Five Steps for Integrating BCMA Bispecific Innovations: From Clinical Data to Clinical Practice in RRMM

Co-Chairs, Prof. Mohamad Mohty, MD, PhD, and Caitlin Costello, MD, discuss refractory multiple myeloma in this CME/CPD activity titled “Five Steps for Integrating BCMA Bispecific Innovations: From Clinical Data to Clinical Practice in RRMM.” For the full presentation, downloadable Practice Aids, and complete CME/CPD information, and to apply for credit, please visit us at https://bit.ly/3UFL0dt. CME/CPD credit will be available until 5 June 2025.

1. Five Steps for Integrating BCMA

Bispecific Innovations
From Clinical Data to Clinical Practice in RRMM

Prof. Mohamad Mohty, MD, PhD Caitlin Costello, MD
Professor of Haematology UC San Diego Health

Moores Cancer Center
La Jolla, California

Haematology and Cellular Therapy Department
Saint-Antoine Hospital

Sorbonne University

Paris, France

Go online to access full CME/CPD information, including faculty disclosures.

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2. “Step 1”: Approved BCMA x
CD3 Bispecifics Represent

Unique Immunotherapy
Options in RRMM1

3. “Step 1”: Approved BCMA x CD3 Bispecifics
Represent Unique Immunotherapy Options in RRMM12

Teclistamab binds to CD3 on „aaa: cir
T cells and BCMA on plasma cells bispecific targeting BCMA and CD3
Myeloma cell death
recita
tr

1603 etes
Tumour cell
King

1. Nooka A et al. ASCO 2022. Abstract 8007, 2. Jakubowiak AJ etal. ASCO 2022, Abstract 8014. 3. Char A et al N Engl J Med. 2022:387:2232-2244, PeerView.com

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4. Regulatory Status of Selected Bispecific Antibodies
For Multiple Myeloma in the US and EU'*

Teclistamab
BCMA x CD3

Elranatamab
BCMA x CD3
Talquetamab
GPRC5D x CD3

Linvoseltamab
BCMA x CD3

Approved in RRMM after 23 lines
Approved in RRMM after 24 lines of prior therapy, including an IMiD,
of prior therapy, including an IMiD, a Pl, and an anti-CD38 antibody
a Pl, and an anti-CD38 antibody and demonstrated disease
progression on the last therapy

FDA priority review for patients with EMA filing acceptance for RRMM
RRMM who have received 23 lines

of prior therapy

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5. Talvey (alquotamab-igvs) Presenting information. tps ww accessdata da govidrugsatiéa docs/abel2023/761342s0000 pa. —

6. Talvey (talquetamab) Prescribing Information. https /hwww.ema. europa. eu/en/documents/overvewtalvey-opar-medicine-overven_en.pdl. PeerView.com

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5. Despite Progress, in the EU ‘Standard’
Options are Re-Used in Later-Line Care!

RW data collected from 2,179 patients Data analysed were collected from five European countries
with MM treated in the EU during 2021 (EUS: France, Germany, Italy, Spain, and the UK)
3L (n = 637) AL (n = 555)

Limited use of
BCMA options

+ Retreatment with the same treatment class was common (range for IMiDs and Pls: 51%-57%)
+ Overall, across all LOT, the agents that patients were most frequently retreated with were
bortezomib (24%) and lenalidomide (17%)

1. Marinez-Lopez etal. Future Oncol. 2023 Oct.10(31) 2103-2121. PeerView.com

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6. Despite Progress, Triple-Exposed Patients
Still Require Better Treatment Options

Tri-exposed (n = 547)
As LOT increased, triple-exposed patients had

increasingly limited therapy options!

