Consolidation and Maintenance Therapy for Multiple Myeloma ... · Novel Agent-Containing Consolidation Therapy Improves Depth of Response and Prolongs PFS • Bortezomib monotherapy

Consolidation and Maintenance Therapy for Multiple Myeloma:

Is it the New Standard?

Paul G. Richardson, MD RJ Corman Professor of Medicine,

Harvard Medical School

Jerome Lipper Multiple Myeloma Center,

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

1. True

2. False

True/False: Consolidation post-SCT has been

associated with PFS, RR, but no OS advantage

1. True

2. False

True/False: Maintenance post-SCT has been

associated with PFS, RR, and OS benefit

Current Paradigm of Initial Treatment

Adapted from Ludwig H, et al. Oncologist. 2012;17(5):592-606.

Richardson PG, et al. Br J Haematol. 2011;154(6):755-762.

Transplant

eligibility

Initial therapy

Autotransplant Consolidation

Continue initial therapy

MaintenanceOR

Treatment Goals Following Induction Therapy for Multiple Myeloma

• Improve progression-free survival (PFS) and overall survival (OS)

• Does improved PFS result in improved OS?

• Is a risk adapted approach justified?

• Continued therapy following Induction

– Timing, duration, intensity & toxicity

(to avoid treatment fatigue)

– Easy to deliver, convenient, improves PFS and OS

Mihelic R, et al. Leukemia. 2007;21(6):1150-1157. Richardson PG, et al. Br J Haematol. 2011;154(6):755-762.

ConsolidationMaintenance

Transplant Eligible

ASCT Induction

ASCT Induction

Maintenance until PD

ConsolidationMaintenance

Transplant Eligible

Supportive care

ASCT Induction

ASCT Induction


Consolidation/Maintenance: Deciding Therapy/Risk Factors

• Age

• Performance status/co-morbidities– PS matters more than age

– Renal failure (bortezomib-containing regimen (BCR)

Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-2955.

• International scoring system– Stage II or III Greipp PR, et al. J Clin Oncol. 2005;23(15):3412-3420.

• Cytogenetics/molecular testing– CD138 selection of marrow aspirate

– Metaphase karyotyping: del(13) (BCR)

Jagannath S, et al, Leukemia. 2007;21(1):151-157.

– FISH: t(4: 14), (14:16) del(1p), +(1q), del(17p) (BCR)

Munshi NC, et al. Blood. 2011;117(18):4696-4700.

– Molecular: GEP 70, EMC-92 (validation and what to do with high risk pts)

Shaughnessy JD Jr, et al. Br J Haematol. 2007;137(6):530-536. Kuiper R, et al. Leukemia. 2012;26(11):2406-2413.

• Other disease features– Extra-medullary disease, plasma cell leukemia, high LDH

Adapted from McCarthy PL, et al. Hematology Am Soc Hematol Educ Program. 2013:496-503.

Adapted from Ludwig H, et al. Oncologist. 2012;17(5):592-606.

Novel Agent-Containing Consolidation Therapy Improves Depth of Response and Prolongs PFS

• Bortezomib monotherapy

(Nordic Myeloma Study Group [NMSG 15/05] trial)1

– Significant improvement in PFS with bortezomib consolidation

compared to control: 27 months vs 20 months, P = .05

• VTD versus TD (GIMEMA trial)2

– VTD consolidation significantly increased CR and CR/nCR

rates versus TD

– Median PFS significantly longer for VTD versus TD:

62 months vs 48 months, P = .001

1. Mellqvist UH, et al. Blood. 2013;121(23):4647-4654. 2. Cavo M, et al. Blood. 2012;120(1):9-19.

Cavo M. Presented at: IMW 2013, oral presentation (S15 consolidation / maintenance)

Straka C, et al. J Clin Oncol. 2015;33(Suppl): Abstract 8511.

