A Promising Future for Treating Multiple Myeloma with Bispecific Antibodies by International Myeloma Foundation

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Through this virtual seminar, you will learn more and gain a better understanding of the following: What is Immunotherapy? What are monoclonal antibodies? What is CAR T-cell therapy? What are Bispecific Antibodies and how do they work? Are there different types of Bi-specifics? How are bi-specific therapies administered? What are the advantages of bi-specific therapies? What are the side effects of bi-specifics and how are side effects managed? Can they be administered in combination? Where in the treatment paradigm will they be used?

Thomas Martin, MD Professor, UCSF Co-Director, Myeloma Program -

Living Well with Myeloma A Focus on Bispecific Antibodies

Improved OS with Novel Therapies 5 classes of Drugs

Courtesy of Shaji Kumar; adapted from Kumar S. Leukemia (2014) 28, 1122–1128.

Proteasome Inhibitors Bortezomib, Ixazomib Carfilzomib Immunomodulatory Drugs Lenalidomide Pomalidomide Alkylator therapy Melphalan Cyclophosphamide Corticosteroids Dexamethasone Methylprednisolone Monoclonal antibodies Daratumumab Isatuximab Elotuzumab

Treatment Paradigm for Multiple Myeloma NDMM Symptomatic

M Protein (g/L)

100

SMM

EARLY RELAPSE

QUADS +CARS +TCE?

Induction (QUAD)

2. RELAPSE

*Single agent Dara - ORR =31% *Single agent Pom - ORR = 25%

1. RELAPSE

Triple Class Refractory

Penta-refractory

Maintenance (TCE)

7-10 years

>3rd-line therapy

1st-3rd-line therapy

Transplant or CAR

Survival: MRD (-)

REFRACTORY RELAPSE

3-5 years

1-2 years

MRD (-)  should OS be our late read-out???

Competitive Landscape for Triple Class Refractory - Multiple

new drugs and new drug classes - “Cure” – is the GOAL!!!

“Novel Immunotherapy”

CELMoDs/ Novel Drugs

Novel Monoclonal Antibodies

Iberdomide (CC-220), CC-94480 Selinexor

BCMA ADCs

BCMA Bispecifics

Cellular Therapies BCMA CARs

SAR442085 Hexabody-CD38 TAK-079

Belantamab mafodotin

Teclistamab AMG-701 CC-93269 Elranatamab

Idecabtagene vicleucel (bb2121) Ciltacabtagene-autoleucel (JNJ-4528)

Venetoclax

TAK-573 AMG-424 GBR-1343

MEDI2228 CC-99712

TNB-3838, PF-06863135, REGN5458,

P-BCMA-101 bb21217 NexT-CAR (JCARH125)

Melphalan flufenamide

Immune – Toxin TAK-169

Non-BCMA STRO-01 FOR46

Non-BCMA Cevostamab Talquetamab

CT053 BCMA-101 ALLO-715

How will we cure multiple myeloma  Full Team Effort Army (monocytes)

Naked Abs

Navy (NK cells)

Bispecific/Trispecific Abs CD38

Marines (T cells)

Cellular Therapies CART

Harnessing the Immune System to Fight Cancer Types of Immunotherapy, Immuno-Oncology Active

Passive Chimeric antigen receptor (CAR) T cells

Monoclonal antibodies Direct effects

1. Extract WBCs from patient

Monoclonal antibody

Vaccines (therapeutic not preventive)

Gene transfer

2. Modify and expand cells in lab

Antigen

ADCC CDC

Myeloma cell

Fc receptor

C1q MAC

Lysis

NK cell

Activating antibodies (Antigen specific) Bispecific Abs

CD3.

BCMA

3. Infuse MM-targeted cells back to patient

Cell death

MAC, membrane attack complex; CDC, complement dependent cytotoxicity; ADCC, antibody directed cellular cytotoxicity

T-cell activation Cytokine secretion

Components of CAR T-Cell Therapy MM

CAR Features

Patient selection: Are you eligible?

