new multiple myeloma update is immunotherapy a game changer … · 2018. 5. 21. · multiple...
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Multiple Myeloma UpdateIs Immunotherapy a Game Changer in Multiple Myeloma?
Professor of MedicineDirector, Myeloma Program
The University of Chicago
Andrzej J Jakubowiak, MD, PhD
…we have made tremendous progress in myeloma…
Barlogie et al, Blood. 2014 Nov 13;124(20):3043-51
Sustained CR duration in subsequent Total Therapies
Sustained MRD – negative status? Sustained MRD – negative status? Sustained MRD – negative status
Since the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs)
• Consistent and deeper responses
• Significantly improved overall survival
KRd +/- Transplant
KRd + High dose
KRd Conventional
Studies not designed for comparisons
Zimmerman et al, TT Meeting 2016; Jakubowiak et al, ASH 2017
Jakubowiak et al, manuscript in preparation
…and we keep making progress using more practical then Total Therapies regimens with new generation of IMiDs and PIs +/- transplant
Surv
ival
(%
)
100
75
50
25
00 30 40 60
Months
20 5010
KRd + ASCT (n=75)KRd w/o ASCT (n=46*)
Median f/u, mo
PFS rate1-yr 2-yr 3-yr 4-yr
47.6 100% 91% 80% 69%†
12.8 96% 90% 82% 80%
Attal et al. ASH 2015, N Eng J Med 2017:376:1311-20
PFS Rate3-yr 4-yr
Arm A—Conventional 47% 35%Arm B—High dose 61% 41%
Months since randomization
RVd +/- Transplant
1.0
0.7
0.5
0.2
00 18 24 4812 366 4230
0.9
0.6
0.4
0.1
0.8
0.3
Arm B – High dose
Arm A – Conventional
Pro
gre
ssio
n-f
ree
surv
ival
Pro
gre
ssio
n-f
ree
surv
ival
…however, even with as most promising like these KRd+transplant results
…can immunotherapy contribute to further improvements?
MRD (-) by NGS
Best ResponseMRD (-) by NGS
Sustained Response MRD (-) by NGS
Sustained Response
…at least 40% of patients are at risk of relapse
Jakubowiak et al ASH 2017; Jakubowiak et al, manuscript in preparation
Strategy #1
Adding monoclonal antibodies to target myeloma cells
…we started with elotuzumab, an anti-SLAMF7 (anti-CS1) antibodySingle agent was not active
Lonial et al, N Eng J Med 2015; 373:621-631
… which was subsequently confirmed in a positive Phase III ELOUENT-2 trial
…although with margin of improvement
smaller than anticipated,
…but based on MOA, elotuzumab was expected to work well with IMiDs
…but still resulting in elotuzumab (EmplicitiTM) approval
…next came anti-CD38 antibodies
Daratumumab as single agent emerged
as one of the most active drugs in myeloma
Basis for daratumumab
(Darzalex) approval
Lonial et al, Lancet 2016:387:1551-1560
…simultaneously, its combinations generated highly promising results
…providing support and very quick enrollment into two phase III studies in Relapsed/Refractory MM
Dimopoulos N Eng J Med 2016:375:1319-31
San Miguel J, et al. EHA 2017; Abstract S101
Palumbo N Eng J Med 2016;375:754-66
Weisel K, et al. EHA 2017, Abstract S459
HR: 0.31(95% CI, 0.24-0.39)p<0.0001
Vd Median: 7.1 months
DVd Median: 16.7 months
% s
urv
ivin
g w
ith
ou
t p
rogr
ess
ion
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 24 30MonthsNo. at risk
Median follow-up: 19.4 months
CASTOR trial
RdDRd
283286
No. at riskMonths
249266
206249
181238
160229
143214
127203
109189
86146
2346
00
HR: 0.41(95% CI, 0.31–0.53) p<0.0001
28
100
80
60
40
20
0Surv
ivin
g w
ith
ou
t p
rogr
essi
on
(%)
0
DRdMedian: NR
3 6 9 12 15 18 21 24 27 33
RdMedian: 17.5 months
30
68%
41%
24-month PFS
Median follow-up: 25.4 months
POLLUX trial(VD +/- daratumumab) (RD +/- daratumumab)
…with hazard ratios and PFS for Rd-Dara exceeding anything we have seen before
…and quickly generating rationale for evaluation of daratumumab in frontline treatment with intent to cure
…with a hope that 2 players (KRd + dara) will
improve a chance to achieve this win
…the initial results were indeed very promising
Depth of response improved
with duration of treatment
• Median number of treatment cycles:
11.5 (range, 1.0-13.0)
10091
43
29
0
10
20
30
40
50
60
70
80
90
100
≥PR ≥VGPR ≥CR sCR
Resp
on
se r
ate
, %
Best Response (n = 21)
DARA (16 mg/kg) + KRd
• Median follow-up: 10.8 (range, 4.0-12.5) months
• Overall survival = 100%
12-month PFS ratea = 94%
No. at risk
% s
urv
ivin
g w
itho
ut
pro
gre
ssio
n
0
20
40
60
80
100
0 3 6 9 15Months
12
22 21 17 12 04
aKaplan-Meier estimate.