• Bortezomib 1.3 mg/m2 16 weekly doses over 20 weeks vs observation

PFS: Consolidation vs Observation

• Median PFS: 33.6 months (bortezomib vs 27.8 months (observation)

Induction treatment = VRD cycles 1,2 and 3 every 21 days

Lenalidomide 25mg/d (days 1 to 14)

Bortezomib 1.3mg/m2 (days 1, 4, 8, 11)

Oral dexamethasone 40mg/d (days 1, 8, 14)

Stem cell collection

ASCT

Consolidation treatment

VRD cycles 4 and 5 every 21 days

Maintenance therapy for 12 months

Lenalidomide 10mg/d for 3 months then 15mg/d if well tolerated

Immunophenotypic analysis

Immunophenotypic analysis

Immunophenotypic analysisResponse assessment

Response assessment

Response assessment

Response assessment

Response assessment

IFM 2008: Phase II Study

in Newly Diagnosed MM Patients <65 Years

Roussel M, et al. J Clin Oncol. 2014;32(25):2712-2717.

IFM 2008: Response Rates (ITT)(VRD x 3 - Transplant - VRD x 2 - Rev 1 year)

After

induction After ASCT

After

consolidation

After

therapy

n (%) n = 31 n = 30 n = 30 n = 31

MRD negative 4/25 (16) 14/26 (54) 15/26 (58) 21/30 (68)

sCR + CR 7 (23) 14 (45) 15 (48) 18 (58)

≥VGPR 18 (58) 21 (68) 26 (84) 26 (84)


IFM 2008: PFS• Median follow up: 39 months (range, 36-42 months), no death

• Estimated 3-year PFS 77% (CI 95%, 57%-88%) and OS 100%

• 10 patients MRD + : 7 relapses

• 21 patients MRD - : No relapse


PFS (ITT) and according to MRD status

IFM, Intergroupe Francophone du Myélome

IFM/DFCI 2009: VGPR Rate During Each Treatment Phase

RVD arm

N = 350

Transplant arm

N = 350P value

Post induction 47% 50% NS

At C4 or post transplant 55% 73% <.0001

Post consolidation 71% 81% <.006

Post maintenance 78% 88% <.001

Attal M. et al. Blood. 2015;126: Abstract 391. IFM, Intergroupe Francophone du Myélome

Maintenance for fixed time

or not if in CR


ASCT

Transplant Eligible

Induction

Maintenance for fixed time

or not if in CR


ASCT

Transplant Eligible

Induction

Supportive Care

Bortezomib and Zoledronate Maintenance Following ASCT

Adapted from: McCarthy PL, et al. J Natl Compr Canc Netw. 2013;11(1):35-42.

Maintenance vs no maintenance

N Initial dose PFS OSBenefit?EFS/OS

Sonneveld P, et al. J Clin Oncol. 2012; 30(24):2946-2955.

827

Bortezomib: 1.3 mg/m2 IV,

every 2 weeks for 2 years

OR

Thalidomide 50 mg daily for

2 years

(V after PAD vs T after VAD)

Med PFS

35 vs 28 months

(P = .002)

Median FU 41 months

OS (MV analysis)

HR 0.77

(95% CI, 0.60-1.00)

P = .049

+/+

Landmark analysis

PFS 45 vs 38% (P = .05)

5-year OS

61 vs 55% (P = .07)+/+

Rosiñol L, et

al Blood.

2012;120(8):

1589-1596.

386

Bort 1.3 mg/m2 IV, d 1, 4, 8, 11 every 3 mo + Thal 100 mg/dOR Thal 100 mg/d aloneORInterferon-α 3 million units SC3 times weekly(VTD vs T vs IFN-α)

2 year PFS

56.2 vs 28.2 vs 35.3

(P = .01)

OS not significantly

different+/NA

Morgan GJ,

et al. Lancet.