Cell targets

Patient

Apheresis ±cryopreservation

Binding domain(s) Transmembrane domain

Vein

Lymphodepleting therapy

Vein

3-5 weeks

CAR T-cell infusion Clinical management

CAR T-cell

Test Tube Gene transfer T cell expansion

Bridging therapy

Signaling Domain -4-1BB, CD28 -CD3z

 RRMM 4 prior lines of therapy  ECOG performance status 0/1, adequate marrow fxn  Adequate cardiopulmonary and organ function

Manufacture CAR T-cells Release testing

CRS Neurotox Cytopenias

BCMA in Multiple Myeloma ▶ ▶ ▶

CARs ADCs Bispecifics

• May overcome exhaustion

Viral vector

CAR T-Cell Signaling domain

scFv

– Local T-cell • Activation • Non-MHC dependent

Bispecific T-Cell Engagers

CAR T-Cells

BCMA

MM cell death Cytotoxic payload released into cell

BCMA

Antibody–Drug Conjugates Cho. Front Immunol. 2018;10:1821.

Bispecific Antibodies

Bispecific Abs – Many Different Types Differences in binding - Target antigen - Immune cell

Bispecific T-cell Engager or BiTE (Amgen)

Dual Affinity ReTargeting or DART (Janssen, Macrogenics)

Tandem diabodies or TandAb (Affimed)

Best current example

BsAb armed activated T-cells or BAT (mostly academic)

- BCMA (on MM) - CD3 (on T-cell) T-cell dependent BsAb Xmab (Xencor, Glenmark, Amgen)

CrossMAb (Celgene, Roche)

Duobody (Genmab) Trifunctional Antibody or TriFAb

Adapted from Lejeune M et al. Front Immunol 2020 11:762.

Bispecifics Antibodies – differences are important ▶ ▶

# Binding domains to BCMA (and other Ags) and strength of binding Strength of binding to CD3 and T cell activation – These may have direct consequences to • Response • Toxicity – CRS – Infection – Organ toxicity (skin and taste: GPRC5D)

▶ ▶

Mode and frequency of administration FDA likely to require prolonged monitoring (hospital stay) for initial tmt

F.V. Suurs et al. Pharmacology & Therapeutics 201 (2019) 103–119, Beulow B, et al. ASCO 2017.

Immune therapy in Relapsed/ Refractory Myeloma: Bispecific Antibodies & Side Effects Donna Catamero, ANP-BC, OCN, CCRC Associate Director, Multiple Myeloma Clinical Research Program Icahn of School Medicine at Mount Sinai

Novel Ways to Direct T-cells Toward Myeloma Cells

Bispecifics: The Future is Here • So many of them (at least 10 in clinical trials) – Targets: • BCMA: Teclistamab, Elranatamab, REGN5758, ABBV-383, AMG701 (pavurutumab) • GPRC5D: Talquetamab • FcRh5: Cevostamab •

Each target = potential for unique side effects

One thing in common … Teclistamab Ph 1/2, n=165

Elranatamab Ph 1, n=65

REGN5458 Ph 1, n=73

Pavurutumab Ph 1, n=75

Talquetamab Ph 1, n=102

Cevostamab Ph 1/2, n=160

Target/ Unique Features

BCMA x CD3

GPRC5D x CD3

FcRH5 x CD3

Dosing Schedule

RP2D: SQ 1.5 mg/kg weekly

215-1000 ug/kg RP2D: SQ 1 mg/kg or 76 mg weekly

QWQ2W IV: 3–400 mg

QW IV: 5 μg–12 mg

SQ 405 ug/kg QW (n=30) SQ 800 ug/kg Q2W (n=25)

Q3W IV (0.15-198 mg)

CRS all (grade 3+), %

71.5% (0.6%)

87% (0%)

38% (0%)

61% (7%)

72–77% (0–3%)

81% (1%)

Neurotox all grades (grade 3+), %

3% (0%)

N/A

4% (0%)

8% (0%)

N/A

14% (0.6%)

Unique Toxicities

Injection reactions Infections (63%)

Neuropathy?

