Targeted Therapy in Myelomatranslational concepts and clinical

applications

Yael Cohen, MDWorkshop - 5 July 2021

12 novel agents approved for MM in the century

2021

RVD+ASCT+LenalidomideMaintenance

Relapse 1

Relapse 2

Relapse 3

Time: Years!

Dise

ase

Activ

ity

Relapse 1

Relapse 1

Relapse 2

Multiple paces of multiple myeloma

Multiple paces of multiple myeloma

Clonal Evolution in Myeloma

Manier S, Nature Review 2916

7

Blood June 2018Morgan G et al

• 1,273 newly diagnosed patients with multiple myeloma

• identify 63 driver genes

• genomic landscape of myeloma is pre-determined by the primary events upon, which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits

NCCN Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf accessed May 2021

ESMO Giodlines 2021 for MM First Relapse

So…. let’s talk about targeted therapy in MM!

• What’s new – recent targets, from bench to bedside• Daratumumab• Selinexor• Belantamab• BITEs – teclistimab, talquetamab, cevostamab• CART – Ide-Cel, Cilta-Cel• How to overcome escape?

• Single-cell RNA sequencing: a molecular microscope for personalized therapy

DARA Clinical development & access

Phase 1: no option patients ---- monotherapy

RRMM: Pollux and Castor studies (DARA-Rd / DARA-Vd)

Upfront therapy: MAIA, Alcyone, Cassiopeia, Griffin

2016

2018

2022?

ORR: 31.1 %; FFSClinical Benefit Rate (ORR + MR): 37.2%Disease Control Rate: (ORR + MR + SD): 83%

Phase 1 – monotherapy for no option patients

Usmani S, et al. Blood 2016. May 23 [Epub ahead of print].

Survival by Response Category:31%52%17%

Synergy of Daratumumab + Lenalidomide in ADCC

van der Veer MS, et al. Haematologica. 2011;96(2):284-290.

3 µM lenalidomide + daratumumab 0.1 µg/mL

BM-MNC, n = 14

Mixed model analysis comparing observed effect of combination treatment vs expected

proportional effect reveals synergy

17

POLLUX: DRd vs. Rd in RRMM

מחלה שאריתית במיאלומה

Minimal Residual Disease

PR

VGPR

CR

Stringent CR

MRD-Negative

Path towards cure of Myeloma?

Paiva B et al. Blood. 2015;125(20):3059-68.

• Estimated 5-year PFS rate was 52.5% with D-Rd and 28.7% with Rd• Estimated 5-year OS rate was 66.3% with D-Rd and 53.1% with Rd

Target: XPO1

BOSTON study:

Target: BCMA

• BCMA: Antigen expressed specifically on PCs and myeloma cells

• Cell-surface receptor in TNF superfamily

• Higher expression on myeloma cells than normal PCs

• Not expressed in other tissues

• Key role in B-cell maturation and differentiation

• Promotes myeloma cell growth, chemotherapy resistance, immunosuppression in bone marrow microenvironment

• Expression of BCMA increases with progression from MGUS to advanced myeloma

• Additional ligands for BMCA include APRIL and BAFF

BCMAImmunoglobulin

BM LN BM, LN

Pro-B Pre-B Transitional Naive GC-B Memory Plasmablast PC

Short-lived PC

Long-lived PC MMBCMABAFF-R

Cho. Front Immunol. 2018;9:1821. Moreaux. Blood. 2004;103:3148. Sanchez. Br J Haematol. 2012;158:727.

BCMA

sBCMA

APRIL

BAFF

γ-secretase

Cell membrane

Belantamab mafodotinDREAMM-2 trial study design• Belantamab mafodotin

– ADC: Anti-BCMA mAb conjugated to auristatin F through a non-cleavable linker

Lonial S, et al. Lancet Oncol. 2020;21:207-221;https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-

belantamab-mafodotin-blmf-multiple-myeloma FDA.gov

Belantamab mafodotin3.4 mg/kg IV (frozen)

Primary Endpoint:•ORR: % of patients with

≥ PR by IMWG 2016 criteria

Belantamab mafodotin2.5 mg/kg IV (frozen)

Belantamab mafodotin administered once every 3 weeks until disease progression or unacceptable toxicity

Belantamab mafodotin 3.4 mg/kg IV (lyophilized)

R 1:1

SCR

EENI

NG

R/R MM ≥ 3 prior lines of therapy

N = 293

Belantamab mafodotin-blmf (2.5 mg/kg): FDA accelerated approval on August 5, 2020 for R/R MM after ≥ 4 prior therapies, including an anti-CD38 monoclonal antibody, a PI, and an immunomodulatory agent

