COMY #4 PARIS FRANCE MAY 2018cme-utilities.com/mailshotcme/Material for Websites/COMy...COMY #4 PARIS FRANCE MAY 2018 THE ROAD TO CURE IN A TRANSPLANT ELIGIBLE PATIENT PRACTICAL EXAMPLES

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%



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%



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%



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%


TT1: UARK 89-001Events / N210 / 231

10-YearEstimate

15% (11, 20)

Time to Complete Response: UARK 89-001

0%

20%

40%

60%

80%

100%


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%


TT1: UARK 89-001Events / N163 / 231

10-YearEstimate67.5%

Time to Relapse from CR: UARK 89-001

0%

20%

40%

60%

80%

100%


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%


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%


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%


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%


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%


<CRCR

Events / N114 / 14071 / 114

5-YearEstimate

31% (24, 39)54% (45, 64)


Progression-Free Survival by Response at LandmarkLandmarked 2 years from registration

TT2 + Thal

0%

20%

40%

60%

80%

100%


<CRCR

Events / N67 / 10975 / 139

5-YearEstimate

56% (47, 65)61% (53, 69)


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

Documents

COMY #4 PARIS FRANCE MAY 2018cme-utilities.com/mailshotcme/Material for Websites/COMy...COMY #4 PARIS FRANCE MAY 2018 THE ROAD TO CURE IN A TRANSPLANT ELIGIBLE PATIENT PRACTICAL EXAMPLES