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VIRTUAL MYELOMA COMMUNITY WORKSHOP: “WHAT’S NEXT?” – MANAGING MYELOMA AT RELAPSE AUGUST 24, 2026

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Thank you to our Sponsors!

Shared Experiences Become Shared Strength! Support Groups empower patients & care partners with information, insight & hope The IMF provides educational support to a network of over 155 myeloma specific groups

155+ Support Groups Across the US and beyond

We are happy to help connect you with an existing support group or help you form a new one! SGTeam@myeloma.org

SHARED EXPERIENCE GROUPS Shared experience groups are designed as a supplemental support for specific populations of patients, in addition to their local Support Groups MM Families For patients & care partners with young children Living Solo & Strong For patients without a care partner

Las Voces de Mieloma For Spanish Speaking patients & care partners Care Partners Only For myeloma care partners only

Veterans For those who served our country

Smolder Bolder For smoldering myeloma patients & care partners

MM in the Middle For those diagnosed before age 50

Living with High-Risk Multiple Myeloma For high-risk myeloma patients & care partners

Your Panel for Today’s Webinar

Joseph Mikhael, MD, Med, FRCPC, FACP, FASCO IMF Medical Advisor

Luciano Costa, MD University of Alabama Medicine, The Kirklin Clinic

Patricia Mangan, Shonali Midha, RN, MSN, APRNMD BC Dana-Farber Cancer University of Institute Pennsylvania, Abramson Cancer Center 9

Agenda Welcome and Introduction – Dr. Joe (10 mins) 1. What is Relapse and How do we Approach it? – Dr. Joe (15 mins) 2. CAR T cell Therapy - What, When and How? – Dr. Luciano Costa (25 mins) 3. Bispecific Antibodies and Antibody Drug Conjugates - What, When and How? – Dr. Shonali Midha (25 mins) Q and A - 15 mins BREAK 10 mins 4. Supportive Care in Relapsed Myeloma - Patricia Mangan (25 mins) 5. The Future of Relapsed Myeloma Therapy – Dr. Joe (10 mins) Q and A - 15 mins © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

MYELOMA 202: WHAT IS RELAPSE AND HOW DO WE APPROACH IT? Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO IMF Medical Advisor Professor, Translational Genomics Research Institute

 Discuss WHY relapses occur  Review important principles of selecting treatment for

relapsed myeloma

 Empower patents to engage in the decision-making process

OBJECTIVES

 Encourage patients to know there are MANY options for

relapsed myeloma

Myeloma almost always Relapses ASYMPTOMATIC

M-Protein g/L

SYMPTOMATIC

ACTIVE MYELOMA

REFRACTORY RELAPSE

RELAPSE

Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc

MGUS or SMOLDERING MYELOMA

PLATEAU REMISSION Therapy

MGUS = monoclonal gammopathy of undetermined significance Adapted from Dr. Brian Durie and Keats JJ, et al. Blood. 2012;120:1067-1076.

Time

Why does Myeloma Relapse? We speculate many reasons for this...

1. It is never fully cleared Minimal Residual Disease (MRD) negativity is not truly NEGATIVE

2. The immune system cannot contain or prevent the disease Remember myeloma is a disease of the plasma cell

Many Treatment Options at Relapse Myeloma Therapy

Common Combinations or Therapy Names

Belantamab mafodotina

BVd, BPd, BKRd

Bortezomib (SQ admin)

VRd, Vd, VCd

Carfilzomib

KRd, Kd, Dara-Kd, Isa-Kd

Car T-cell

Cilta-Cel®, Ide-Cel®

Daratumumab

Dara-Rd, Dara-Vd, Dara-Pd, Dara-VMp, Dara-Kd, Dara-Tecvayli®

Elotuzumab

ERd, EPda

Iberdomide

ZDd (Zenbexus®-Dara-Dex)

Isatuximab

Isa-Pda, Isa-Kd

Click to edit Master text styles Ixazomib

IRd

• Second level Lenalidomide

VRd, Rd, KRd, Dara-Rd, ERd, IRd

– Third level

1 5

Pomalidomidea  Fourth level Fifth level Selinexor

Pda, Dara-Pd, EPda, PCdc

T cell Engager (Bispecific)b

Elrexfio®, Lynozyfic™, Talvey®, Tecvayli®

Xd, XVd, XKdc, Dara-Xdc

New agents or regimens in clinical trials may be an option...

SUCCESSOR-2

CELMoD Mechanism of Action •

Mezi and iberdomide (Iber) are CELMoDs that bind cereblon uniquely and more effectively, delivering superior MM cell killing and immune stimulation, compared to IMiDs 1

IMiD

Faster and more complete target protein degradation

Ub Ub Ub Ub

Direct MM cell cytotoxicity and activity in IMiD resistance

Aiolos/ Ikaros

Cereblon (~20% in active state)

T/NK cell activation and mitigation of immune exhaustion

CELMoD Aiolos/ Ikaros

Cereblon (50%-100% in active state)

Single enantiomer/substrate preference potentially minimizing nonhematological effects

• Mezi is being investigated in combination with PIs in two phase 3 trials: SUCCESSOR-1 and SUCCESSOR-2 4 –

Mezi and PIs demonstrated preclinical synergistic antitumor activity superior to POM + PI,4 with phase 1/2 data of Mezi-d, MeziVd, and MeziKd yielding promising efficacy and a manageable safety profile 5,6

DARA, daratumumab; FDA, Food and Drug Administration; Mezi-d, mezigdomide and dexamethasone; MeziVd, mezigdomide, bortezomib, and dexamethasone; NK, natural killer; PDUFA, Prescription Drug User Fee Act; PI, proteasome inhibitor; POM, pomalidomide; Ub, ubiquitin.1. Watson ER, et al. Science 2022;378:549-553. 2. Lonial S, et al. Future Oncol 2025;24:1761-1769. 3. NCT05827016. 4. Dimopoulos M, et al. Clin Lymphoma Myeloma Leuk 2024;2a:S258. 5. Richardson PG, et al. N Engl J Med 2023;389:1009-1022. 6. Sandhu I, et al. Blood 2024;144:1025.

Richardson PG, et al. ASCO 2026, Presentation LBA7506

STUDY DESIGN

EXCALIBER-RRMM: IberDd vs DVd in RRMM

2-stage, randomized phase 3 trial1,2

•

Stage 1 (Dose Optimization, n=279) N=939 Inclusion criteria:     

Age ≥18 years ECOG PS 0–2 1 or 2 prior lines of therapy ≥PR achieved with ≥1 prior therapy PD during or after last regimen

Arm A1 Iberdomide 1 mg PO D1-21 + Dara + Dex

Arm A2 Iberdomide 1.3 mg PO D1-21 + Dara + Dex Arm A3 Iberdomide 1.6 mg PO D1-21 + Dara + Dex Control DVd

Stage 2 (Efficacy/Safety, n=660) Selected stage 2 dose

Iberdomide at selected dose from stage 1 + Dara + Dex DVd IA1: dose selection IA2: 30% PFS events IA3: 75% PFS events

Primary endpoints: MRD-negative CR rate at any time, PFS 

Combining MRD testing with IMWG response criteria provides a stringent measure of biochemical and clinical response depth

CR, complete response; Dara, daratumumab; Dex, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; ECOG, Eastern Cooperative Oncology Group; IA, interim analysis; IberDd, iberdomide, daratumumab, dexamethasone; MRD, minimal residual disease; PD, progressive disease; PO, orally; PR, partial response; PS, performance status; 1. EXCALIBER RRMM. ClinicalTrials.gov identifier: NCT04975997. Updated April 03, 2026. Accessed August 14, 2026. https://clinicaltrials.gov/study/NCT04975997. 3. Lonial S, et al. Future Oncol. 2025;21:1761-1769.