ADC, antibody-drug conjugate

BITEs

CAR-T

EFFICACY AND SAFETY OF THE BCMA-DIRECTED CAR T-CELL THERAPY, CILTACABTAGENE AUTOLEUCEL, IN PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1–3 PRIOR LINES OF THERAPY: INITIAL RESULTS FROM CARTITUDE-2Mounzer Agha1,*, Adam Cohen2, Deepu Madduri3, Yael C Cohen4, Michel Delforge5, Jens Hillengass6, Hartmut Goldschmidt7, Katja Weisel8, Marc-Steffen Raab9,10, Christoph Scheid11, Jordan M Schecter12, Kevin C De Braganca12, Helen Varsos12, Liwei Wang12, Martin Vogel13, Marlene J Carrasco-Alfonso14, Muhammad Akram14, Xiaoling Wu14, Tonia Nesheiwat14, Hermann Einsele15

1UPMC Hillman Cancer Center, Pittsburgh, PA, USA; 2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 3Mount Sinai Medical Center, New York, NY, USA; 4Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 5Universitaire Ziekenhuizen Leuven, Leuven, Belgium; 6Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; 7University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany; 8University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 9University Hospital Heidelberg, Heidelberg, Germany; 10Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany; 11University of Cologne, Cologne, Germany; 12Janssen R&D, Raritan, NJ, USA; 13Janssen Global Services, LLC, Raritan, NJ, USA; 14Legend Biotech USA, Inc, Piscataway, NJ, USA; 15Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany

An electronic version of the poster can be viewed by scanning the QR code or accessing this link: https://oncologysciencehub.com/EHA2021/cilta-cel/Agha. The QR code is intended to provide scientific

information for individual reference. The PDF should not be altered or reproduced in any way.

CARTITUDE-2: Introduction• Treatment options are limited for patients who have progressive MM after 1–3 lines of

treatment and are refractory to lenalidomide and/or proteasome inhibitors1,2

• A recent study with daratumumab + Pd and Pd group alone in lenalidomide exposed patients (lenalidomide refractory: 80%) reported a reduced risk in disease progression with a median PFS of 12.4 and 6.9 months, respectively3

• There is an unmet need for novel and durable treatment options in this patient population

• Cilta-cel is a CAR T-cell therapy expressing 2 BCMA-targeting, single-domain antibodies designed to confer avidity

• In CARTITUDE-2, a multicohort phase 2 study, cilta-cel is being evaluated in patients with MM in earlier-line settings than in CARTITUDE-14

• Here, we present initial results from patients (n=20) in Cohort A of CARTITUDE-2 who had progressive MM after 1–3 prior lines of therapy and were refractory to lenalidomide (median follow-up: 5.8 months)

VHHVHH

Binding domains

CD3ζ

4-1BB

Cilta-cel AbstractEP972

BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; MM, multiple myeloma; Pd, pomalidomide and dexamethasone; PFS, progression-free survival; VHH, variable heavy chain. 1. Richardson PG, et al. Lancet Oncol 2019;20:781-94. 2. Moreau P, et al. Leukemia 2017;31:115-22. 3. Dimopoulos M, et al. Blood 2020;136(Suppl 1):5-6. 4. CARTITUDE-1 phase 1b/2 efficacy and safety results will be presented at EHA Virtual Congress 2021 (Abstract EP972 available by scanning the QR code on this slide).

Screening(1 to ≤28 days)

ApheresisLymphodepletion

Cy/Flu(Day -5 to -3)

Cilta-cel infusion

(Target: 0.75×106

CAR+ T cells/kg)

Follow-up

T-cell transduction and expansion to manufacture cilta-cel

Cohort A (n=40)Progressive disease after 1−3 lines of MM

therapy and lenalidomide refractory

Cohort B (n=20)Early relapse:

<12 months after frontline therapy or <12 months after ASCT

Cohort C (n=20)RRMM after PI, IMiD, anti-CD38, and BCMA-

targeting therapya

Cohort D (n=20)<CR after ASCT with or without consolidation in

NDMM + len

Cohort E (n=20)NDMM with no prior therapy and high-risk per

ISS stage III criteria

Consolidation

Cohort D+ Len

(2 years)

Cohort E+ Len Dara (2 years)

Cohort ED-VRd

Induction if applicable

Bridging therapy as needed

CARTITUDE-2: Phase 2 Multi-Cohort Study in Various MM Settings

aExcluding prior BCMA-targeting cellular therapy.ASCT, autologous stem cell transplant; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CR, complete response; Cy, cyclophosphamide; Dara, daratumumab; D-VRd, daratumumab, bortezomib, lenalidomide, and dexamethasone; Flu, fludarabine; IMiD, immunomodulatory drug; IMWG, International Myeloma Working Group; ISS, International Staging System; Len, lenalidomide; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma.