Compared with patients who were non-triple-
exposed, triple-exposed individuals experienced
significantly worse

+ Symptomatic disease burden
+ Impairment
+ HRQOL

1. Martinez-Lopez etal. Future Oncol. 2023 Oct:19(31)2109-2121. PeerView.com

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7. Our Goals for Today

Augment your knowledge of latest efficacy and safety data,
including unique AE profiles, with BCMA bispecific antibodies
in RRMM

Equip you with the skills you need to develop treatment
plans that integrate BCMA bispecifics into RRMM care

Provide you with guidance on how to address practical
aspects of care when using BCMA bispecifics, such as step-
up dosing, toxicity management, and transition from inpatient
to outpatient care

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8. “Step 2”: Recapping
the Evidence with

BCMA x CD3
Bispecifics In MM

9. Opening Case: A Patient With TCR MM
Requiring Immediate Therapy

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1q21 amplification (2 extra copies), +11, del(13q)
Treatment history

+ D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years
(patient did not wish to receive maintenance with dara)

+ D-Pd: best response PR; DOR = 11 months

+ KCd: best response PR; DOR = 4.5 months and aggressive relapse

Options for this patient include BCMA bispecific antibodies—what is the evidence
supporting this choice?

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10. What Is the Efficacy Evidence With Teclistamab in RRMM?

Results from the MajesTEC- trial led to the ORR in patients with no prior
approval of teclistamab 80 BCMA therapy: 63%

Take-homes after the 22-month follow-up
from MajesTEC-1
(N = 165 patients with RRMM)!

ORR 63% (no prior BCMA)
ORR 59% in BCMA exposed?

Responses deepened over time

Overall median PFS: 11.3 months
Median OS was 21.9 months =PR =VGPR "CR msCR

1. Van de Donk N ot a. ASCO 2023. Abstract 8011. 2. Touzeau C etal. ASCO 2022, Abstract 8013. PeerView.com

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11. MagnetisMM-3 Showed Elranatamab
Was Highly Active in Patients With RRMM

SC administration of 109
elranatamab in RRMM 90
(N = 123; cohort A, 80
BCMA-naive patients)! 70
+ Median number of prior
regimens was 5;

ORR: 61% (95% Cl, 51.8-69.6)

91% were TCR

Patients, %

ORR: 61% 30 2VGPR: 56.1
MRD negativity of 10°° 20
was achieved by 90.9% 10
of evaluable patients 0
n=123
=PR BVGPR =CR msCR
1.Lesokhin A et a. Nat Mod. 2023; 29:2259-2267, PeerView.com

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12. Longer Follow-Up From MagnetisMM-3
Confirms Efficacy of Elranatamab in RRMM

> i

> i
After a median follow-up => ee
of 15.9 months! q E ! 68.8% (95% Cl, 56.5-78.2)
Confirmed ORR was 61% Ë > !
>CR in 37.4% of patients — IA AA
Median PFS 17.2 mos mem

Median OS: 21.9

*
(95% Cl, 13.4-NE) 3
3
— OS not mature because 3
>50% of patients are “a
y 10 | Median PFS: 172 mo (95% Cl, 98-NE)
still censored DEEE SE USE E SE E E E
Time, mo
No 12 78 67 Tk
1. Tomasson M et al ASH 2023. Abstract 3385. PeerView.com

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13. Other BCMA x CD3 Bispeci

s in Development?

Dosing Current Status/Comment

+ In LINKER-MM1, ORR of 69.2%
IV QW through week 14, then once every 2 + Median PFS not reached
Linvoseltamab' weeks; response-adapted dosing from cycle 6. | \NKER-MM3 testing linvoseltamab
(week 24) onwards if 2VGPR (200-mg cohort)” versus EPdin RRMM (NCT05730036)

Q3wiv + ORR of 60-65% at 40 mg Q3W, 60 mg

ABBV-383? Q4W IV Q3W, and 60 mg Q4W

+ ORR of 50% across dosing levels
Alnuctamab? SC: D1, 4, 8, 15, and 22 of C1; QW in C2-C3; + high antitumour activity was observed at

(CC93269) Q2W in C4-C6; and Q4W in C7 and beyond doses 230 mg and specifically at the 30-
mg dose
1. Jagannath S etal, ASH 2023. Abstract 4746. 2. Vj R et al. ASH 2023. Abstract 3378, 3. Barr Net al, ASH 2023. Abstract 2011. PeerView.com

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14. “Step 3”: Other Factors
Informing Use of

Bispecific Antibodies

15. Case Revisited: Other Factors to Help Choose Therapy

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1q21 amplification (2 extra copies), +11, del(13q)
Treatment history

D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years
(patient did not wish to receive maintenance with dara)

D-Pd: best response PR; DOR = 11 months

KCd: best response PR; DOR = 4.5 months and aggressive relapse

Discussion
+ What other factors might help support the use of bispecifics?