STUDY DESIGN

EXCALIBER-RRMM: Efficacy and Safety Analysis Study Populations Stage 1 (n=279) + Stage 2 (n=660)

Total patients randomized N=939

Iberdomide 1 mg PO D1-21 + Dara + Dex

DVd

Primary efficacy population N=First 420 patients randomized

n=207 (Stage 1 Arm A1 + Stage 2)

n=213 (Stage 1 Control + Stage 2)

n=204 (Stage 1 Arm A1 + Stage 2)

n=204 (Stage 1 Control + Stage 2)

Safety population N=408, patients who received ≥1 dose of the study drug

Zenbexus. Package insert. Bristol-Myers Squibb Company; 2026.

PRIMARY ENDPOINT

EXCALIBER-RRMM: MRD-Negative Complete Response Rate P<0.000 1 50

41%

MRD-negative CR (±95% CI)

21%

IberDd (N=207)

DVd (N=213)

Median follow-up: 16 mo

CELMoD; cereblon E3 ligase modulator; CI, confidence interval; CR, complete response; DVd, daratumumab + bortezomib + dexamethasone; FDA, US Food and Drug Administration; IberDd, iberdomide + daratumumab + dexamethasone; MRD, measurable residual disease. 1. Zenbexus. Package insert. Bristol-Myers Squibb Company; 2026. 2. Eaton, ES. “BMS wins first FDA approval for oral CELMoD in MM.” FirstWord Pharma. Published August 13, 2026. Accessed August 14, 2026. https://firstwordpharma.com/story/7846611.

Key Principles of Treatment Selection 1.

Change current mechanism of action

Don’t save the best for last!

Increasing use of CAR-T Cell Therapy, Bispecific Antibodies or Antibody-Drug Conjugates earlier in relapse

Consider Patient – Disease and Treatment Factors

Depth of Response Matters

Combinations are very common to leverage multiple mechanisms

Sequencing is important but is not fully Known

Always include a Quality of Life Discussion

Use the Shared Decision Making Model

1. Change current mechanism of action

Key – when myeloma relapses, it “overcomes” the current therapy being used, so it is necessary to change the approach to the disease with a new a mechanism of action

Drug Class Overview

Class

Drug Name

Abbreviation

IMiD immunomodulatory drug

Thalomid (thalidomide)

T or Thal

Revlimid (lenalidomide)

R, Rev, Len

Pomalyst (pomalidomide)

P or Pom

Velcade (bortezomib)

V or Vel or B

SC/SQ or IV

Kyprolis (carfilzomib)

C or K or Car

Ninlaro (ixazomib)

N or I

Oral

Cytoxan (cyclophosphamide)

C, CTX

Alkeran or Evomela (melphalan)

M or Mel

Oral IV

Decadron (dexamethasone)

Dex or D or d

Prednisone

P or Pred

Monoclonal Antibodies

Darzalex (daratumumab) Sarclisa (isatuximab) Empliciti (elotuzumab)

Dara Isa Elo

IV or SQ IV/SQ/OBI IV

XPO1 Inhibitors

Xpovio (selinexor)

X or Sel

Oral

Proteasome inhibitor

Chemotherapy Steroids

Administration Oral (PO)

Oral IV

Drug Class Overview Class

Drug Name

Abbreviation

Administration

Peptide Drug Conjugate*

Pepaxto (Melphalan Flufenamide)

Melflufen

BCMA Targeted Antibody Drug Conjugate (ADC)*

Blenrep (belantamab mafodotinblmf)

Bela, Belamaf, or B

Abecma (idecabtagene vicleucel)

Ide-cel

Carvykti (ciltacabtagene vicleucel)

Cilta-cel

Bispecific Antibodies

Tecvayli (teclistimab) Talvey (Talquetamab) Elrexfio (Elranatamab) Lynozyfic (Linvoseltamab)

Tec Talq Elra Linvo

SC/IV

CELMoDs (Cereblon E3 Ligase Modulators)

Zenbexus (Iberdomide)

Z or Iber

Oral

CAR T Cell therapy

Pipeline

Cevostamab, Mezigdomide, Ententamig, Anitocel, Arlo-cel, AZD0120 …………………………… MORE TO COME!

* These agents are currently off the market but available through special programs © 2026, Myeloma Foundation.Under All rights reserved. IMF= Confidential SCInternational or SQ = Subcutaneous, the skin; IV Intravenous

2. Don’t Save the Best for Last! Typically the most durable remissions occur earlier in the disease course So, we want to use the best possible therapies before the disease becomes more resistant

Therapies tend to have a greater effect earlier in the disease course...

3. Increasing use of CAR-T Cell Therapy, Bispecific Antibodies or Antibody-Drug Conjugates earlier in relapse As will be discussed today, options for relapsed myeloma have grown and these three approaches have the best outcomes

This has to be balanced with patient characteristics and preferences – so other options (like doublets) can be considered © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

4. Consider Patient, Disease and Treatment Factors • • • • • •

Renal insufficiency Hepatic impairment Comorbidities Preferences Social factors – Support system – Accessibility to treatment center – Insurance coverage

• •

•

Patient Disease Treatment

Previous therapies Prior treatment-related adverse event(s)

Nature of relapse – Biochemical vs symptomatic Risk stratification – High-risk chromosomal abnormalities: del(17p), t(4;14), t(14;16) Disease burden

• •

Regimen-related toxicity Depth and duration of previous response

5. Depth of Response Matters MRD refers to the persistence of residual tumor cells after treatment and is responsible for relapse1

Current techniques can detect MRD with a sensitivity of 10-6 for MM cells2

TUMOR LOAD

R3 MR→PR→ VGPR→CR →sCR

10–2

MRDhigh MRDlow

10–6

MRDpos

MRDneg

Induction

Consolidation

Maintenance

Preemptive

TIME MINIMAL RESIDUAL DISEASE DETECTION

1. Adapted from Hauwel M, Matthes T. Swiss Med Wkly 2014:144:w13907 2. Biran N, et al. Curr Hematol Malig Rep 2014;9:368–78 © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

Measuring Disease Response: IMWG Response Criteria

sCR Molecular CR

Response

Myeloma Cells & Protein

Flow MRD negative*

Negative by next generation flow (NGF) (minimum sensitivity 1 in 10-5 nucleated cells or higher)* mCR AND normal Free Light Chain ratio, Bone Marrow negative by flow, 2 measures CR AND negative PCR

Complete Response: Negative immunofixation (IFE); no more than 5% plasma cells in BM; 2 measures

VGPR

Very Good Partial Response: 90% reduction in myeloma protein

PR MR SD PD

Partial Response: at least 50% reduction in myeloma protein Minimal Response Stable Disease: Not meeting above criteria Progressive Disease: At least 25% increase in identified myeloma protein from lowest level

MRD = Minimal Residual Disease sCR = Stringent Complete Response; BM = Bone Marrow

Kumar, S., Paiva, B., Anderson, K. C., Durie, B., Landgren, O., Moreau, P., ... & Dimopoulos, M. (2016). International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The lancet oncology, 17(8), e328-e346.

6. Combinations are very common to leverage multiple mechanisms

OUTSIDE THE CELL GPRC5D

INSIDE THE CELL Myeloma Cell

FcRH5 CD38

SLAMF7

ic ptot o p ia Ant Effects

Myeloma Cell

NFkB AKT MAPK

JAK–STAT

SHP2

NFkB–IkB complex Protein kinases

MEK

SDF1 IL-6 IGF1 TNFα

Increase in cytokine B k F N e production and g Sit Block n adhesion i of d Bin FAS molecules (CD95) programme d Pro-caspase B cFLIP/FADD cell death FAS ligand Cell organelles

cFLIP

FADD

VLA4

LFA1

Collagen fibers

VCAM1

T Cells Fibronectin

MEK/MAPK

VEGF

NFkB–IkB complex

NFkB Binding Site

NFkB

BM Stromal Cells

Angiogenesis Migration Growth

Dendritic Cells Bruno B et al. Lancet Oncol. 2004;5:430-442.

