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The journey with Claes Doctor Hareth Nahi, Patient Claes
The journey with Claes
Doctor Hareth Nahi, Patient Claes
Claes
CyberD HDT Len main.
7 months
Which drugs to combine/Induction
0 1 2 3 4 5 6 7 8 9 10
Time to progression, years
0,0
0,2
0,4
0,6
0,8
1,0
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Pro
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urv
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VCB
VAD/CyBet
Log rank test. p=0.018
0 3 6 9 12 15 18 21 24
Months since treatment start
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Cu
mu
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ve
Pro
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Progression Free Survival
VCD, n=213
VRD, n=50
Logrank test=0.034
Cyclo+Dex +BortezomibCyclo+Dex
Bortezomib+Lenalidomide+DexCyclo+Dex +Bortezomib
Cyclo+Dex +Bortezomib+DaraBortezomib+Lenalidomide+Dex
Maintenance, the strategy at KI
MRD +
Yes, maintain
MRD-
Discuss, probably no
Lenalidomide
until
Len+Daratumumab
Is approved
CyberD HDT Len main.
7 months
What happened with Claes after the 7m
Len main. Daratumumab
Non-inferiority of subcutaneous vs intravenous daratumumab for multiple myelomaMaria-Victoria Mateos,1 Hareth Nahi,2 Wojciech Legiec,3 Sebastian Grosicki,4 Vladimir Vorobyev,5 Ivan Spicka,6 Vania Hungria,7 SibirinaKorenkova,8 Nizar Bahlis,9 Max Flogegard,10 Joan Bladé,11 Philippe Moreau,12 Martin Kaiser,13 Shinsuke Iida,14 Jacob Laubach,15 Hila Magen,16
Michele Cavo,17 Cyrille Hulin,18 Darrell White,19 Valerio De Stefano,20 Pamela L.. Clemens,21 Tara Masterson,21 Kristen Lantz,21 Lisa O’Rourke,21
Christoph Heuck,21 Xiang Qin,22 Dolly A. Parasrampuria,21 Zhilong Yuan,22 Steven Xu,21,* Ming Qi,21 Saad Z. Usmani23
Response
n (%)
(95% CI)*
DARA SC
(n=263)
DARA IV
(n=259)
Overall response
(sCR+CR+VGPR+PR)
108 (41)
(35.1–47.3)
96 (37)
(31.2–43.3)
CR (sCR+CR)5 (2)
(0.6–4.4)
7 (3)
(1.1–5.5)
VGPR (sCR+CR+VGPR)50 (19)
(14.5–24.3)
44 (17)
(12.6–22.1)
Len main. Daratumumab ??????
4 years
Nothing last for ever5y since diagnosis
Min Myelom resa
• Diagnos i September 2014 efter ca. 1,5 år av symptom, främst ont i ryggen.
• Jag fick stiga av min älskade cykel under hela 2014.
• 2015 kantades av en hel del bakslag och osäkerhet efter stamcellstransplantation.
• Deltagit i en studie (2016) samt deltar i en ytterligare forskiningsstudie (2018). Båda har haft fin effekt, särskilt den senare.
• Nuvarande behandling sker var 14e dag på Huddinge Sjukhus med fullgott resultat. Tidsåtgång ca. 3 timmar
What are cell and gene therapies
• Cell Therapies - Administration of whole living cells to a patient for therapeutic benefit.
• Autologous – Cells derived from same patient
• Allogeneic – Cells derived from donors
• Examples: Kymriah (Licensed in US, pending in EU); Yescarta (Licensed in US, pending in EU) are autologous gene-modified cell therapies (CAR-Ts)
• Gene Therapies – Modify expression of, or repair damage to, abnormal genes for therapeutic benefit.
Successful application to a wide range of previously untreatable and rare diseases
Patient
Ex Vivo Gene Therapy: Putting Functional Genes Into Marrow Stem Cells or T cells Outside of the Body
Patient
Ex Vivo Gene Therapy: Putting Functional Genes Into Marrow Stem Cells or T cells Outside of the Body
Mobilization
Leukapheresis
OR
Bone Marrow Harvest
Patient
Ex Vivo Gene Therapy: Putting Functional Genes Into Marrow Stem Cells or T cells Outside of the Body
Virus-Mediated Transfer of Therapeutic Gene
GOAL: Gene modified cells
engraft and correct or treat
the disease
- Cancer
- Genetic disease
- Infectious disease
Patient
Ex Vivo Gene Therapy: Putting Functional Genes Into Marrow Stem Cells or T cells Outside of the Body
Reinfusion
Multiple Myeloma
• Summary of the CAR-T trials
BCMA CAR-T Cell Trials Summary ASH 2018
CAR T – bb 2121 - Progression-Free Survival in RR MM • mPFS of 11.8 months at active doses (≥150 106 CAR+ T cells) in 18 patients in
dose escalation phase
• mPFS of 17.7 months in 16 responding patients who are MRD-negative
Raje N et al. J Clin Oncol. 2018: Abstract 8007; NEJM 2019.
New cancer therapies have arrived…
Immunotherapy
Antibodies
Checkpoint inhibitors
Bispecific T-cell engagers (BiTEs)
CAR-T cells
http://www.genscript.com/immune-checkpoint-inhibitors.htmlWu J, et al. J Hematol Oncol. 2015;8:104.
Ongoing BiTe/Duo AB/ BCMA conjugates at KI
Duo AB JanssenBiTe CGBCMA conjugate GSK
Common to all is the BCMA-B-cell maturation antigen.Actually, BCMA, it is the bases for CAR-T therapies
Could T-cells stimulation without CAR-T work?
• The none CAR-T approch
BCMA, B-cell maturation antigen; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; FTIH, first-time-in-human; IV, intravenous;
MM, multiple myeloma.