CARTITUDE-2 Cohort A: Study DesignPrimary Objectives

• MRD 10-5 negativity as assessed by next-generation sequencinga

Secondary Objectives

• ORR; per IMWG response criteria

• Duration of response

• Time and duration of MRD negativity

• Incidence and severity of AEsb,c

Key Eligibility Criteria

• Progressive MM after 1–3 prior lines of therapy

• Including a PI and an IMiD

• Lenalidomide refractory

• No prior exposure to BCMA-targeting agents Follow-up

Post treatment assessments(Day 101 up to end of cohort)

Safety, efficacy, PK, PD, biomarker

Postinfusion assessments (Day 1 to 100)Safety, efficacy, PK, PD, biomarker

Cilta-cel infusion Target: 0.75×106 (0.5–1.0×106) CAR+ viable T cells/kg (Day 1)

Cy (300 mg/m2) + Flu (30 mg/m2)(Day -5 to -3)

Bridging therapy (as needed)

Apheresis

Screening (1 to ≤28 days)

Cohort A: Patients with progressive MM after 1–3 prior lines of therapy, lenalidomide refractory

aClonoSEQ, Adaptive Biotechnologies. bAssessed according to the Common Terminology Criteria for AEs version 5.0. cCRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria.AE, adverse event; BCMA, B-cell maturation antigen; cilta-cel, ciltacabtagene autoleucel; CRS, cytokine release syndrome; Cy, cyclophosphamide; Flu, fludarabine; ICANS, immune effector cell–associated neurotoxicity; IMiD, immunomodulatory drug; IMWG, International Myeloma Working Group; MRD, minimal residual disease; MM, multiple myeloma; ORR, overall response rate; PD, pharmacodynamics; PI, proteasome inhibitor; PK, pharmacokinetics.

CARTITUDE-2: Baseline CharacteristicsCharacteristic N=20Male, n (%) 13 (65)

Years since diagnosis, median (range) 3.5 (0.7–8.0)

Age, years, median (range) 60 (38–75)

Extramedullary plasmacytomas ≥1, n (%) 3 (15)

Bone-marrow plasma cellsa ≥60%, n (%) 3 (15)

Prior lines of therapy, median (range) 2 (1–3)

Number of prior lines of therapy, n (%)

<3 prior lines 12 (60)

3 prior lines 8 (40)

High-risk cytogenetic profile, n (%) 7 (35)b

del17p 3 (15)

t(14;16) 5 (25)

t(4;14) 0

Characteristic N=20Previous stem-cell transplantation, n (%)

Autologous 17 (85)

Allogeneic 0

Triple-class exposed,c n (%) 13 (65)

Triple-class refractory,c n (%) 8 (40)

Penta-drug exposed,d n (%) 4 (20)

Penta-drug refractory,d n (%) 1 (5)

Refractory status, n (%)

Bortezomib 8 (40)

Carfilzomib 2 (10)

Pomalidomide 7 (35)

Daratumumab 12 (60)

Refractory to last line of therapy, n (%) 19 (95)

• All patients were refractory to lenalidomide• All patients were exposed to a PI, an IMiD, and dexamethasone• 95% were exposed to alkylating agents and 65% to daratumumab

aMaximum value from bone marrow biopsy and bone marrow aspirate is selected if both results are available. bOne patient had both del17p and t(14:16). c≥1 PI, ≥1 IMiD, and 1 anti-CD38 antibody. d≥2 PIs, ≥2 IMiDs, and 1 anti-CD38 antibody.IMiD, immunomodulatory drug; PI, proteasome inhibitor.

10%

10%

30%

45%

0

10

20

30

40

50

60

70

80

90

100

sCRCRVGPRPR

≥VGPR85%

≥CR 75%

ORR: 95% (19/20a)

Patie

nts,

%CARTITUDE-2: Overall Response Rate and MRD Negativity

• Median time to first response: 1.0 month (range, 0.7–3.3)

• Median time to CR or better: 1.9 months (range, 0.9–5.1)

• All patients (n=4) with MRD-evaluableb

samples at the 10-5 threshold were MRD negative at data cut-off

Data cut-off date: Jan 2021. aPatient who did not respond had stable disease. bMRD was assessed in evaluable samples (ie, patients with identifiable clone at baseline and sufficient cells for testing at 10-5 threshold in post treatment samples) by next-generation sequencing (clonoSEQ, Adaptive Biotechnologies) in all treated patients. CR, complete response; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