Natural-Killer Cells

TNFα

Monocytes

Inhibition of Anti-Myeloma Immunity

7. Sequencing is Important but not fully Known

We are still learning what is the “optimal” sequence of therapies but it is clear there is no “optimal” sequence as so many variables influence choice

But a few lessons are being learned: 1. In general if a patient is CAR T eligible, it is preferred prior to bispecific antibodies 2. All therapies can be sequenced in any order but it can reduce its efficacy – T cells in particular may need a “rest” © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

8. Always include a Quality of Life Discussion

We do not treat myeloma, but PEOPLE! How it affects your life and your preferences is critical and should be considered...

9. Use the Shared Decision Making Model “The aim of shared decision making is to ensure that: - Patients understand their options and the pros and cons of those options. - Patient's goals and treatment preferences are used to guide decisions.”

10. Consider an Expert Opinion • You have the right to get a second opinion. Insurance providers may require second opinions. • A second opinion can help you: – Confirm your diagnosis – Give you more information about options – Talk to other experts – Introduce you to clinical trials – Help you learn which health care team you’d like to work with, and which facility © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

The Evolution of Myeloma Therapy

Now

VD Rev/Dex CyBorD VTD VRD KRD D-VMP DRD

ASCT Tandem ASCT (?)

Front line treatment

Induction

New

D-VRD Isa-VRD D-KRD Isa-VRD

Consolidation

“More” induction?

Nothing Thalidomide? Bortezomib Ixazomib Lenalidomide Combinations

Bortezomib Panobinostat Lenalidomide Daratumumab Carfilzomib Ixazomib Pomalidomide Elotuzumab Selinexor Isatuximab Belantamab mafodotin* Melphalan flufenamide* Idecabtagene autoleucel Ciltacabtagene autoleucel Teclistamab, Talquetamab Elranatamab, Linvoseltamab Iberdomide

Maintenance

Relapsed

Post Consolidation

Rescue

Daratumumab? Carfilzomib? Lenalidomide + PI

ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; Cy, cyclophosphamide; d- daratumumab; D/dex, dexamethasone; isa, isatuximab; K, carfilzomib; M, melphalan; PD-L1, programmed death ligand-1; PI, proteasome inhibitor; Rev, lenalidomide; V, bortezomib. Speaker’s own opinions.

Novel *CAR Ts – Anito-cel, AZD0120, in vivo, allo *Bispecifics – cevostamab, etentamig *Tri-specifics...

* These agents are currently off the market but available through special programs

Mezigdomide Sonrotoclax Venetoclax KLN-1010 PD/PDL-1 Inhibition? Small Molecules

CAR T CELL THERAPY – WHAT, WHEN AND HOW? Luciano costa, MD university of Alabama, the Kirklin clinic

CAR T cell Therapy - What, When and How?

Luciano J. Costa, MD, PhD Mary and Bill Battle Professor of Multiple Myeloma University of Alabama at Birmingham

Disclosures •

Speaker/honorarium: BMS, Johnson&Johnson, Pfizer, Adaptive Biotechnologies, AstraZeneca, Caribou, Sanofi

• Consultant and part of Advisory board: Amgen, BMS, Johnson&Johnson, Pfizer, Caribou, Genentech, AbbVie • Research support: Amgen, BMS, Johnson&Johnson, Pfizer, Caribou, Genentech, AbbVie, Moderna

What is CAR T- cell therapy? Chimeric antigen receptor T-cell

Chimera of Arezzo

What is CAR T- cell therapy?

CAR T- cell therapy for MM 2 approved products Both target B-cell maturation antigen (BCMA)) Idecabtagene vicleucel (ide-cel) – Abecma ® First CAR T-cell approved in multiple myeloma Approved for patients with 2+ prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody

Ciltacabtagene autoleucel (cilta-cel)- Carvykti® Approved for patients with lenalidomide (Revlimid)refractory MM and 1+ prior lines of therapy

HISTORY- Outcomes with Relapsed MM after prior treatment with IMiDs, PI, anti-CD38 mAB OS

Disease control ~ 4 months

Survival ~ 12 months

M.-V. Mateos et al. Leukemia 2022

IDE-CEL, KARMMA

Munshi et al. N Engl J Med 384 ;705, 2021

IDE-CEL, KARMMA-3 2-4 prior LOT Refractoriness to last line Exposure to PI, IMiD, Anti-CD38 MoAb 2:1 Randomization Apheresis-> SOC regimen-> Idecel SOC regimen to progression SOC Regimens -DPd -KD -DVD -IRd -Epd Ide-cel provided after PD in the control arm Rodriguez-Otero et al. N Engl J Med 388:1002, 2023 Ailawadhi et al. Blood 144:2389, 2024

ORR: 71% vs. 42% CRR: 44% vs. 5%

Cilta-cel in patients with 3+ prior LOT- CARTITUDE 1 PFS

32 (33.0%) treated patients alive and progression free for ≥5 y

46.4% alive and in long-term follow-up

Biomarkers significantly associated with ≥5 y of PFS status: higher fraction of naive T cells in the drug product, lower neutrophil-to-T cell ratio, higher baseline hemoglobin and platelets, higher effectorto-target ratio.

Patients Progression Free and Alive, %

Patients Alive, %

100 80 60

60.7 mo

40 20 0

100 75 50 25 0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 No. at risk OS

Time, mo

97 91 85 79 74 66 58 53 51 48 36 5

PFS

mOS, 60.7 mo No new cases of movement Jagannath S, et al. J Clin Oncol. 2025;43.

or45 neurocognitive

Time Since cilta-cel Infusion, mo

No. at risk 1

Presented by L Costa at the 67th American Society of Hematology (ASH) Annual Meeting; December 6–9, 2025; Orlando, FL, USA

CARTITUDE-4 CILTA-CEL vs Standard Regimens 34 mo. median follow up

San-Miguel et al. N Engl J Med 389:335, 2023 Mateos MV et al, IMS 2024

Overall Survival with Earlier use of Cilta-Cel

 Samir Parekh, ASH 2025

Samir Parekh, ASH 2025

 Samir Parekh, ASH 2025

The How

CAR T-cell: Bridging therapy

Adapted from Costa LJ, et al. Leukemia 39:543, 2025

CAR T-cell: Bridging therapy •

Rapidly reduce disease burden •

Avoid disease-related clinical deterioration, avoid attrition

•

Reduce toxicity post CAR T-cell administration

•

OK to continue holding regimen if still active (relevant in earlier lines).

•

If no holding, or holding not working, introduce new agents.

•

Avoid agents with same target than CAR T-cells.

•

OK to use drugs “prohibited” during holding: alkylators, bispecific, etc.

Costa LJ, et al. Leukemia 39:543, 2025

Some prior treatments may affect the results of CAR T-cell CAR T-cell after Bispecific or ADC -> Decreased feasibility and efficacy (~ ⇩ 30% ORR!) Cilta-cel after BCMA-directed therapy

Cohen AD, et al. Blood. 2023;141:219

Sidana et al, Blood. 2025;145:85

CAR T-cell may affect the results of subsequent treatments Elranatamab

Nooka, et al. ASCO 2023

CAR T-cell may affect the results of subsequent treatments Talquetamab

77.8

64.7 (11/17)

Prior CAR T-cell N=56

ORR

71%

Prior Bispecific N=26

58%

29.4

≥CR:

33.3

≥CR:

22.2

5.9 17.6

mPFS

12.3 mo

4.1 mo

≥CR:

30.4

21.7 22.2

11.8 CAR-Tᵇ

Ye, et al. IMS, 2024, Dholaria, et al. ASCO, 2023 Bahlis, et al. IMS, 2024

4.3 26.1

35.3

(11/19)

(14/23)

33.3 Patients, %

MonumenTAL-1 Single agent

57.9

60.9

(7/9)

VGPR

31.6

5.3

Non-GPRC5D BsAbs ͨ CR

≥CR:

21.1

8.7

Anti-BCMA CAR-T

31.6

Anti-BCMA BsAbs Scr

Adaptado de Sanchez L, et al. 2023.1 | 1. Sanchez L, et al. ASH 2023. Clinical Outcomes of Subsequent Therapies in Patients With Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses From the Phase 1/2 MonumenTAL-1 Study 1. Sanchez L, et al. ASH 2023. Clinical Outcomes of Subsequent Therapies in patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses From the Phase 1/2 MonumenTAL-1 Study.