Skin/nail 𝛥𝛥s (75%) Dysgeusia (49%)

Cytokine Release Syndrome (CRS) with Bispecifics Severity is Typically Mild: Early Recognition and Treatment is Key Tremors Difficulty RESPIRATORY

HEPATIC

breathing Shortness of Breath Altered Liver Function tests in the blood

NEUROLOGIC

CARDIOVASCULAR

↑ Serum creatinine Renal insufficiency

GASTROINTESTINAL

HEMATOLOGIC

Anemia Thrombocytopenia Neutropenia

MUSCULOSKELETAL

CONSTITUTIONAL

Fever Fatigue Headache

RENAL

Altered wakefulness Difficulty speaking Rapid heart rate Low blood pressure Arrhythmias Nausea Vomiting Diarrhea Weakness

Mitigation & Monitoring for CRS

• Step up dosing with hospitalization for monitoring • Frequent vital signs • Rule out infection • Laboratory monitoring • Early intervention with Tocilizumab

ALP = alkaline phosphatase; CPK = creatine phosphokinase; CRP = C-reactive protein; CRS = cytokine release syndrome; LDH = lactate dehydrogenase; O2 = oxygen; TLS = tumor lysis syndrome.

Oluwole OO, Davila ML. J Leukoc Biol. 2016;100:1265-1272. June CH, et al. Science. 2018;359:1361-1365. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330. Brudno JN, Kochenderfer JN. Blood Rev. 2019:34:4555. Shimabukuro-Vornhagen, et al. J Immunother Cancer. 2018;6:56. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.

Neurotoxicity Teclistamab Ph 1/2, n=165

Elranatamab Ph 1, n=65

REGN5458 Ph 1, n=73

Pavurutumab Ph 1, n=75

Talquetamab Ph 1, n=102

Cevostamab Ph 1/2, n=160

Target/ Unique Features

BCMA x CD3

GPRC5D x CD3

FcRH5 x CD3

Dosing Schedule

RP2D: SQ 1.5 mg/kg weekly

215-1000 ug/kg RP2D: SQ 1 mg/kg or 76 mg weekly

QWQ2W IV: 3–400 mg

QW IV: 5 μg–12 mg

SQ 405 ug/kg QW (n=30) SQ 800 ug/kg Q2W (n=25)

Q3W IV (0.15-198 mg)

CRS all (grade 3+), %

71.5% (0.6%)

87% (0%)

38% (0%)

61% (7%)

72–77% (0–3%)

81% (1%)

Neurotox all grades (grade 3+), %

3% (0%)

N/A

4% (0%)

8% (0%)

N/A

14% (0.6%)

Unique Toxicities

Injection reactions Infections (63%)

Neuropathy?

Skin/nail 𝛥𝛥s (75%) Dysgeusia (49%)

Neurotoxicity is Rare & Most Cases are Mild Difficulty staying awake/walking Difficulty/inability to speak

Caregivers are Important!

Shaking movement Loss of coordination

Neurotoxicity

The majority of neurological toxicities exhibited in clinical trials have been reversible

Delirium Headaches Confusion

May be in the presence of CRS

BCMA Bispecific Antibodies Infections Bispecific Antibody

AMG-701

CC-93269

Elrantamab

REGN5458

Teclistamab

TNB-383B

Treatment

Weekly IV

Weekly SC

Weekly IV

Weekly SC

IV q3w

26% all patients

10/12 (83%)

9/13 (69%)

22/37 (75%)

93/150 (62%)

60% in > 40

5/6 (83%) most recent cohort

≥ 6mg IV

1000 μg/kg SC

200-800 mg IV

1500ug/kg SC (RP2D)

40-60 mg IV

17/21 (81%) ongoing at median 5.6 months

90% @ median 8 months

91% > 6 mos

64% (9%) (17%) 25% 42% 21% 4 (5%) Neurotoxicity 8% (0%)

90% (5%) NR (26%) NR (53%) NR (42%) NR (21%) 1 (5%)

87% (0%) NR 71% (67%) 32% (23%) 21% (13%) 5 (7%) ISR 56% (0%)

38% (0%) NR 23% (22%) 32% (23%) 21% (13%) 5 (7%)

72% (1%) 63% (35%) 66% (57%) 49% (35%) 38% (22%) 9, 7 COVID ISR 35% (0%) Hypogamma 72%

54% (3%) 32% (17%) 27% ( 22%) 25% (14%) 22% (11%) 6, 3 COVID

ORR @ therapeutic dose

Duration of Response AEs, (All/(Gr 3+) CRS Infections Neutropenia Anemia Thrombocytopenia Deaths Other

Harrison, et al. ASH 2020; Costa, et al. ASH 2019; . Sebag M, et al. ASH 2021; Zonder et al ASH 2021; Moreau P, et al. ASH 2021;. Kumar S, et al. ASH 2021

