targeted therapy in myeloma - hematology.org.il
TRANSCRIPT
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...