Side Effects of MM CAR T-cell therapies CRS

ICANS

◆ The main symptom is fever ◆ Severe cases: hypotension and hypoxia ◆ Treatment: tocilizumab, steroids ◆ Consider prophylactic strategies

◆ Confusion, delirium, dysgraphia, word-finding difficulties ◆ Severe cases: seizures ◆ Treatment: steroids ◆ For severe cases, may use lymphotoxic agents such as cyclophosphamide

when CAR-T infusion or BsAb ramp-up occurs in the outpatient setting

Infections ◆ Most common cause of non-relapse mortality ◆ Prophylaxis is crucial: - VZV/HSV (acyclovir or valacyclovir) - PJP: 1st line TMP/SMX, alternative: atovaquone, dapsone, pentamidine - Anti-bacterial/fungal prophylaxis when ANC < 0.5 x 10^9/L - HBV: entecavir (chronic carriers) - Primary IVIG prophylaxis - Revaccinations

Danai D, Banerjee R, and Hansen DK. Hematology ASH Education Program 2025

Other Neurotoxicity ◆ Nerve palsies, GuillainBarré syndrome, Parkinsonism ◆ Mainly seen with cilta-cel ◆ No standard treatment - Consider steroids, IVIG - Severe cases: consider lymphotoxic agents (cyclophosphamide)

IEC-HS ◆ Hyperinflammatory syndrome ◆ Hyperferritinemia, hepatic dysfunction, coagulopathy, cytopenias ◆ Treatment: anakinra +/steroids For severe cases: ruxolitinib, low dose etoposide, emapalumab

Cytopenias ◆ Most common AE with CAR-T and BsAb ◆ Grading per CTCAE version 5.0 or ICAHT ◆ Management includes: - G-CSF for neutropenia - TPO antagonists for thrombocytopenia - Blood product transfusions - Stem cell boosts - If persistent: bone marrow biopsy to assess for therapy-related myeloid neoplasms

CAR T-cell: Current Challenges •

•

Access •

Requires a specialized cellular therapy center

•

Costly, available only in a few countries

Timeline, several potential bottle necks: •

Assessment at treatment center

•

Wait for apheresis

•

Manufacturing

•

Efficacy – room for improvement.

•

Safety – more room for improvement.

 Samir Parekh, ASH 2025

The Future: Off-the-shelf approaches

 Samir Parekh, ASH 2025

The Future: Off-the-shelf approaches

BISPECIFIC ANTIBODIESAND ANTIBODY DRUG CONJUGATES – WHAT, WHEN AND HOW? Shonali Midha, MD Instructor, Harvard Medical School Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute

Disclosures

Advisory Board – Simcere, Pfizer, Janssen, BMS Consultancy/Honoria – Pfizer, Janssen, Legend Biotech Research Funding - Pfizer Stock Ownership - Abbvie

Evolution of Myeloma Treatment Landscape

6 0

The ABC’s of BsAbs & ADCs

Bispecific antibodies are able to bring together a myeloma cell with a T cell —a cell of the immune system that can kill the myeloma cell Readily accessible for patients whose disease may progress too quickly for CAR-T manufacturing

Requires no lymphodepletion chemotherapy

The ABC’s of BsAbs & ADCs Antibody drug conjugates are antibodies that activate the immune system and contain a chemotherapy payload to kill the myeloma cell ADC is internalized into MM cell and chemotherapy agent is released to arrest cell division Readily accessible for patients whose disease may progress too quickly for CAR-T manufacturing

Diving into BsAbs

How given

Bispecific antibody

Myeloma Target

T Cell Target

Administration

Frequency

Teclistamab (Tecvayli)

BCMA

CD3

Subcutaneous

(Every 2 weeks if CR for 6 mos)

Elranatamab (Elrexfio)

BCMA

CD3

Subcutaneous

Linvoseltamab (Lynozyfic) Talquetamab (Talvey)

BCMA GPRC5D

CD3 CD3

Intravenous Subcutaneous

Weekly

Weekly (Every 2 weeks if CR for 6 mos)

Weekly x 10

Every 2 weeks x 6 months Every 4 weeks

Weekly or Every 2 weeks

For patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy

• Each starts as 2-3 “step-up” injections where patients may be hospitalized for monitoring of side effects • Full treatment after step-up typically starts as a weekly injection followed by every other week and then monthly depending on how patients respond to treatment (and the bispecific How long antibody used) • Until the myeloma no longer responds or the patient cannot tolerate the treatment

Diving into BsAbs Teclistamab1 (MajesTEC-1)

Elranatamab2 (MagnetisMM-3)

Moreau et al, NEJM 2022 Cohen et al, ASCO 2023 3 Lee et al, Clin Lymphoma Myeloma Leuk 2025 4 Chari et al, ASH 2023 1 2

Linvoseltamab3 (Linker-MM1)

Talquetamab2 (MonumenTAL-1)

BsAbs show impressive single-agent efficacy Teclistamab1

Elranatamab2 Linvoseltamab3 Talquetamab4

Number of patients (n)

165

123

117

143

Median follow-up (mos)

30.4

28.4

21.3

25.6

Overall response rate (%)

Complete response (CR) or better (%)

37.4

85.7 (48/56)

Not reported

Median progression-free survival (mos)

11.4

17.2

7.5

Duration of response (mos)

Not reached

29.4

9.5

Median overall survival (mos)

22.2

24.6

31.4

Not reached

MRD negativity, %

MRD, minimal residual disease; ICANS, immune effector cell associated neurotoxicity syndrome 1. Garfall AL et al. J Clin Oncol. 2024;42. Abstract 7540; 2. Prince HM et al. Blood. 2024;144. Abstract 4738; 3. Lee HC et al. Clin Lymphoma Myeloma Leuk. 2026;26:e201; 4. Chari A et al. Lancet Haematol. 2025;12:e269.

Toxicity Comparison

Teclistamab

Elranatamab

Linvoselatamab

Talquetamab

Any grade

Grade 3– 4

Any grade

Grade 3–4

Any grade

Grade 3– 4

Any grade

Grade 3– 4

Hematologic

71%

64%

26-48%

27-59%

62-97%

64%

15-44%

35-45%

CRS

72%

0.6%

57.7%

46%

0.6%

72.479%

0.62.1%

Time to onset Median duration Neurotox

2 days

11 hrs

27 hours

2 days

15 hrs

17 hours

14.5%

0.6%

7.7%

2.8%

10%

2.5 days

1 day

2-3 days

N/A *Delayed neurotoxicity seen in some patients (etiology unclear).2 days

2 days

2-3 days

Time to onset Median duration

CRS, cytokine release syndrome

N/A

3.4%

BCMA-Targeting Therapies: Adverse Events of Interest - Infection Teclistamab

Elranatamab

Any grade

Grade 3– 4

Any grade

Grade 3–4

76%

44%

69.9%

Upper Respirator y

57.6%

19.4% (1.2%)

Pneumonia

*All respiratory

Infections

COVID19

29.1%

n/a

Sepsis PJP

21.2% (10.9%)

4.2%

Linvoseltamab

Talquetamab

Any grade

Grade 3– 4

Any grade

Grade 3–4

39.8% (6.5%)

74.4%

35.9%

59-76%

18-26%

16.3%

35%

17%

16.3%

8.1%

28%

21%

16.3%

8.1%

29.3%

16.4% (1.6%)