BCMA Targeted Therapies are Associated with an Increased Risk of Infections ▶

Both viral and bacterial

– Up to a 3rd of patients on clinical trials has serious infections (requiring IV antibodies or hospitalization) ▶

Increased risk of serious COVID complications despite history of vaccination

– Antibody levels – Tixagevimab co-packaged with cilgavimab (EVUSHELD) – Immediate treatment once diagnosed Nirmatrelvir with Ritonavi (Paxlovid) • Start as soon as possible; must begin within 5 days of when symptoms start

Infection Prevention • Avoid crowds • Ensure handwashing, hygiene • Growth factor (eg, filgrastim) • IVIG for hypogammaglobulinemia • Know your healthy IgG level

• Immunizations (No live vaccines)

– COVID-19 vaccination + booster(s) – Pneumococcal 20-valent conjugate vaccine – Seasonal inactivated influenza vaccine (×2 or high-dose) – Shingles vaccine: zoster vaccine recombinant, adjuvanted

• COVID-19 prevention

– Antibody levels – Tixagevimab co-packaged with cilgavimab

Prevention: Avoid being exposed to the covid virus Virus spreads from person-to-person through respiratory droplets –

Not infected (Exposed)

–

Respiratory droplets are from coughs, sneezes, talking of an infected person beginning ~2-14 days post exposure More droplets with louder talking, yelling, singing

–

Virus does not live long on surfaces

Close contact (within 6 feet) and indoors increases risk of spread

▶

–

Airflow, ventilation matters

–

~25X less transmission outdoors vs indoors

▶

High quality masks provide a physical barrier that prevents airborne viral spread

–

Especially important for people at increased risk

–

Important in situations where distancing is not possible

COVID Images: CDC CDC = Centers for Disease Control; MIT = Massachusetts Institute of Technology MIT Medical website. COVID-19 Updates. How safe are outdoor activities? Accessed January 30, 2022. https://medical.mit.edu/covid-19-updates/2021/08/how-safe-outdoor-activities CDC website. Types of Masks and Respirators. Accessed January 30,2022, 2020.. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/types-of-masks.html CDC website. Your Guide to Masks. Accessed January 30, 2022. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/about-face-coverings.html

Infected

CDC Now Recommends

N95

KN95

Surgical

Cloth

This Photo by Unknown Author is licensed under CC BY

CDC website. Types of Masks and Respirators. Accessed January 30,2022, 2020.. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/types-of-masks.html CDC website. Your Guide to Masks. Accessed January 30,2022, 2020.. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/about-face-coverings.html This Photo by Unknown Author is licensed under CC BY

Time to Infectious Dose for Someone Not Infected with COVID-19

COVID Image: CDC

Person Infected Is Wearing COVID Images: CDC

Nothing

Cloth Mask

Surgical Mask

(10% leakage)

<15 min*

20 min

30 min

2.5 hrs

Cloth Mask

20 min

27 min

40 min

3.3

Surgical Mask

30 min

40 min

60 min

hrs

N95 Mask

2.5 hrs

3.3

Nothing

Person Not Infected Is Wearing

N95 Mask

(10% leakage)

hrs

*New research shows that 9.8 feet (3 meters) of social distancing are not enough to ensure protection from Covid-19. Even at that distance, it takes less than five minutes for an unvaccinated person standing in the breath of a person with Covid-19 to become infected with almost 100% certainty. ACGIH website. COVID-19 Fact Sheet: Workers Need Respirators. Accessed January 30, 2022. https://www.acgih.org/covid-19-fact-sheet-worker-resp/ Cornell University website. Cornell Chronicle: Better-fitting masks offer better COVID protection. Accessed January 30, 2022. https://news.cornell.edu/stories/2021/12/better-fitting-masks-offer-better-covid-protection

Low blood counts Bispecific Antibody

AMG-701

Elrantamab

REGN5458

Teclistamab

Cevostamab[

Treatment

Weekly IV

Weekly SC

Weekly IV

Weekly SC

IV q3w

n= 85

n=55

n=73

n= 165

33%

62%

50%; 22% prior BCMA-directed

19%

78%

85%

64% (9%) (17%) 25% 42% 21% 4 (5%) Neurotoxicity 8% (0%)

87% (0%) NR 71% (67%) 32% (23%) 21% (13%) 5 (7%) ISR 56% (0%)

38% (0%) NR 23% (22%) 32% (23%) 21% (13%) 5 (7%)