2010;376(975

7):1989-1999

1960 (ITT)

Zoledronic acid 4 mg IV every 3-4 weeks ORClodronic acid 1600 mg daily

IT Median PFS

19.5 vs 17.5 months

(P=.07)

Med OS IT

NR vs 62.5 months

P = .0854

NA/trend+

Median OS all pats

50 vs 44.5 mos

P = .04

+

Randomization

MM stage II or III, age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

Depending on local

policy for patients PR

MEL 200 + PBSCT

MEL 200 + PBSCT

Depending on local

policy for patients PR

MEL 200 + PBSCT

Thalidomide

50 mg/day for

2 years

maintenance

Allogeneic

Tx

Bortezomib

1.3 mg/m2 / 2 weeks

for 2 years

maintenance

Phase III: PAD vs VAD induction, High-Dose Melphalan (HDM) and

Bortezomib or Thalidomide Maintenance (HOVON 65 MM / GMMG-HD4 )


n = 371n = 373

n = 744, median age 57

VAD: vincristine,

doxorubicin, and

dexamethasone

PAD: bortezomib,

doxorubicin, and

dexamethasone

CAD: cyclophosphamide,

doxorubicin, dexamethasone

Scheid C, et al. Haematologica. 2014;99(1):148-154.

PFS and OS According to Treatment Arm According to Baseline Creatinine and Treatment Arm

PFS OS



PAD B PAD B

PFS OS



VAD T

VAD T

PAD B PAD B

PFS OS

PFS and OS for Thalidomide (Arm A) vs Bortezomib (Arm B) Induction and Maintenance by Cytogenetic Risk

del(17p)

t(4;14)

del(13/13q)



del(17p)

t(4;14)

del(13/13q)

PAD B PAD B



del(17p)

t(4;14)

del(13/13q)

VAD T

PAD B PAD B

VAD T


McCarthy P, et al. N Engl J Med. 2012;366(19):1770-1781.

CALGB 100104 Schema

• Stratification based on registration -2M level and prior thalidomide and lenalidomide

use during Induction.

• Primary Endpoint: Powered to determine a prolongation of TTP from 24 months to

33.6 months (9.6 months)

• The study was un-blinded at a median 18 months and 86/128 placebo patients without

progressive disease chose to cross over to receive lenalidomide.

Lenalidomide

10 mg/d with

↑↓ (5–15 mg)

n = 460

D-S Stage 1-3, ≤70 years

≥2 cycles of induction

Attained SD or better

≤1 year from start of therapy

≥2 x 106 CD34 cells/kg

Placebo

n = 229

Restaging

days 90-100

Registration

CR

PR

SD

Mel 200

ASCT

Randomization

McCarthy P, et al. N Engl J Med. 2012;366(19):1770-1781. Updated: Holstein SA, et al. J Clin Oncol. 2015;22(suppl):

Abstract 8523.

Lenalidomide Improves TTP and OS

Median: 53 vs 26 mos

Hazard ratio 0.54

(P<.001)

Median: NR vs 76 mos

Hazard ratio 0.60

(P = .001)

Holstein SA, et al. J Clin Oncol. 2015;22(suppl): Abstract 8523.Intent-to-treat analysis, data cut-off Nov 2014

Subgroup Analysis of TTP and OS

Holstein SA, et al. J Clin Oncol. 2015;22(suppl): Abstract 8523.

Intent-to-treat analysis, data cut-off Nov 2014

The Cumulative Incidence Risk (CIR) for Progression, Death and Second Primary Malignancy (SPM) During Maintenance Therapy: Placebo Versus Lenalidomide

SPM vs PD/Death SPM vs Death SPM Death vs Death

Holstein SA, et al. J Clin Oncol. 2015;22(Suppl): Abstract 8523.

The Cumulative Incidence Risk (CIR) for Progression, Death and Second Primary Malignancy (SPM) During Maintenance Therapy: Placebo Versus Lenalidomide

The CIR of developing a SPM (p=0.005) or dying from an SPM (p=0.02) is higher with Len

compared with placebo. The CIR of PD (p<0.001) or death (p<0.001) is higher for placebo as

compared with Len.

SPM vs PD/Death SPM vs Death SPM Death vs Death

Holstein SA, et al. J Clin Oncol. 2015;22(Suppl): Abstract 8523.

• ITT Analysis; median follow-up from transplant ~48 months

• Median TTP: 50 months versus 27 months P < .001

• Median OS: Not reached versus 73 months P = .008

McCarthy P, et al, Presented at: IMW 2013.