17%

11-25%

6.5%

10%

6.5%

4.9%

4.1%

4.2%

Talquetamab: AE’s of Interest 0.4 mg/kg SC QW (n=143) mFU, 11.0 months

0.8 mg/kg SC Q2W (n=145) mFU, 5.1 months

AEs (≥20% of any RP2D cohort), Any Any n (%) Grade Grade 3/4 Grade Grade 3/4 CRS 113 (79.0) 3 (2.1) 105 (72.4) 1 (0.7) Skin-related AEs 81 (57) 0 113 (71) 1 (1) Nail-related AEs 79 (55) 0 82 (53) 0 Dysgeusia 103 (72) NA 110 (71) NA Rash-related 57 (40) 2 (1.4) 45 (29) 8 (5.5) AEs Weight 57 (39.9) 3 (2.1) 56 (36) 8 (5) decreased Pyrexia 53 (37.1) 4 (2.8) 35 (24.1) 1 (0.7) Asthenia 37 (25.9) 3 (2.1) 13 (9.0) 2 (1.4) Dry mouth 36 (25.2) 0 53 (36.6) 0 Diarrhea 34 (23.8) 3 (2.1) 32 (22.1) 0 Dysphagia 34 (23.8) 0 33 (22.8) 3 (2.1) Fatigue 32 (22.4) 5 (3.5) 29 (20.0) 1 (0.7) Decreased 25 (17.5) 2 (1.4) 29 (20.0) 2 (1.4) appetite

• Most common AEs were CRS, skin-related events, nail-related events, and dysgeusia ‒ Dysgeusia was managed with supportive care, and at times with dose reduction • At 0.4 mg/kg QW and at 0.8 mg/kg Q2W, ‒ 8.4% and 13.8% had dose delays due to AEs ‒ 14.7% and 6.2% had dose reductions due to AEs • At time of data cut-off, no patients in these cohorts died due to drugrelated AEs

Boosting Effectiveness: Bispecific Antibody Combinations Teclistamab (tec) + daratumumab (D) vs D-pomalidomide (P)-dexamethasone (d) or D-bortezomib (V)-d1 Tec-D

DPd or DVd

Number of patients

291

296

Overall response rate, %

89.0

75.3

MRD negativity, % (next-generation sequencing, 10-5)

58.4

17.1

Not reached

18.1

Median progression-free survival, months Infections Any grade, %

96.5

84.1

Grade 3/4, %

54.1

43.4

CRS, %

60.1

─

ICANS, %

1.1

─

Costa LJ et al. N Engl J Med. 2026;394:739.

Boosting Effectiveness: Bispecific Antibody Combinations

Boosting Effectiveness: Bispecific Antibody Combinations (Tec + Talq) in EMD

Current Dilemmas in TCR Therapy •

Sequencing (target BCMA or GPRC5D first?)

•

Sequencing (CARs to BiTEs or vice versa?)

•

Sequencing (one BiTE right after another?)

•

Dosing frequency (how often and for how long?)

T-cell exhaustion

The “DREAM”M-7 of more?

Belantamab mafodotin – The eye of the storm…

Best corrected visual acuity (BVCA) improved in 98% of patients with a decrease to 20/50 and 100 of patients with a decrease to 20/200

Can we treat sequentially & how?

Sidana et al. Blood. 2025;145(1):85-97; Oeklen et al. Blood 2023;141(7): 756–765.

Can we treat sequentially & how?

Lee H, et al. ASH 2023, Abstract 1945; Dima et al, Transplant Cell Ther. 2024 Mar;30(3):308 Dhakal, et al. ASH 2024, Abstract 931

Approach to maintaining immune activation • Decrease dosing frequency early on, e.g.: •

After deep response achieved (e.g. CR, MRD-neg)

•

After some degree of response achieved at some arbitrary timepoint

•

After severe infectious AE

•

After detection of exhausted phenotype in blood/marrow

• Combine TCExhausting with TCEnergizing drugs (e.g. BsAb/IMiD) • Sequence TCEnergizing before/after TCExhausting drugs • Fixed-duration dosing

So where do we stand? • BsAbs and ADCs offer effective, durable, off-the-shelf options that can now be used alone or in combination with other myeloma therapies in early relapse • Toxicity profiles vary greatly and should be weighed against personal goals and preferences • The evolution of therapy for RRMM includes strategies to: • Improve the patient experience and accessibility by moving from inpatient to outpatient administration • Reduce the frequency of dosing or limit the amount of time on therapy necessary to maintain a response • Combination regimens to improve response rates and progression-free survival, even in patients with EMD • Utilizing similar targets sequentially is possible, however understanding how best to maintain immune activity or limit antigen loss remain areas of study

AUDIENCE Q & A

10-MINUTE BREAK

MYELOMA: PUTTING THE PIECES OF THE PUZZLE TOGETHER Patricia Mangan, RN, MSN, APRN-BC University of Pennsylvania, Abramson Cancer Clinic IMF Nurse Leadership Board

Myeloma: Putting the Pieces of the Puzzle Together RRMM Treatment

Myeloma Basics Living Well

Managing Disease

Managing Symptoms .

 Relapsed Myeloma

AGENDA

(RRMM) and Shared Decision Making

 Managing Symptoms  Living Well

Relapsing Nature of Myeloma HR-SMM Therapy

M-Protein g/L

Front-Line Therapy

Second-Line Therapy

≥ Third-Line Therapy

ACTIVE MM

ACTIVE MM d

MGUS SMM HR-SMM REMISSION

Dominant MM Clones Change Over Time

REMISSION

Time Misc

Clone 1.1

Clone 1.2

Clone 2.1

HR-SMM = high risk smoldering multiple myeloma; M-protein = monoclonal protein; MGUS = monoclonal gammopathy of undetermined significance; misc = miscellaneous (no dominant clone); MM = multiple myeloma; SMM = smoldering multiple myeloma. Adapted from Durie B. Keats JJ, et al. Blood. 2012;120(5):1067-1076.

Clone 2.2

8 4

Deciding on Treatment With Relapsed Myeloma Disease-Related Factors • Duration of response to initial therapy • High-risk vs low-risk status • Molecular relapse vs symptomatic relapse • Other medical conditions or frailty Treatment-Related Factors • Previous/Current therapy exposure and response (relapsed vs refractory) • Toxicity/Tolerability of the previous regimen • Mode of administration (ie, PO or IV) • Cost and convenience (out-of-pocket co-pays for IV vs PO)

Data and Experience

Patient Prefere nce

Disease Characteris tics & Prior Therapy

Administrat ion, Chair Time

Efficacy of Regimen

Finances/ Insurance

Comorbid Conditions

Social Status/ Support

Your preference! IV = intravenous; PO = by mouth. Noonan K, et al. J Adv Pract Oncol. 2022;13(suppl 4):15-21. Faiman B, et al. J Adv Pract Oncol. 2016;2016:7(suppl 1):17-29.

Why Shared Decision Making in Multiple Myeloma? “The aim of shared decision-making is to ensure that: - Patients understand their options and the pros and cons of those options. - Patient's goals and treatment preferences are used to guide decisions.”

The relapsing nature of multiple myeloma means patients and their care partners may have multiple points to make decisions about treatment People with myeloma are living longer; goals, preferences, and values may change over time 86

Patient and Care Partner’s Roles in Shared Decision Making Ask questions (write them down in advance of visit)

Express your desire to participate in the treatment decisions

Ask for time (if needed/ appropriate)

• What are my treatment options? • What are the pros and cons of each option? Efficacy? Side effects? Administration? Insurance nuances? • Are there treatments that wouldn’t be a good option for me? Why?

• I want to make sure the treatment we chose is the best option for me • I want to be sure we a choosing the best therapy for my loved one

• There is a lot to think about. Can I/we have some time to consider the options? • Ask for information you can consider at home • Note: if medical emergency/high risk, may not be appropriate

Patient and Care Partner’s Roles in Shared Decision Making Understand options; consider priorities

• Use reliable sources of information like the IMF and Myelo • Use caution when considering stories of personal experiences • Consider your goals, values and preferences

Express your goals/values/preferences; create a dialog

Arrive at a treatment decision together

• My top priority is [goal/value]; additional [preferences] are also important. • I think [treatment] may be a good choice given my priorities… What do you think? • What treatment would you recommend given my goals and priorities? 88

IMF Has Resources to Help You Be A Part of Your Treatment Decisions •

Be empowered to be part of decision-making

• Stay informed, understand options

Research Results

HCP Clinical Experience TREATMENT DECISION

• Use reliable and current sources of

information

• Use caution considering stories of

personal experiences

•

Your Preference

Philippe Moreau. ASH 2015.