72% (1%) 63% (35%) 66% (57%) 49% (35%) 38% (22%) 9, 7 COVID ISR 35% (0%) Hypogamma 72%

80% (2%) 43% (19%) 18% (16%) 32% (22%) % not reported 6 (3.7%)

Patients Median prior lines Triple-class refractory AEs, (All/(Gr 3+) CRS Infections Neutropenia Anemia Thrombocytopenia Deaths Other

Harrison, et al. ASH 2020; Costa, et al. ASH 2019; . Sebag M, et al. ASH 2021; Zonder et al ASH 2021; Moreau P, et al. ASH 2021;. Kumar S, et al. ASH 2021

Low Blood Counts

▶ ▶ ▶ ▶ ▶

Decreased White Blood Cells, Hemoglobin, & Platelets More common in the first few cycles Need for growth factor support Can be seen regardless of how a patient is responding to therapy May be caused by a release of cytokine release

Skin Toxicities

Injection Site Reactions – Reported in ~25% of patients • Typically, in first cycle – Treated with topical steroids and oral antihistamine ▶

Skin Toxicities (Associated with Talquetamab – GPRC5D)

▶

Peeling, thin nails that lift from nail bed

▶

Palmar Plantar Desquamation

• Recommend an OTC nail hardener – Usually painless and presents in first cycle • Topical triamcinolone ointment if inflamed • Treated with ammonium lactate (Lac-Hydrin • Topical vitamin E oil and moisturized cuticles may lotion) be helpful 33

Oral Toxicities (Associated with Talquetamab – GPRC5D) ▶ ▶ ▶

Altered taste

Managed with

Dry mouth

 saliva substitute sprays and rinses

Difficulty swallowing

 dose adjustments

– May lead to weight loss

Conclusions •

T cell redirection therapies are generating unprecedented response rates and bispecifics with wide therapeutic index

•

With novel therapies comes unique potential side effects

•

CRS is common and is mitigated with step dosing and prompt intervention

•

Anti BCMA bispecifics have are associated with an increased risk of infection

•

Lack of COVID vaccine response and COVID deaths warrants vaccination prior to start and reinforcement of prophylaxis therapy and prompt treatment for active infection

•

Talquetamab novel agent, lack of infection - oral/skin supportive care cocktail

•

Cevostamab novel agent encouraging, minimal non heme toxicity, ? COVID/infection

Thomas Martin, MD Professor, UCSF Co-Director, Myeloma Program

Bispecific Antibodies

So how active are these agents? Where will these be used in the future?

Teclistamab: Mechanism of Action  Prognosis is poor for patients who progress on available classes of therapies, with ORR ~30%, mPFS of ~3 mo, and mOS between 6 and 11 mo1  Teclistamab (JNJ-64007957): a humanized BCMA x CD3 bispecific IgG-4 antibody that redirects CD3+ T-cells to BCMA-expressing MM cells  Teclistamab induces T-cell–mediated killing of MM cells from heavily treated patients and in xenograft models2-4  Currently ongoing phase I study of teclistamab administered IV or SC in patients with R/R MM (NCT03145181)5,6

1. Ghandi. Leukemia 2019;33:2266. 2. Labrijn. PNAS. 2013;110:5145. 3. Frerichs. Clin Cancer Res. 2020;26:2203. 4. Pillarisetti. Blood Adv. 2020;4:4538. 5. Krishnan. ASCO 2021. Abstr 8007. 6. Garfall. ASH 2020. Abstr 180.

+ CD3 T-cell activation Cytokine secretion

BCMA

Teclistamab

Cytotoxic cytokines

CD3

BCMA

MM Cell Death

MajesTEC-1: Phase 2 Study Design • MajesTEC-1 is a first-in-human, phase 1/2, open-label, multicohort, multicenter dose escalation study to evaluate teclistamab in patients with RRMM who previously received ≥3 prior lines of therapy and were triple-class exposed SCREENING Key eligibility criteria • Measurable MM • RRMM, ≥3 PL • Prior PI, IMiD, and anti-CD38 • No prior BCMA therapy

TREATMENT Week 1

• Step-up

doses of teclistamab SC (0.06 mg/kg and 0.3 mg/kg)