CARTITUDE-2: Duration of Response

• Responses deepened over time

• No progression of disease at median follow-up of 5.8 months

CR, complete response; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

CARTITUDE-2: Safety

Haematologic AEs ≥20%, n (%)N=20

Any grade Grade 3/4

Neutropaenia 19 (95) 18 (90)

Thrombocytopaenia 16 (80) 7 (35)

Anaemia 13 (65) 8 (40)

Lymphopaenia 12 (60) 11 (55)

Leukopaenia 11 (55) 11 (55)

Nonhaematologic AEs ≥20%, n (%)N=20

Any grade Grade 3/4Metabolism and nutrition disorders

Hypokalaemia 8 (40) 0Hypocalcaemia 7 (35) 3 (15)Hypophosphataemia 7 (35) 3 (15)Hypomagnesaemia 6 (30) 0Decreased appetite 5 (25) 3 (15)

GastrointestinalDiarrhoea 9 (45) 3 (15)Nausea 5 (25) 0Constipation 4 (20) 0Vomiting 4 (20) 0

OtherFatigue 9 (45) 1 (5)Back pain 5 (25) 2 (10)Pyrexia 5 (25) 0Arthralgia 4 (20) 0Renal impairment 4 (20) 0

• Incidence of prolonged Grade 3/4 cytopaenias beyond Day 60:

– Neutropaenia: 25%– Thrombocytopaenia: 0%– Lymphopaenia: 45%

AE, adverse event.

CARTITUDE-2: SafetyMaximum CRS Grade (N=20)

0

10

20

30

40

50

60

No CRS Grade 1 Grade 2 Grade 3 Grade 4

Patie

nts,

%

1 (5%) 1 (5%)

3 (15%)4 (20%)

11 (55%)

• 1 death occurred on Day 100 after infusion due to COVID-19, and was assessed as treatment-related by the investigator

CRS N=20

Patients with a CRS event, n (%) 17 (85)

Time to onset, days, median (range) 7 (5–9)

Duration, days, median (range) 3.5 (2–11)

Supportive measures,a n (%)Tocilizumab 14 (70)Corticosteroids 6 (30)IV fluids 6 (30)Oxygen 4 (20)Anakinra 1 (5)Vasopressor 1 (5) CRS resolved or recovered in 94% of patients at the time of data cut-off

Neurotoxicity N=20

ICANS, n (%) 3 (15)

Median time to onset, days (range) 8 (7–11)

Median duration, days (range) 2 (1–2)All ICANS were grades 1/2

No cases of movement and neurocognitive TEAEs

aIncludes supportive measures to treat CRS events and symptoms. Data cut-off date: Jan 2021 AE, adverse event; CRS, cytokine release syndrome; ICANS, immune effector cell–associated neurotoxicity; IV, intravenous; TEAE, treatment-emergent adverse event.

CARTITUDE Program: Safety No movement and neurocognitive TEAEs were observed in patients of Cohort A in CARTITUDE-2

AbstractEP1003

Patient Management Strategiesc

• Enhanced bridging therapy to reduce tumour burden

• Early and aggressive treatment of CRS and ICANS

• Handwriting assessments and extended monitoring

CARTITUDE Program Level>100 additional patients

have been dosedd

• Patient management strategies to prevent or reduce these AEs have been successfully implemented in new and ongoing cilta-cel studies

• This is reliant on effective implementation of these patient management strategies

Movement andNeurocognitive TEAEsa

Risk factors (2 or more)• High tumour burdenb

• Grade ≥2 CRS• ICANS• High CAR T-cell expansion

and persistence

aAs observed in 5 of 97 patients in CARTITUDE-1. bDefined as high tumour burden when any of the following parameters were met: bone marrow plasma cell ≥80%, serum M-spike ≥5 g/dL, serum free light chain ≥5000 mg/L. cAdditional details will be presented at the EHA Virtual Congress 2021 (Abstract EP1003, available by scanning the QR code on this slide). dIncluded patients treated in earlier-and later-line settings across the CARTITUDE program.AE, adverse event; cilta-cel, ciltacabtagene autoleucel; CRS, cytokine release syndrome; ICANS, immune effector cell–associated neurotoxicity syndrome; TEAE, treatment-emergent adverse event.