Consider your priorities •

Discuss with your care partner

• Consider your goals/values/preferences •

Be a part of the conversation, create a dialog •

Ask questions & express your goals and preferences

•

Ask for time to consider options, if needed

•

Arrive at a treatment decision together

•

Arrange follow-up to review and adjust, if needed

Decision Aids available at Myeloma.org

 Relapsed Myeloma (RRMM)

and Shared Decision Making

AGENDA

 Managing Symptoms  Living Well

Communicate Proactively with Your Healthcare Team Your team may be able to help, but only if they know how you feel. Unmanaged Myeloma can cause: • • • • • • • •

Calcium elevation Renal dysfunction Low blood counts Infection Risk Blood clots Bone pain Neuropathy Fatigue

How You Feel

Side Effects of Treatment can cause: • • • • • • •

GI symptoms Renal dysfunction Low blood counts Infection Risk Blood clots Neuropathy Fatigue

Tip: proactively discuss common side effects and Tip: proactively discuss what to doand if common side effects what to do they if theyoccur occur

Tip: Keep a Symptom Diary and bring it to appointments

CAR T-Cell Therapy BCMA target: potential for infection • Abecma® (ide-cel) • Carvykti® (cilta-cel) • (anito-cel – pending FDA approval )

Apheresis to Collect T Cells

T Cell Manufacturing

Bridging therapy, if needed; Lymphodepleting therapy when CAR T cells are ready

T Cell Infusion

4 5

Close monitoring and Management of side effects HOME!

T-Cell Engager (TCE) Therapy TCE are innovative immunotherapies used in the

treatment of relapsed multiple myeloma. These therapies work by redirecting the patient's own T-cells to recognize and attack myeloma cells. Bispecific antibodies • About 7 in 10 patients respond • Off-the-shelf treatment; no waiting for engineering cells

Cytotoxic cytokines

T cell

CD3

BCMA target: potential for infection • Tecvayli® (teclistamab) • Elrexfio® (elranatamab) • Lynozyfic™ (linvoseltamab) GPRC5D target: potential for skin and nail side effects, GI issues of taste change, anorexia and weight loss • Talvey® (talquetamab)

MM cell

Target

Bispecific antibody

MM cell death

FcRH5 target: new myeloma target • (cevostamab - pending FDA approval)

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; GPRC5D = G protein–coupled receptor, class C, group 5, member D; CAR = Chimeric Antigen Receptor; LOT = Lines of Therapy; MM = multiple myeloma. Hucks G, Rheingold SR. Blood Cancer J. 2019;doi:10.1038/s41408-018-0164-6. Shah N, et al. Leukemia. 2020;34(4):985-1005.

9 2

CAR T and Bispecific Antibodies: Unique Side Effects CYTOKINE RELEASE SYNDROME (CRS) • Fever • Fatigue & Weakness • Headache • Nausea/Vomiting/Diarrhea • Chills • Low blood pressure • Rapid heart rate • Difficulty breathing

CRS is a common but typically mild & manageable side effect

PREVENTION AND MANAGEMENT of CRS • Disease management to reduce tumor burden • Bispecific Step-up Dosing (SUD) • Tocilizumab • Steroids • Anti-Seizure medications • Close monitoring

ICANS AND NEUROTOXICITY • Headache

• Difficulty concentrating • Lethargy • Agitation • Hallucinations • Tremors • Confusion

Neurotoxicit y is a rare but serious side effect

• Memory loss • Aphasia (difficulty with speech, reading, writing, or understanding language) • Personality change • Delayed Neurotoxicity can include Parkinsonism, Cranial Nerve Palsies and Peripheral Neuropathy/Guillan Barré syndrome (GBS)

CAR = chimeric antigen receptor. ICANS = Immune Effector Cell-Associated Neurotoxicity Syndrome Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625638. Kumar, et al. Blood (2024) 144 (Supplement 1): 4758.

9 3

Infections Are Serious for People with Myeloma Preventing infections is paramount. Infection remains the leading cause of death in patients with multiple myeloma. Several factors account for this infection risk, including the overall state of immunosuppression from multiple myeloma, treatment, age, and comorbidities (e.g., renal failure and frailty). IMWG Consensus guidelines and recommendations for infection prevention in multiple myeloma; Lancet Haematol.2022;9(2):143– 161.

Infection Prevention Tips Good personal hygiene (skin, oral)

Environmental control

(avoid crowds and sick people; use a high-quality mask when close contact is unavoidable)

Report fever of more than 100.4°F, shaking chills even without fever, dizziness, shortness of breath, low blood pressure to HCP as directed.

As recommended by your healthcare team:

Immunizations:

Flu, COVID, RSV & and pneumococcal vaccinations; avoid live vaccines

IMWG = International Myeloma Working Group; HCP = healthcare provider. Raje NS, et al. Lancet Haematol.2022;9(2):143–161. IMF Nurse Leadership Board ONS Symposia 2024.

Preventative and/or supportive medications 9 4

Infection: Medications Can Reduce Risk Type of Infection Risk

Medication Recommendation(s) for Healthcare Team Consideration

Viral: Herpes Simplex (HSV/VZV); CMV

Acyclovir prophylaxis

Bacterial: blood, pneumonia, and urinary tract infection

Consider prophylaxis with levofloxacin

PJP (P. jirovecii pneumonia)

Consider prophylaxis with trimethoprim-sulfamethoxazole

Fungal infections

Consider prophylaxis with fluconazole

COVID-19 and Influenza

Antiviral therapy if exposed or positive for covid per institution recommendations

IgG < 400 mg/dL (general infection risk)

IVIg recommended for patients receiving CAR T or TCE therapies

ANC < 1000 cells/μL (general infection risk)

Consider GCSF 2 or 3 times/wk (or as frequently as needed) to maintain ANC > 1000 cells/μL and maintain treatment dose intensity

Some people receiving BCMA-targeting therapies have experienced infections that are less common like CMV, PJP and fungal infections ANC = absolute neutrophil count; BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; CMV, cytomegalovirus; GCSF = granulocyte colony-stimulating factor; HSV = herpes simplex virus; IVIg = intravenous immunoglobulin; PJP = Pneumocystis jirovecii pneumonia; VZV = varicella zoster virus. Raje NS, et al. Lancet Haematol.2022;9(2):143–161.

9 5

Management of Skin and Nail Side Effects Possible side effect to some treatments and supportive care medications Skin Rash

Prevent dry skin; apply lotion Report changes to your care team Medication interruption or alternative, as needed Steroids: • Topical for grades 1-2, • Systemic and topical for Grade 3 Antihistamines, as needed

Nail Changes Keep your nails short and clean. Watch for “catching and tearing” Apply a heavy moisturizer like Vaseline or salve. Wear cotton hand coverings to bed A nail hardener may help with thinning Tell the team if you have signs of a fungal infection, like thickened or discolored nails Photos: Mount Sinai Hospital, NY, NY Nurse Leadership Board

9 6

Management of Oral Side Effects Xerostomia= Dry Mouth OTC dry mouth rinse, gel, spray are recommended. Avoid hot beverages. Anti-fungal therapy for oral thrush.

Dysgeusi = Taste Change a Dexamethasone oral solutions “swish and spit” may provide benefit. Sour citrus or candies before meals are also recommended.

Dysphagia = Difficulty Dietary Swallowing modifications with small

bites, eating upright, and sips with food can help manage symptoms

Weight Monitoring Some medications lead to weight gain, others to weight loss. Meet with a nutritionist Consider diet changes, supplements

Dental Care Attention to oral hygiene. Regular dental cleaning and evaluation. Close monitoring for ONJ, oral cancer and dental caries

Work closely with your entire health care team to manage oral side effects.