+ Would the presence of kidney failure, EMD, or prior exposure to BCMA-targeted
therapy influence this choice?
+ What is the role of sBCMA in informing treatment decisions?

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16. Case Revisited: Other Factors to Help Choose Therapy

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1q21 amplification (2 extra copies), +11, del(13q)
Treatment history

D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years
(patient did not wish to receive maintenance with dara)

D-Pd: best response PR; DOR = 11 months

KCd: best response PR; DOR = 4.5 months and aggressive relapse

Recap
+ Kidney dysfunction may not be a contraindication to bispecifics; evaluate patients
carefully when making treatment decisions

+ EMD is challenging to treat, often regardless of treatment
+ BCMA bispecifics can be options in BCMA-naive or exposed individuals

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17. Principles for Choosing Between Bispecifics and CAR-T

Candidates for BCMA bispecifics can include

Patients with RRMM progressing after 3-5 prior LOT who are unable to
access CAR-T or at high-risk of manufacturing failure

Patients with rapidly progressing or aggressive disease who are unable to
wait for CAR-T

Patients failing treatment with CAR-T

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18. High Disease Burden and EMD Associated
With Lower Responses to BsAb!

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1. Moreau P et al. N Engl J Med. 2022:387:495-505. PeerView.com

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19. BCMA Bispecifics Retain Activity in Patients
Exposed to Prior BCMA Treatment Platforms

Pooled Analysis of Elranatamab MagnetisMM-1, -2, -3, -91

80) PR nVGPR asCR "CR

Median PFS: 5.5 months
+ Prior ADC PFS: 3.9 months
+ Prior CAR-T PFS: 10 months

Patients, %

Median DOR: 17.1 months
+ Prior ADC DOR: 13.6 months
+ Prior CAR-T DOR: NE

ADC Exposed CART Exposed _ Any Prior
(n= 59) (n= 36) ‘BCMA Therapy
(n=87)

Results support treatment in patients with RRMM post BCMA-directed therapy

1.Nocka A et al, ASCO 2023. Abstract 8008. PeerView.com

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20. “Step 4”: Bispecific
Antibody Dosing &

Administration

21. Case Continued:
Starting on Bispecific Antibody Therapy

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1q21 amplification (2 extra copies), +11, del(13q)
Treatment history
D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years on

(patient did not wish to receive maintenance with dara)

D-Pd: best response PR; DOR = 11 months

KCd: best response PR; DOR = 4.5 months and aggressive relapse (CAR-T has not been
planned)

BCMA x CD3 bispecific antibody recommended

Discussion
+ Assuming Charlotte initiates treatment with elranatamab, what should be
communicated regarding step-up dosing and the hospitalisation period?

+ What about subsequent dosing (including transition to biweekly dosing)?

+ What are the expected benefits when attempting to modify the schedule?
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22. Case Continued:
Starting on Bispecific Antibody Therapy

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1q21 amplification (2 extra copies), +11, del(13q)

Treatment history
D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years (er

(patient did not wish to receive maintenance with dara)

D-Pd: best response PR; DOR = 11 months =
KCd: best response PR; DOR = 4.5 months and aggressive relapse (CAR-T has not been
planned)

BCMA x CD3 bispecific antibody recommended

Recap
+ Work with healthcare team to prepare patients for step-up and hospitalization period

+ Partner with nurses, pharmacists, and hospital staff to ensure adequate training
+ Counsel patients and caregivers on acute and longer-term safety considerations

+ Provide education on step-up dosing and subsequent changes in dosing frequency
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23. BCMA Bispecifics: Understanding Step-Up
and Subsequent Dosing for Elranatamab'?