§ Overall, 38 patients were evaluated in Part 1 – no DLTs were observed
§ Part 2: Expansion
§ Cohort 1: relapsed/refractory MM (N=35; enrollment complete)
§ Cohort 2: BCMA-positive relapsed DLBCL or follicular lymphoma
§ Expansion dose: 3.4 mg/kg
§ Schedule: 1h IV, once every 3 weeks
§ Treatment duration: up to 16 cycles (up to 1 year)
0.030.480.240.120.06
1.920.96 3.4 4.6n=1 n=4n=1 n=4 n=4 n=3 n=4 n=3 n=6
N=35
N=6/10
Cohort 1: 3.4 mg/kg
N=38
Cohort 2: 3.4 mg/kg
Part 1
completed
Part 2
completed
2.5 n=8
Additional dose evaluation
DREAMM-1: FTIH Study Overview
MM
NHL
Belantamab Mafodotin Efficacy in Multiple Myeloma:
ORR From DREAMM-1 Study
BCMA, B-cell maturation antigen; CI, confidence interval; CR, complete response; dara, daratumumab; IMiD, immunomodulatory drug; ORR, overall response rate; PI, proteasome inhibitor; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.Trudel S, et. al. Blood Cancer J 2019; 9(4): 37.
Patients previously treated with dara (n=14)
• ORR=42.9% (95% CI [17.7%, 71.1%])
Patients refractory to IMiD+PI (n=32)
• ORR=56.3% (95% CI [37.7%, 73.6%])
Patients previously treated with dara and
refractory to IMiD+PI (n=13)
• ORR=38.5% (95% CI [13.9%, 68.4%])
Overall ORR = 60.0% 95% CI (42.1%, 76.1%); n=35
sCR (n=2), CR (n=3), VGPR (n=14), PR (n=2)
Patients enrolled regardless of BCMA expression levels
No dose-limiting toxicities observed in dose-finding phase
Belantamab Mafodotin efficacyin refractory populations
DREAMM-1: Belantamab Mafodotin Monotherapy Induces
Durable Responses and Has Manageable Toxicity Profile
AE, adverse event; CI, confidence interval; IRR, infusion-related reaction; N/A, not available; Q, quartile
Trudel S, et. al. Blood Cancer J 2019; 9(4): 37.
Progression-free survival (months)
Belantamab mafodotin was well tolerated and side effects were manageable
• Corneal events (69%) and thrombocytopenia (63%) emerged as the most frequent AEs and reasons for dose modification:
– Corneal events are mostly low grade (14% Grade 3), manageable with steroid eye drops, dose reductions and interruptions
• IRRs occurred in 29% of patients (without pre-medication)
Duration of response (months)
Progression-free survival Duration of response
Median (95% CI) - 12.0 mos. (3.1, -)
Median (95% CI) - 14.3 mos. (10.6, -)
Control of Immune Responses via CD28
The CD28 signaling pathway are important participants in a very complex group of regulatory events that
maintain immunologic homeostasis.
Experimental manipulation of these pathways is being employed with increasing frequency to optimize
immune responses to various diseases.
Activation of a resting T cell requires two complementing signals. Engagement of the T cell receptor must be
accompanied by a second signal that results from the ligation of receptors on the T cell with either soluble
factors, such as IL-2, or cell-surface molecules on the antigen-presenting cell.
Aberrations at diagnosis and relapses, Is Claes unique?
• Add 1q……..High Risk
• T(11;14)
0 12 24 36 48 60 72 84 96 108 120
Time
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Su
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HDT/OS
HR
t(11;14)+HR
t(11;14)+SR
SR
HR/SR 0.069
HR/t(11;14)+HR 0.341
HR/t(11;14)+SR 0.300
SR/t(11;14)+HR 0.049
SR/t(11;14)+SR 0.800
How about infusion of autologous immune cells
• Alone or in combination with antibodies?
cGMP certified expansion process
ACP-001
• First-in-man, Phase I
• Open, single arm study
• Primary objective: • Safety and tolerability
• Secondary objective: • Effect on serum Ig levels
• Inclusion: • MM patients eligible for
ASCT
• 3 escalating infusions/patient
• 106, 5X107 and 108
cells/kg
• Evaluation: • 4 weeks after infusion,• 6 months follow up.
Hareth Nahi
27/09/2019 Hareth Nahi
0 6 12 18 24 30 36 42 48
Months since the start of the the start of myeloma treatment
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PFS-NK
OS-NK
PFS-control, all patients treated with HDT at the same time peroid
OS-control, all patients treated with HDT at the same time peroid
The phase II trial to be started Dec 2019
An open, randomised, controlled phase II trial of ACP-002 in combination with isatuximab antibody versus antiCD38 antibody alone as maintenance treatment in patients with Multiple Myeloma undergoing high dose treatment
27/09/2019 Hareth Nahi
It might last for ever, Claes, if not?
• Venetoclax+Daratumumab or other antiCD38 AB
0 6 12 18 24 30 36 42 48
Months since the start of the the start of myeloma treatment
0,0
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Cum
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PFS-NK
OS-NK
PFS-control, all patients treated with HDT at the same time peroid
OS-control, all patients treated with HDT at the same time peroid
Or, if you want
Mina reflektioner
• Idag mår jag lika bra som innan jag blev sjuk.
• Jag har haft tur i oturen – Tidpunkten för min diagnos verkar vara vara väl “timad” ---Forskningmediciner verkar komma i precis rätt tid
• Vårdpersonalens bemötande har gett mig stor flexibilitet i min vardag – Jag har möjlighet att leva ett normal liv – Tack!
• Min egen träning och ett aktivt liv hjälper mig att passera eventuella bi-effekter. Det hjälper mig att se möjligheter istället för hinder.
