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COMY #4PARIS FRANCE MAY 2018
THE ROAD TO CURE IN A TRANSPLANT ELIGIBLE PATIENTPRACTICAL EXAMPLES
Bart BarlogieMt. Sinai School of Medicine
New York, NY, USA
CURE IN MYELOMA
• DEFINITION– SUSTAINED CR OR PFS > 10‐15YR– NON‐CR CURES ARE MGUS‐LIKE
• REQUIRES SUSTAINED REGULAR FOLLOW UP WITH APPROPRIATE TESTING– MM MARKERS, BM, IMAGING
• SECONDARY CURES AFTER RELAPSE HAVE BEEN DOCUMENTED
HOW TO APPROACH CURATIVE THERAPY IN MYELOMA?
• LEARNING FROM LESSONS IN ACUTE LEUKEMIA– EMPLOY ALL CURRENTLY AVAILABLE TREATMENTS UPFRONT INCLUDING REGIMENS FOUND EFFECTIVE IN RELAPSE THERAPY
– AS IN TOTAL THERAPY AT ST. JUDE– JUSTIFIED BY PRESENCE OF INTRA‐CLONAL INCLUDING SPATIAL HETEROGENEITY IN MM
TT1 TT2 (‐ / + thal) TT3
Induction VAD X 3 VAD VTDPACE ‐ HPC
CTX – HPC DCEP VTDPACE
EDAP CAD – HPC
DCEP
Transplant MEL200 MEL200 MEL200
MEL200 MEL200 MEL200
Consolidation ‐‐‐‐ DPACE X 4 VTDPACE X 2
Maintenance IFN IFN + DEX VTD
TT1: OS and PFS
Alive: 30; PFS: 19
TT1: CRD
CCR: 10
TT2: OS by arm
TT2: PFS by arm
TT2: CRD by arm
TT3A: OS and PFS
TT3A: CRD
Cure Model Estimates from Baseline and from 5 Year LandmarkCure model estimates are shown by the dotted lines. Kaplan‐Meier estimates are shown as solid lines
PFS CRD
From 5-yr landmark
Cure fraction estimates by protocol
ProtocolPFS CRD
N Cure Fraction N Cure
FractionTT1 231 8.8% 79 17.9%TT2 ‐Thal 345 15.5% 146 28.2%TT2 +Thal 323 25.1% 200 35.6%TT3a 303 32.9% 189 48.8%
TT1 65 28.4% 33 32.3%TT2 –Thal 145 39.2% 84 47.4%TT2 +Thal 150 51.1% 134 55.9%TT3a 197 69.8% 148 74.7%
From baseline
From 5‐yr landmark
Progression Estimates by Protocol and GEP‐70 Risk
Progression-Free Survival by ProtocolGEP-70 Low Risk Only
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 - ThalTT2 + ThalTT3a
Events / N127 / 15698 / 149
109 / 236
5-YearEstimate
41% (33, 49)59% (51, 67)71% (65, 77)
Logrank P-value < .0001
Progression-Free Survival by ProtocolGEP-70 High Risk Only
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 - ThalTT2 + ThalTT3a
Events / N19 / 2023 / 2633 / 40
5-YearEstimate
10% (0, 20)19% (5, 33)
25% (12, 38)Logrank P-value = .10
Time to ProgressionGEP-70 Low Risk Only
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 - ThalTT2 + ThalTT3a
Events / N101 / 15667 / 14969 / 236
5-YearEstimate46.8%26.2%17.8%
P < .0001
Time to ProgressionGEP-70 High Risk Only
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 - ThalTT2 + ThalTT3a
Events / N12 / 2017 / 2620 / 40
5-YearEstimate60.0%61.5%47.5%
P = .10
Common to all endpoints examined, plateaus are reached earlier at 5yr in high‐risk compared to 10yr in the majority of 85% with low‐risk myeloma
Low Risk High Risk
Example of Cure after Relapse
Total Therapy I 3/9/1994; Off maintenance 9/1997 PDDexamethasone added 1/1999; Developed CVA with left hemiparesis Off Dex; SDEmbrel therapy 2/2000 due to rising markers PDIMID protocol 9/2003, Rev 25 d1‐20, Rev 5 21‐28 CRContinued on Revlimid 2/2004 CROff all therapy 4/2014 → present sCR
YB DOB 12/1944 73 yoIgG kappa myeloma Stage II‐A; diagnosed in 12/1993 at the age of 59.