Dosing Schedule Day Dose

Step-up dosing il Step-up dose 1 12 mg
schedule 4 Step-up dose 2 32 mg
(48-hour

hospitalization after

first step-up dose; 8 First treatment dose 76 mg

24-hour after second
step-up dose)

1 week after first

Weekly dosing treatment dose and Subsequent 76m
schedule weekly thereafter treatment doses 9
through week 24
Biweekly dosing Week 25 and every 2 Subsequent 76m
schedule weeks thereafter treatment doses 9
1. texto (otanatamab-temen) PresctngIformaton, Nips: accossdataóagovirgsatión docafabeV2029/761345004 30000 pa. ‘
2. Elexfo (olranatamab) Prescribing Information. https /www.ema.europa.eulen/documents/overviewlerexfo-epar.medicine-overview_en pd. PeerView.com

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24. BCMA Bispecifics: Understanding Step-Up
and Subsequent Dosing for Teclistamab‘?

Dosing Schedule Day Dose

Step-up 1 Step-up dose 1 0.06 mg/kg
dosing schedule 4 Step-up dose 2 0.3 mg/kg
(48-hour

hospitalization after U First treatment dose 1.5 mg/kg

each step-up dose)

1 week after first
treatment dose and
weekly thereafter
For patients with RRMM who have achieved
and maintained 2CR for a minimum of 6 months:
Reduce dosing to 1.5 mg/kg every 2 weeks

Weekly
dosing schedule

Subsequent treatment 1.5 mg/kg
doses once weekly

Biweekly
dosing schedule

Step-up doses may be administered between 2 to 4 days after the previous dose and may be given up to
7 days after the previous dose to allow for resolution of any adverse reactions

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25. “Step 5”: Prevention,
Planning, and

Practicalities of Safety
Management

26. Case Continued: Principles of Safety Management

Charlotte presents with high-risk RRMM; she is now 77 years old, with a PS of 2
+ 1921 amplification (2 extra copies), +11, del(13q)

Treatment history

+ D-Rd (no ASCT) then R maintenance; VGPR; DOR = 3 years

(patient did not wish to receive maintenance with dara)
+ D-Pd: best response PR; DOR = 11 months

+ KCd: best response PR; DOR = 4.5 months and aggressive relapse (CAR-T has not been
planned)

+ BCMA x CD3 bispecific antibody recommended

Discussion

+ Again, assuming Charlotte initiates treatment with elranatamab, what principles should
inform infection prevention?

+ How would these differ or remain the same with teclistamab?

+ What has been the clinical experience with CRS and ICANS with bispecific antibodies?
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27. Summarising the Safety Experience
With Approved BCMA Bispecifics

Elranatamab AEs of Interest? Teclistamab AEs of Interests

Infections
+ All grade: 70%
+ Grade 3/4: 47%

Infections
+ All grade: 78%
+ Grade 3/4: 52%

CRS

+ All grade: 57.7%

+ No grade 3/4 CRS

+ 90.6% of CRS events occurred
with the step-up doses

CRS

+ All grade: 72

+ Only 0.6% of CRS were grade 3
+ No grade 4/5 CRS events

ICANS was reported in 4.9% of
patients

ICANS was reported in 3% of patients

1. Lesokhin A et al. Nat Med. 2023;29:2250-2267. 2. Tomasson M etal. ASH 2023. Abstract 3385. 3. Van do Donk N et al. ASCO 2023. Abstract 801.

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28. Summary Points for Infection
Management With Bispecific Antibodies

a Ensure preventive protocols are in place

a PJP prophylaxis (eg, TMP/SMX, pentamidine)

a HSV/VZV viral prophylaxis
a IVIG supplementation

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29. Take-Homes on BCMA Bispecifics in RRMM

Bispecific antibodies as monotherapy are efficacious in patients with RRMM,
including with prior exposure to BCMA-directed therapy (ADC and/or CAR-T)
- Early, deep, and durable responses

Overall management strategy may help mitigate CRS and ICANS: events are
mostly low grade and infrequent

Vigilant monitoring, prophylaxis, and treatment can help mitigate risk of
infections

Current data support the use of bispecifics as a treatment option for pts with
triple-exposed/refractory RRMM

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