CARTITUDE-2: Conclusions

• A single infusion of cilta-cel led to early and deep responses in patients with MM who received 1–3 prior lines of therapy and were lenalidomide refractory

• ORR was 95%, with 75% of patients achieving CR or better and 85% achieving VGPR or better

• Responses deepened over time and follow-up is ongoing

• The safety profile was manageable

• CRS was mostly grades 1/2; median time to CRS onset was 7 days (range, 5–9)

• No incidence of movement and neurocognitive TEAEs with this patient management strategy

• Cilta-cel is being evaluated in the phase 3 CARTITUDE-4a study in patients with 1–3 prior lines of therapy versus D-Pd or PVd

aClinicalTrials.gov: NCT04181827.Cilta-cel, ciltacabtagene autoleucel; CR, complete response; CRS, cytokine release syndrome; D-Pd, daratumumab, pomalidomide, and dexamethasone; MM, multiple myeloma; ORR, overall response rate; PVd, pomalidomide, bortezomib, and dexamethasone; TEAE, treatment-emergent adverse event; VGPR, very good partial response.

Original Article

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma

Nikhil C. Munshi, M.D., Larry D. Anderson, Jr., M.D., Ph.D., Nina Shah, M.D., Deepu Madduri, M.D., Jesús Berdeja, M.D., Sagar Lonial, M.D., Noopur Raje, M.D.,

Yi Lin, M.D., Ph.D., David Siegel, M.D., Ph.D., Albert Oriol, M.D., Philippe Moreau, M.D., Ibrahim Yakoub-Agha, M.D., Ph.D., Michel Delforge, M.D., Michele Cavo, M.D., Hermann Einsele, M.D.,

Hartmut Goldschmidt, M.D., Katja Weisel, M.D., Alessandro Rambaldi, M.D., Donna Reece, M.D., Fabio Petrocca, M.D., Monica Massaro, M.P.H., Jamie N. Connarn, Ph.D., Shari Kaiser, Ph.D.,

Payal Patel, Ph.D., Liping Huang, Ph.D., Timothy B. Campbell, M.D., Ph.D., Kristen Hege, M.D., and Jesús San-Miguel, M.D., Ph.D.

N Engl J Med 2021Volume 384(8):705-716

February 25, 2021

Baseline characteristicsCharacteristic N=128

Median age (range) years 61 (33–78)Male, n (%) 76 (59Extramedullary disease 50 (39)Years since diagnosis, median

(range)6 (1–18)

High-risk cytogenetics, n (%) 45 (33)del(17p) 23 (18)t(4;14) 23 (18)t(14;16) 6 (5)

Tumor BCMA expression ≥50% at

screening, n (%)109 (58)

Characteristic N=128Prior lines of therapy, median (range) 6 (3–16)Previous autologous stem-cell transplantation, n

(%)120 (94)

Refractory to an IMiD, n (%) 126 (98)Refractory to a PI, n (%) 116 (91)Refractory to an anti-CD38 antibody, n (%) 120 (94)Double-refractorya disease, n (%) 114 (89)Triple-refractoryb disease, n (%) 108 (84)Penta-refractoryc disease, n (%) 33 (26)

BCMA, B cell maturation antigen; IMiD, immunomodulatory drug; PI, proteasome inhibitor.aDouble refractory defined as refractory to an IMiD and a PI; bTriple refractory defined as refractory to an IMiD, a PI and an anti-CD38 mAb; cPenta refractory defined as refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib and daratumumab.

Munshi NC, et al. N Engl J Med. 2021;384(8):705-716

Efficacy – Response

Munshi NC, et al. N Engl J Med. 2021;384(8):705-716

Progression-free Survival, Duration of Response, and Overall Survival

Munshi NC et al. N Engl J Med 2021;384:705-716

Munshi NC, et al. N Engl J Med. 2021;384(8):705-716

PFS 8.8 months OS 19.4 months

Conclusions• Ide-cel induced responses (ORR 73%) in a majority of heavily

pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients

• Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome

Munshi N, et al.N Engl J Med 2021

Volume 384(8):705-716February 25, 2021

CART–איך ניתן להתגבר על המגבלות?פתרוןמגבלה

...התאים לא מחזיקים די זמןמערכת החיסון מחסלת אותם-מאבדים מכוחם-

CART"אנושי"CARTמלימפוציטים מתחילת המחלה

"זכרון"מסוג Tשיטות להעשרת תאי שיטות להגברת מערכת השפעול של

Tתאי ה שמפחיתים פעילות Tשינויים בתאי ה מערכת החיסון

אוניברסלי CART....צורך להכין לכל חולה, מוצר מותאם)דואליCART(מטרה כפולה "מטרה"מפחיתה –" בורחת"המיאלומה

CARTהעשרת המטרה על ה

דואליקארטי

Best BCMA therapy?

CARTADC

BiTE

Remains to be seen!

CART–למטופל ולהמטולוג...