Presentation: lower back pain; various imaging studies revealed a compression fracture at L5Cytogenetics normal at dx, GEP Low Risk, CD‐2 subgroup.Enrolled in Total Therapy I protocol (UARK 89‐001) 3/9/1994. CR achieved.
Induction: VAD x3, HD‐CX + HPC collection, EDAPTransplant: Mel 200 x 2Consolidation: not applicableMaintenance: IFN TiW
Maintenance continued until September 1997 and was stopped due to progressive disease.Dex added Feb 2000, started on Enbrel therapy due to PD +rising M markers. Enrolled in the IMiD study in September of 2003 with Rev 25mg on days 1through 20 and 5 mg on days 21 through 28 every 28 days due to disease progression. Continued revlimid until early 2014, over a decade. Has remained in uninterrupted stringently defined CR off therapy.
IMPORTANCE OF IMAGING IN MM
• “SPATIAL HETEROGENEITY” OF MM AND MICRO‐ENVIRONMENT– PERFORM RANDOM BM AND FNA OF FOCAL LESIONS
• SERIAL MRI AND PET TO DETERMINE IMAGING‐BASED CR– RANDOM BM MRD NEGATIVITY ALONE NOT SUFFICIENT FOR CURE‐INTENDED TREATMENT APPROACH
CONCLUSIONS
• MM has finally joined the “club” of curable cancers• High‐risk MM can also be cured but only in 15% and cure plateau is apparent at 5yr as opposed to 10yr in low‐risk disease with cure projection in 50%
• Follow‐up of solely novel agent trials is too short to determine curability– Also issue whether all CR’s created equally
• Typically longer unmaintained CR after transplant
• We therefore recommend not to abandon transplant approach prematurely– Test novel agents first in high‐risk MM and determine whether plateau emerges
QUO VADIS?• PERFORM GEP AND MUTATIONAL ANALYSES• LOW‐RISK
– CONTINUE TT3 APPROACH WITH TANDEM TRANSPLANTS AND VRD‐TYPE MAINTENANCE + DARATUMUMAB FOR 3 YEARS
• HIGH‐RISK– INDUCTION WITH VTD‐PACE AND HSC COLLECTION (20+ M CD34/KG)– DARATUMUMAB BEFORE AND AFTER MEL 200 OR BEAM TRANSPLANT– DARATUMUMAB + VRD MAINTENANCE FOR 3 YEARS
• HIGH‐RISK RELAPSE– METRONOMIC 28‐D THERAPY PLUS DARA– MUTATION‐DIRECTED THERAPIES
• TRAMETINIB FOR RAS MUTATIONS• DABRAFENIB + TRAMETINIB FOR BRAF V600E
– VENETOCLAX 800MG + BORTEZOMIB + NELFINAVIR• WORKS ALSO IN MM WITHOUT T(11;14)
• APPLY IMMUNE CHECKPOINT INHIBITORS (PEMBROLIZUMAB – PD1, IPILILUMAB – CTLA‐4, NIVOLUAMB – PDL1)
– ESPECIALLY EFFECTIVE WHEN MUTATIONAL BURDEN IS HIGH
THANKS TO
• PATIENTS AND REFERRING DOCTORS– FOR CONFIDENCE IN OUR TREATMENT APPROACH
• HEALTH CARE TEAMS AT MD ANDERSON, ARKANSAS AND NOW MT SINAI
• NIH AND PHILANTHROPY• MMRF, IMF, IMS• PHARMA FOR PURSUING MM THERAPIES
Long Term Follow Up of TT1Overall Survival: UARK 89-001
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Registration
TT1: UARK 89-001Events / N196 / 231
10-YearEstimate
33% (27, 39)
Progression-Free Survival: UARK 89-001
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Registration
TT1: UARK 89-001Events / N210 / 231
10-YearEstimate
15% (11, 20)
Time to Complete Response: UARK 89-001
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5Years from Registration
TT1: UARK 89-001Events / N77 / 226
2-YearEstimate32.3%
CR Duration: UARK 89-001
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from CR
TT1: UARK 89-001Events / N
66 / 77
10-YearEstimate
21% (12, 30)
Time to Progression: UARK 89-001
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Registration
TT1: UARK 89-001Events / N163 / 231