ONJ = Osteonecrosis of the Jaw; OTC = Over The Counter Catamero D, Purcell K, Ray C, et al. Presented at the 20th International Myeloma Society (IMS) Annual Meeting Nurse Symposium; September 27–30, 2023; Athens, Greece.

9 7

GI Symptoms: Prevention & Management Fluid intake can help with both diarrhea and constipation and helps kidney function

Constipation is more

common in the induction phase Opioid pain relievers, antidepressants, heart or blood pressure medications (check with provider, pharmacist) Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency Increase fiber Stay well hydrated Fruits, vegetables, high fiber whole grain foods Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

Anorexia, the inability to eat, is common during transplant and resolves with time. • Hydration is most important • Small, frequent meals with a

focus on protein intake • You will work closely with a dietician to help monitor your calorie intake

Diarrhea is common during transplant and long-term maintenance therapy.

Other medications and supplements can cause GI issues. Hydration is very important Electrolyte replacement is common Good skin care will help prevent irritation Stool exam may be needed to rule-out infection If no infection, anti-diarrheal medication may be prescribed

Discuss GI issues with healthcare providers to identify causes and adjust medications and supplements Smith LC, et al. Clin J Oncol Nurs. 2008;12(3)suppl:37-52. Faiman B. Clin J Oncol Nurs. 2016;20(4):E100-E105.

9 8

Fatigue, Anxiety and Depression Fatigue

98.8% Anxiety

>35% Depression

≈25%

Fatigue is the most reported symptom. Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression. Symptoms can improve with continued physical activity. Symptoms are under-reported: “I mentioned it before. Nothing can be done.” “I don’t want to be put on another medication.”

Join a support group! https://www.myeloma.org/support-groups

Talk to your healthcare team if you have thoughts of self-harm. Support is available. Rosenthaler C, Kane P, Gao W Eur J Haematol. 2016; Mondy, et al., Blood, 2024 Abstract 3771; Chang D. et al., Blood 2024, Abstract 2287.

9 9

Pain Management Pain can significantly compromise quality of life and add to distress. Sources of pain include bone disease, neuropathy and medical procedures. Prevention

Treatment

•

Decrease fracture risk through myeloma treatment, bone strengthening agents, physical activity, preventative surgery

•

Prevent Nerve Damage: prevent shingles, manage diabetes, myeloma medication dosing and route of administration

•

Combine scheduled medical procedures, when possible (Ex. blood draw, biopsy), use sedation if available

Interventions depend on source of pain, may include • Medications, Surgery, Radiation therapy, etc. • Physical therapy & continued activity, complementary therapies (Mind-body, meditation, yoga, supplements, acupuncture, etc.) • Scrambler therapy for neuropathy

Discuss with your healthcare provider new bone pain or chronic pain that is not well controlled and decreasing pain medication if pain has improved. 1 0 0

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Sweiss, K. et al. ASH Abstract #283, 2024. Joseph, J., et al. ASH abstract #705, 2024. Chang D., et al., Blood 2024, Abstract 2287.

1 0

 Relapsed Myeloma (RRMM)

and Shared Decision Making

AGENDA

 Managing Symptoms  Living Well

101

Kidney and Bone Health Protect Kidney Function

Protect Bone Health

Myeloma Treatment

•

Myeloma Treatment

Stay hydrated--drink water

•

Nutrition

Avoid certain medications

•

Vitamin D

•

Calcium (if approved by doctor)

•

Weight-bearing activity (e.g., walking, standing, climbing stairs, stretching, dancing)

•

Bone-strengthening agents (prescribed by your healthcare team)

• •

IV contrast dyes NSAIDs like Advil (ibuprofen), Aleve (naproxen)

Be alert: symptoms of kidney dysfunction • • • • • • • • •

Fatigue and weakness Nausea and vomiting Foamy or dark urine Swelling in feet, ankles, or face Shortness of breath Persistent itching Loss of appetite Muscle cramps High blood pressure

Report any new or worsening bone pain to your healthcare provider

Raje NS, et al. Lancet Haematol.2022;9(2):143–161. IMF Nurse Leadership Board ONS Symposia 2023. Miceli TS, et al. Clin J Oncol Nursing. 2011;15(4)suppl:9-23; Dimopoulous M, et al. Leukemia. 2009; 23(9):1545-56.

1 0

Healthy Practices: Part of the Big Picture Adopt Healthy Behaviors • Mental health / social engagement • Stress reduction; relaxation • Sufficient Sleep • Maintain a healthy weight; eat nutritiously • Activity / exercise / prevent falls, injury • Stop smoking • Sexual health / intimacy • Complementary or alternative therapy

Have a PCP for general check ups, preventative care, health screenings, vaccinations

Have specialists for dental care, eye exams/screening, skin cancer screening

Recommended Health Screenings  Blood pressure  Cholesterol  Cardiovascular disease  Colonoscopy  Dental checkups & cleaning  Dermatologic evaluation  Diabetes  Hepatitis  Hearing  Vision  Women specific: mammogram, pap smear

 Men specific: prostate

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56. Brigle K, et al. CJON. 2017;21(5)suppl:60-76. Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Faiman B, et al. CJON. 2011;15suppl:66-76. Miceli TS, et al. CJON. 2011;15(4)suppl:9-23.

1 0

Care Partners: Essential Pieces of the Puzzle Multiple studies demonstrate that strong social ties are associated with • Increased longevity, including people with cancer • Improved adherence to medical treatment leading to improved health outcomes • Lower risk of cardiovascular diseases • Increased sense of purpose & life satisfaction • Improved mood and happiness • Reduced stress and anxiety • Enhanced resilience

Caring for the care partner • • •

Recognize that caregiving is difficult and stressful Encourage care partners to maintain their health, interests, and friendships The IMF has information and resources to help care partners

Care partners may help with medical appointments, managing medication, daily living, physical assistance, emotional support, myeloma knowledge, healthy lifestyle, patient advocacy, financial decisions Care partners can be a spouse, close relative, a network of people (family, friends, neighbors, church members, etc) Martino J, et al. Am J of Lifestyle Med. 2015;11(6):466-475. Yang YC, et al. Proc Natl Acad Sci U S A. 2016;113(3):578-583. Pinquart M and Duberstein PR. Crit Rev Oncol Hematol. 2010; 75(2):122–137.

IMF Tip Cards 1 0

IMF Offers Resources to Help You Fit It All Together

Website: http://myeloma.org

Download or order at myeloma.org

IMF InfoLine 1-800-452-CURE 9am to 4pm PST

You are not alone!

IMF Videos

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“THANK YOU!” FROM THE NLB AND THE IMF

PANEL Q&A TO FOLLOW

THE FUTURE OF MYELOMA THERAPY Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO IMF Medical Advisor Professor, Translational Genomics Research Institute

THE FUTURE OF RELAPSED MYELOMA

CAR T Cell Therapy

Myeloma Cell CAR T Cell .

CAR T Cell Therapy

Abecma (Idecabtagene vicleucel)

Ide-cel

Carvykti (ciltacabtagene autoleucel)

cilta-cel

Intravenous

The Future of CAR T Cell Therapy Novel CAR Ts with unique features non BCMA targets (GPRC5D, FcRH5 and others)  “fast Cars” with shorter manufacturing time  enhanced binding 

 

dual targeting d-domain binding

in vivo CAR T – without the need of T cell collection or lymphodepleting chemotherapy Allo-CAR T – external T cells infused into the patient

GC012F/AZD0120: BCMA/CD19 dual targeting CAR-T

BCMA

Universally expressed on malignant plasma cells and a well-established target

CD19

Expressed on majority MM cells and progenitor cells 1-3

Next generation manufacturing based on FAST CAR platform

Faster availability to patients

Enhanced T-cell fitness

• Manufactured in <3 days

• Younger, fitter, naïve T cells

• GC012F/AZD0120 is an autologous CAR-T therapy that targets both BCMA and CD19 • GC012F/AZD0120 has demonstrated deep and durable responses with a manageable safety profile in RRMM patients4

111

1. Boucher K, et al. Clin Cancer Res. 2012;18:6155–6168. 2. Garfall AL, et al. JCI Insight 2018;3:e120505. 3. Jiang H, et al. Presented at: ASH Annual Meeting 2020; December 5–8, 2020; virtual. Oral presentation 178. 4. Juan Du, et al. Presented at: EHA2023 Congress; June 8-11, 2023; Frankfurt & Virtual. Poster presentation P869. MM, multiple myeloma; RRMM, relapsed / refractory multiple myeloma.