POST-TREATMENT

Cycles 1+

• Weekly

treatment dose of Tec SC 1.5 mg/kg • Continue until progressive disease

Follow-up 2 years after LPI

• Primary endpoint: ORR • Key secondary endpoints: DOR, ≥VGPR, ≥CR, sCR, TTR, MRD status, PFS, OS, safety, pharmacokinetics, immunogenicity, PRO

CR = complete response; DOR = duration of response; IMiD = immunomodulatory drug; LPI = last patient in; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PI = proteosome inhibitor; PL = prior line; PRO = patient reported outcome; sCR = stringent CR; TTR = time to response; VGPR = very good partial response. Moreau P et al. Updated results from MajesTEC-1: Phase 1/2 study of teclistamab, a b-cell maturation antigen x CD3 bispecific antibody, in relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021.

NEJM 2022

MajesTEC-1: Overall Response Rate and Duration

Median PFS 11.3 months, Median DOR 18.3 months Moreau et al, NEJM 2022

MajesTEC Trials  Majest-TEC-2: A Multi-arm Phase 1b Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma  Majest-TEC-3: Phase III Study of Teclistamab in Combination With Daratumumab Subcutaneously (SC) (Tec-Dara) Versus Daratumumab SC, Pomalidomide, and Dexamethasone (DPd) or Daratumumab SC, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma  MajesTEC-4: Phase III Study of Teclistamab in Combination With Lenalidomide Versus Lenalidomide Alone in Participants With Newly Diagnosed Multiple Myeloma as Maintenance Therapy Following Autologous Stem Cell Transplantation

ORR=60-70% (BCMA-CD3) Bispecific

ORR=60-70%

Phase I Trial: Talquetamab Mechanism of Action  GPRC5D x CD3 bispecific antibody Cytotoxic cytokines

‒ Orphan GPCR of unknown function with limited expression in healthy human tissue; primarily plasma cells and hair follicles ‒ Highly expressed in MM cells and associated with poor prognostic features in MM

CD3 T-cell activation Cytokine secretion

GPRC5D

MM cell death

‒ No known extracellular shedding + CD3

Berdeja. ASCO 2021. Abstr 8008.

GPRC5D

Talquetamab

Talquetamab in R/R MM: Efficacy ORR 80

Patients (%)

60 40 20 0

VGPR

ORR: 53.3% 18% 6.7% 2.7% 34.7%

≥VGPR: 44%

sCR ORR: 70% 6.7% 3.3%

50.0%

SC Talquetamab (N = 82) 5-800 µg/kg SC RP2D: 405 µg/kg†

 At RP2D of 405 µg/kg SC ̶

≥VGPR: 60%

70.0% ORR (21/30); 60% ≥VGPR ‒ Median time to first confirmed response: 1 mo (range: 0.2-3.8) ‒ Median DoR: not reached; 17 of 21 responders remained on treatment after median follow-up of 6.3 mos (range: 1.4-12.2) ‒ ORR in triple-refractory: 65.2% (15 of 23 patients) ‒ ORR in penta-refractory: 83.3% (5 of 6 patients)

9.3%

10.0%

SC Dosing (n = 75)

RP2D: 405 μg/kg SC (n = 30)

 In IV and SC cohorts, 4 of 6 evaluable patients achieved MRD negativity (at 10-6), including 1 patient at RP2D

Talquetamab had an ORR of 70% with ≥VGPR of 60% at the RP2D (405 μg/kg) dose in heavily pretreated MM patients Berdeja. ASCO 2021. Abstr 8008.

Also be tested at every 2 wk dosing - SC

Summary of Bispecific Antibodies in R/R MM (ASH2021) Drug

Target

Median prior lines, n

Dosing

ORR, %

CRS, %

Neurotoxicity, %

Notes

Teclistamab1 (n = 165 RP2D)

BCMA

5 (2-14) TCR 78%

SC QW for RP2D

62 @ RP2D (25% MRD (-))

71.5 @ RP2D (0.6 grade 3)

12.7 @ RP2D (HA 8.5%, no Gr 3)

SC dosing! EMD had lower ORR

TNB-383B2 (n = 118, 75)

BCMA

5 (1-15)

IV, Q3W

60 @ higher doses (n = 60)

Dose 40 mg: 69% (Gr 3: 4%)

HA 15: ICANS 2

No step-up, Q3W, allowed for CrCl 30

REGN-54583 (n = 73, 24)

BCMA

5 TCR 20%

IV, Q2W

75 @ doses (200-800) (n = 24)

38 (no grade 3)

4 (3 Gr2)

Step-up doses(2), weekly x 16, then Q2W

Pavurutamab/ AMG-7014 (n = 85, 6)

BCMA

6 (2-25)

83 @ most recent doses (n = 6)

64 (9% grade 3)

3.8

Elranatamab5 (n = 30)

BCMA

8 (3-15)

SC weekly

70 @ ≥215 μg/kg

SC dosing!