Jakubowiak et al, ASCO 2017, oral presentation, Chari ASH 2017, Abstract 3110 (updated results)
KRd+Daratumumab
…although no clear signal from this pilot study
…with several larger KRd-dara frontline studies in progress
…leading to recent approval of daratumumab with VMP in newly diagnosed myeloma
…but we now have the first evidence that daratumumab can improve the results
of standard of care in frontline myeloma from the ALCYONE phase III trial
…including an increase of MRD (-) disease
…so naked antibodies work,
…how about antibody conjugates
ORR = 60% (21/35; 95% CI: 42.1%, 76.1%)
• 1 sCR, 2 CR, 15 VGPR, 3 PR
…supporting further development of antibody conjugatesTrudel et al, ASH 2017, Oral Presentation (Abstract #741)
…the most advanced work is with antibody conjugate targeting BCMA
Strategy #2
Overcoming immune suppression
PD1/PDL-1 checkpoint inhibitors
…the promise of checkpoint inhibition is well established in many cancers
• Myeloma like other cancers cells express
“neo-antigens” that allow them to be
recognized by the immune system
• Immune evasion mechanisms are
prominent in myeloma
• The PD-1 / PD-L1 axis is a dominant
immune escape pathway across many
human cancers including myeloma
• PD-1 blocking antibodies have shown
remarkable activity across a growing
number of cancer types
…making future development of check-point inhibitors in
myeloma more challenging
…however, check-point inhibition does not seem to work in myeloma
Strategy #3
Activating myeloma-specific immunity
Cancer vaccines
…the strategy is pursued in several cell-based and non-cell based vaccine trials in myeloma in progress
TrialStudyPhase Site(s)
Survivin Vaccine 1 H. Lee Moffitt Cancer Center
Vaccination with PD-L1 Peptide 1 Non-US
Enhancing Anti-Myeloma Vaccine Response After Autologous Stem Cell Transplantation 2 Emory University
Dendritic Cell/Myeloma Fusion Vaccine 2National Heart, Lung, and Blood Institute (NHLBI) (CTN 1401)
SVN53-67/M57-KLH Peptide Vaccine in Treating Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide Maintenance Therapy
1 Roswell Park Cancer Institute
CT7, MAGE-A3, and WT1 mRNA-electroporated Autologous Langerhans-type Dendritic Cells as Consolidation
1 MSKCC
A Study of PVX-410, a Cancer Vaccine, and Durvalumab +/- Lenalidomide for Smoldering MM
1 Massachusetts General Hospital
Vaccine Therapy With or Without Cyclophosphamide in Treating Patients With Recurrent or Refractory Multiple Myeloma
1/2 Mayo Clinic
…they are all too early
to draw conclusions on the future role of this strategy in myeloma
Strategy #4
Directing T-cells to fight myeloma
BiTESCART cells
Other engineered T-cell strategies
CAR modified T cells are clearly “hot” as candidate cancer therapy
Chimeric Antigen
Receptors
CD28 or 4-1BB
…and the first results are highly promising
Berdeja et al, ASH 2017, Oral Presentation (Abstract #740)
…importantly, with manageable toxicity
1Data cut-off of October 2, 20172Neurotoxicity includes the preferred terms: depressed level of consciousness, confusional state, bradyphrenia, somnolence
Preferred TermOveralln (%)
Grade 3 or highern (%)
Cytokine release syndrome 15 (71) 2 (10)
Neurotoxicity2 5 (24) 0
Neutropenia 18 (86) 18 (86)
Thrombocytopenia 11 (52) 9 (43)
Anemia 14 (67) 12 (57)
Dose Escalation Patients
(N = 21)1
Berdeja et al, ASH 2017, Oral Presentation (Abstract #740)
PHASE I, OPEN-LABEL TRIAL OF ANTI-BCMA CHIMERIC ANTIGEN RECEPTOR T CELLS IN PATIENTS WITH RELAPSED/ REFRACTORY
MULTIPLE MYELOMA
LCAR-B38M CAR-T Cells designed based on proprietary
bispecific CAR platform
Zhang et al, first at ASCO 2017, updated at EHA 2017, Oral presentations
…and it is getting even better
…showing again very promising results
Patients treatedbefore April 5, 2017
Total PR VGPR sCR
Best efficacy 30 2 9 19
% 100% 6.7% 30% 63.3%
Objective response rate (ORR): 100%
1 year
Chance of cure ?
Zhang et al, EHA 2017, Oral Presentation
…which can be very durable
…in summary, immunotherapy is almost certainly a game changer in myeloma
• Anti-CD-38 antibodies (darumumab) and and CARTs are making great entry
• More developments are likely
• It will likely contribute to an increase of the rate of cure for myeloma
Thank you!
I would like to thank:
Members of the Myeloma Program at the
University of Chicago
The investigators, nursing staff, and research
support staff in participating institutions
The Multiple Myeloma Research Consortium and
PCCC, under whom our multi-site trials were
conducted.
Acknowledgments
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