Juan Du, MD, PhD

67th ASH Annual Meeting December 6–9, 2025

Anitocabtagene autoleucel (anito-cel/CART-ddBCMA)

Autologous BCMA-directed CAR T-cell therapy using a novel, D-Domain binder1,2 D-Domain Attributes:

Non-Antibody Derived Synthetic Protein1,2

scFv (~25 kDa)

Bivalent camelid VHH (~30 kDa)

D-Domain (~8 kDa)

Size

Small D-Domain construct facilitates high transduction efficiency and CAR positivity2-4 resulting in a low total cell dose

Structure & Stability

D-Domain CARs are stable and lack tonic signaling4,6 due to the rapid folding, lack of disulfide bonds, and hydrophobic core5,6 of the D-Domain

Binding

The D-Domain binder has a fast off-rate4 and high CAR surface expression4. This combination may allow optimal tumor cell killing without prolonged inflammation

Rotte, et al. Immuno-Oncology Insights 2022; 3(1), 13–24; 2Frigault, et al. Blood Adv. 2023; 7(5):768-777; 3Cante-Barrett, et al. BMC Res. Notes 2016; 9:13; 4Buonato, et al. Mol. Cancer Ther. 2022; 21(7):1171-1183; 5Zhu, et al. Proc. Nat. Acad. Sci. 2003; 100(26): 15486-15491; 6Qin, et al. Mol. Ther. 2019; 27(7): 1262-1274.

Patel et al, American Society of Hematology 2025, Abstract 256

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Expanding the reach of CAR-T cells with in vivo gene delivery

KLN-1010: A modified LVV generating anti-BCMA CAR-T cells in vivo3

In vivo CAR T with lentiviral particles1,2 Reduced cost of goods and manufacturing Simplified logistics to expand access

Eliminates preconditioning chemotherapy

VSV-G mutation Detargeted fusogen,

T cell retargeting with CD3 tropism molecule

CAR molecule

In vivo CART generation

Proprietary, fully-human BCMA scFv Direct infusion

4-1BB CD3ζ

No ex vivo culture may increase T-cell fitness BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CD3, cluster of differentiation 3; CD3ζ, cluster of differentiation 3 zeta chain; LVV, lentiviral vector; scFv, single-chain variable fragment; VSV-G, vesicular stomatitis virus glycoprotein. 1. Bot A et al. Nat Rev Drug Discov. 2025 Sep 30. doi: 10.1038/s41573-025-01291-5; 2. Najibi AJ. T cell-specific in vivo transduction with preclinical candidate KLN-1010 generates BCMA-directed CAR-T cells with potent anti-multiple myeloma activity (abstract #48). Poster presented at: AACR Annual Meeting; April 5-10, 2024. 3. Wood JT et al. Toward treatment with gene-modified B cells engineered in vivo using iGPS particles (abstract #1281). Poster presented at: ASGCT 28th Annual Meeting; May 1317, 2025.

CB-011: a differentiated allogeneic CAR-T cell therapy for r/r MM B2M–HLA-E protein fusion insertion

CB-011 Manufactured from healthy donor T cells with 4-1BB Vispa-cel costimulatory domain Manufactured from

healthy donor T cells

Anti-BCMA CAR insertion

TCR knockout

B2M knockout

Rossi A et al. TANDEM 2026 presentation RDE: recommended dose for expansion r/r MM: relapsed/refractory multiple myeloma 1

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CB-011 immune cloaking strategy enhances functional persistence and antitumor activity

450M cell dose selected as RDE following deep, durable responses and manageable safety profile1

CB-011 demonstrates potential to address unmet need in both BCMAnaïve and BCMA-exposed patients

Bispecific Antibodies – BCMA • Incorporates 2 antibody fragments to target and bind both tumor cells and T cells • Brings target-expressing MM cells and T cells into close proximity, enabling T cells to induce tumor-cell death • Targets • BCMA = B Cell Maturation Antigen • GPRC5d • FcRH5 © 2026, International Myeloma Foundation. All rights reserved. IMF Confidential

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The Future of Bispecific Antibodies Novel targets 

FcRH5 (Cevostamab)

More convenient dosing and less CRS 

monthly (Etentamig)

Trispecific Antibodies 

dual MM Cell targeting – potential for enhanced binding and less resistance

New Combinations with other MM agents (eg. TeclistamabDaratumumab already approved, but others coming Talquetamab-Daratumumab-Pomalidomide...)

Cevostamab

Cevostamab4

• Cevostamab (FcRH5xCD3 bispecific antibody)1 – FcRH5: novel target expressed exclusively in B-cell lineage and ubiquitously on MM cells 1,2

Anti-FcRH5 Fab region

Anti-CD3 Fab region

• Ongoing Phase I study of cevostamab monotherapy (GO39775)3* – fixed-duration treatment in patients with heavily pretreated RRMM – prior BCMA and GPRC5D allowed, with increased exposure during the course of enrollment (2017–2023) No current agent targets FcRH5 *NCT03275103; BCMA, B-cell maturation antigen; C, Cycle; CRS, cytokine release syndrome; Fab, fragment antigen binding; FcRH5, Fc receptor-homolog 5; GPRC5D, G-protein coupled receptor, family C, group 5, subtype D; MM, multiple myeloma; PD, disease progression; RRMM, relapsed/refractory MM

1. Li et al. Cancer Cell 2017;31:383–95 2. Sumiyoshi et al. EHA 2021; 3. Trudel et al. ASH 2021

Prophylactic tocilizumab use with etentamig resulted in a 0% CRS incidence

Incidence of CRS (%)

100

No SUD

1 SUD

Arm B

Arm A

Arm C

30%

27%

1 SUD

+ Prophylactic tocilizumaba

Grade 1 Grade 2

57% 12

N=42

N=23

N=60

n=16

Etentamig’s safety profile can overcome bispecific antibody implementation barriers and improve accessibility across treatment settings Prophylactic tocilizumab given per investigator discretion. CRS, cytokine release syndrome; dex, dexamethasone; mod, modified; SUD, step-up dose.

Arm A data cutoff: July 12, 2024; Arm B data cutoff: March 31, 2026; Arm C data cutoff: March 31, 2026.

Several Trispecific Antibodies are being developed Ramantamig BCMAxGPRC5DxCD3

ISB2001 BCMAxCD38xCD3

MBS314 BCMAxGPRC5DxCD3

IBI3003 BCMAxGPRC5DxCD3

• Potential Advantages of Trispecifics • More “specificity” to myeloma cells • Overcome resistance of one target • Reduced dosing of each drug so less side effects

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The Evolution of Myeloma Therapy

Now

VD Rev/Dex CyBorD VTD VRD KRD D-VMP DRD

ASCT Tandem ASCT (?)

Front line treatment

Induction

New

D-VRD Isa-VRD D-KRD Isa-VRD

Consolidation

“More” induction?

Nothing Thalidomide? Bortezomib Ixazomib Lenalidomide Combinations

Maintenance

Relapsed

Post Consolidation

Rescue

Daratumumab? Carfilzomib? Lenalidomide + PI

Novel *CAR Ts – Anito-cel, AZD0120, in vivo, allo *Bispecifics – cevostamab, etentamig *Tri-specifics...

* These agents are currently off the market but available through special programs

Mezigdomide Sonrotoclax Venetoclax KLN-1010 PD/PDL-1 Inhibition? Small Molecules

AUDIENCE Q & A

Workshop Video Replay & Slides

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Thank you to our Sponsors!

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