriers CAR-T remains largely hospital-based, and bispecific antibodies carry complex monitoring, REMS requirements, and logistical challenges that create significant friction for community oncology practices — limiting access for the patients who need

Utilization Topping Out at ~25% Among Eligible Patients

these therapies most.

The QI Opportunity The same quality improvement framework that drove Quad and CD38 adoption — clinician-defined benchmarks, transparent dashboards, and collaborative review — can be applied to bispecific and CAR-T utilization to close the gap between evidence and real-world practice. Bispecifics and CAR-T represent the next chapter for quality improvement — the same data-driven approach that moved the needle on Quad and CD38 can address the adoption gap in community oncology.

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PANEL DISCUSSION Panelists:

S. Vincent Rajkumar, MD Alissa Visram, MD

WORKING COMMITTEE MEETINGS Immune Therapy– Stay in this room Smoldering Multiple Myeloma – Room 15, Third Floor Quality of Life – Room 1, Second Floor Combined Mass Spectrometry and MRD – Room 6+7+8, Second Floor