10-YearEstimate67.5%
Time to Relapse from CR: UARK 89-001
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Registration
TT1: UARK 89-001Events / N
55 / 73
10-YearEstimate69.9%
Overall and Progression‐free Survival Pairs by Protocol
Overall and Progression-Free SurvivalTT1
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT1: Overall SurvivalTT1: Progression-Free Survival
Events / N196 / 231210 / 231
5-YearEstimate
58% (51, 64)28% (22, 34)
Overall and Progression-Free SurvivalTT2 - Thal
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 - Thal: Overall SurvivalTT2 - Thal: Progression-Free Survival
Events / N227 / 345276 / 345
5-YearEstimate
65% (60, 70)42% (37, 47)
Overall and Progression-Free SurvivalTT2 + Thal
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT2 + Thal: Overall SurvivalTT2 + Thal: Progression-Free Survival
Events / N183 / 323217 / 323
5-YearEstimate
68% (63, 73)56% (50, 61)
Overall and Progression-Free SurvivalTT3a
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years After Enrollment
TT3a: Overall SurvivalTT3a: Progression-Free Survival
Events / N116 / 303153 / 303
5-YearEstimate
74% (69, 79)65% (60, 70)
OS and PFS curves show progressive narrowing from TT1 to TT2‐ to TT2+ to TT3a
Progression‐free Survival by CR Status at 2 Year
Landmark by ProtocolProgression-Free Survival by Response at Landmark
Landmarked 2 years from registrationTT1
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Landmark
<CRCR
Events / N82 / 9344 / 54
5-YearEstimate
29% (20, 38)48% (35, 61)
Logrank P-value = .08
Progression-Free Survival by Response at LandmarkLandmarked 2 years from registration
TT2 - Thal
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Landmark
<CRCR
Events / N114 / 14071 / 114
5-YearEstimate
31% (24, 39)54% (45, 64)
Logrank P-value = .0002
Progression-Free Survival by Response at LandmarkLandmarked 2 years from registration
TT2 + Thal
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Landmark
<CRCR
Events / N67 / 10975 / 139
5-YearEstimate
56% (47, 65)61% (53, 69)
Logrank P-value = .25
Durable PFS also in absence of CR but at lower levelHypothesis: MGUS‐like residual disease?
Supported by MGUS‐like signature on 8‐color FCM
MRD in Low and High Risk MM
• TT4 for low risk MM– @ <0.01% level (n=223)
• MRD‐negative: 70%– @ <0.001% level (n=198)
• MRD‐negative: 35%
• TT5 for high risk MM– @ <0.01 level (n=35)
• MRD‐negative: 51%– @ <0.001% level (n=32)
• MRD‐negative: 34%
• Determinations made after 2nd transplant
• Conclusion – Similar rates of MRD
negativity in low and high risk of ~1/3 when applying stringent criteria
– Shorter PFS in high risk MM not related to MRD
• Caveat – Focal lesions often persist
in MRD‐negative MM
EXAMPLES OF DURABLE DISEASE CONTROL
AGE@ Dx
Gender MM Type
Start of Rx
Protocol Response Ever Relapsed
Alive# years
59 F IgGk 3/1994 TT1 sCR yes 24
61 M KLC 1/2005 TT3A CR no 13
46 M IgGk 12/2001 TT2+Thal sCR no 17
58 F IgGL 12/2004 TT3A sCR no 14
42 F Non‐sec 6/1995 TT2‐Thal sCR no 19
65 F IgAk 1/2003 TT2+Thal sCR no 15
53 F IgAk 12/2005 TT3A sCR no 13
68 F IgAk 12/2005 TT2+Thal sCR no 13
58 F IgGL 7/2004 TT3A sCR no 14
OS by TT3A and TT3B
PFS: TT3A and TT3B
CRD: TT3A and TT3B
TT3B: OS and PFS
TT3B: CRD
OS by TT2 arms and TT3A
PFS by TT2 arms and TT3A
CRD by TT2 arms and TT3A
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