GPRC5D

6 (2-17)

SC weekly RP2D: 450 μg/kg

69 all SC (70.0 @ 405ug/kg QW and 67% @800 Q2W)

(75 @ RP2D) (2% grade 3 @ RP2D)

SC dosing! 22% of pts had prior BCMA tx Some grade 3 skin rash, oral toxicity, dysgeusia

FcRH5

6 (2-16) TCR 85%, prior BCMA 33.5

IV, Q3W

57, higher doses 61, highest dose (n = 18) 63 in prior BCMA (n = 8)

80 (with 2 step-up) (2.3% grade 3)

DOR=11.5m

Talquetamab6 (n = all SC, 55@RP2D) Cevostamab7 (n = 143, 60)

1. Moreau. ASH 2021. Abstr . 2. Kumar. ASH 2021. Abstr . 3. Zonder. ASH 2021. Abstr 160. 4. Harrison. ASH 2020. Abstr 181. 5. Bahlis. ASCO 2021. Abstr 8006. 6. Krishnan. ASH 2021. Abstr . 7. Trudel. ASH 2021. Abstr 292.

Comparing Options Among BCMA Modalities CAR T-Cell

Bispecific mAbs

ADCs

Treatment logistics

Specialized center, need to wait for production

TBA, likely community practice friendly, Off the shelf, need for long half-life

Community practice friendly, Off the shelf

Length of treatment

~2 mo

Possibly limited cycles

CRS, neurotoxicity, cytopenias

CRS, pneumonia

Corneal, thrombocytopenia

? $400K

? But have to consider length of treatment

$24K/mo

Toxicities Cost

Slide credit: clinicaloptions.com

Quad Induction

(4-6 cycles) Q/Triplet Induction (4-6 cycles)

CAR T-cell (1x 4wk)

Maintenance (+/- TCE)

CAR vs. TCE

NDMM #’s 32,000/yr 12,000/yr

Relapse

SCT ineligible

SCT eligible

ND Myeloma treatment paradigm in 5+ years

Quad Induction followed by continuous therapy (8-12 cycles or more?)

14,000/yr

QUADS

Tumor Burden

CAR/TCE

TCE

VGPR

MRD Goal 80-90% Sustained MRD (-)

6,000/yr

Next Gen CAR/ Trispecific PD

Prediction: Future Strategies in MM (2025-2030) Where and in what combination will immunotherapy have the most Impact? Newly Diagnosed MYELOMA

SMM Bispecific - MRD x 6-12m - STOP

M Protein (g/L)

100

MM SMM

EARLY RELAPSE

Front-line therapy

REFRACTORY RELAPSE

2. RELAPSE 1. RELAPSE

Induction --- QUAD (mAb) Consolidation

Frontline QUAD: No transplant

Symptomatic

Plateau remission

--- CAR vs. Bispecific Maintenance

MRD (+): Consolidation: CAR (TE) vs. Bispecific (TI) MRD (-): Maintenance: Len/mAb vs. Bispecific

2nd-line therapy

3rd-line therapy

Early Relapse (1-3 Prior Lines) Novel CAR (Different Ag) Novel Ab: ADC-combo vs. Bi-/Trivalent Ab

Tom Martin

Late Relapse Third party cellular therapy (NK + T) Crispr strategies Bispecific combinations

Conclusions: Immunotherapy in MM  IT has made a dramatic entry into R/R MM space  TCEs have potent activity and will be used broadly in MM space ‒ ND MM ‒ Replace SCT (CARTITUDE and KarMMA trials) ‒ Consolidation for <adequate response

‒ Early relapse ‒ R/R MM

 Innovation will drive future success ‒ Biomarkers T-cell health ‒ Better combinations: IMiDs, CELMoDs ‒ Best outcome => Limited duration tmt ‒ Final goal => MM CURED!!! Tom Martin

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