146/229 events (64%) on placebo

104/231 events (45%) on lenalidomide

CALGB 100104: Updated TTP/OS

Estimated HR=0.51

(95% CI = 0.39 to 0.66)

49% reduction in risk of

progression

69/229 (30%) deaths on placebo

47/231 (20%) deaths on lenalidomide

Estimated HR=0.61

(95% CI = 0.41 to 0.87)

39% reduction in the risk of death

[86 of 128 non-progressing

placebo pts received lenalidomide

at study un-blinding in Jan 2010]

Lenalidomide Maintenance Therapy: CALGB 100104 Update

• Cumulative incidence of second primary cancers greater in lenalidomide group (P = .034)

• Cumulative incidence of risk of PD (P = .004) and death (P<.001) greater in placebo group

Lenalidomide arm Placebo arm P

Median PFS 47 mos 27 months <.001

McCarthy P, et al, Presented at: IMW 2013 and ASH 2013.

Attal M, et al. N Engl J Med. 2012;366(19):1782-1791. Attal M, et al. Blood. 122: Abstract 406.

• PFS benefit: 42 vs 24 months overall; benefit seen in low and high risk

cytogenetic populations

• del17p: 29 vs 14 months; t(4;14): 27 vs 15 months. (Avet L’Oiseau H, et al. Blood. 2010;116: Abstract 1944)

• IMW 2014: PFS for t(4:14) 27 vs 24 mos.

• Maintenance stopped at a median of 2 years (range 1-3) due to SPM concern

IFM 2005-02: PFS and OS From Randomization(Study Unblinded 1/2010)

Maintenance Following ASCT

• 402 patients (younger than 65 years) randomized from 62 centers• Patients: Symptomatic disease, organ damage, measurable disease

Treatment Schedule

*MPR vs MEL 200; R maintenance vs no maintenance; Anti-thrombotic substudy: Aspirin vs Low molecular weight heparin

Rd (R: 25 mg/d, days 1-21; d: 40 mg/d, days 1,8,15,22); MPR (M: 0.18 mg/Kg/d, days 1-4; P: 2 mg/Kg/d, days 1-4; R: 25 mg, d 1-21), MEL 200 (M:

200 mg/m2 day -2); R maint (R: 10 mg/day, days 1-21); # One course MEL 200 if patients achieves VGPR after cycle 1; R: lenalidomide; MEL200:

melphalan 200 mg/m2 and autologous stem cell transplant; MPR: melphalan-prednisone-lenalidomide; NDMM: newly diagnosed multiple myeloma.

Rdfour 28-day courses

MEL 200Two courses#

NO MAINTENANCE

R MAINTENANCE28-day courses until PD

MPRsix 28-day courses

R MAINTENANCE28-day courses until PD

NO MAINTENANCE

*Randomization (2 x 2 design)

MPRsix 28-day courses

MEL 200Two courses#

Palumbo A, et al. N Engl J Med. 2014;371(10):895-905.

MPR, melphalan-prednisone-lenalidomide

0

25

50

75

100

0 10 20 30 40 50 60 70

MEL200-R

MEL200

MPR-R

MPR

Months

100

0 10 20 30 40 50 60 70

0

25

50

75

MEL200-R

MEL200

MPR-R

MPR

Months

Progression-free survival Overall survival

MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

MPR vs MEL200 vs MPR-R vs MEL200-R


R maintenance vs No maintenance

Median PFS

R maint. 37 months

No maint. 26 months

5-year OS

R maint. 75%

No maint. 58%

HR 0.52, 95% CI 0.40-0.67, P <.0001

Months

HR 0.62, 95% CI 0.42-0.93, P =.02

Months

0

25

50

75

100

0 10 20 30 40 50 60 70

0

25

50

75

100

0 10 20 30 40 50 60 70

R, lenalidomide

Progression-free survival Overall survival48% reduced risk of progression 38% reduced risk of death


Lenalidomide Maintenance Therapy Meta-Analysis

Singh M, et al. Blood. 2013;122: Abstract 407.

There was

significant

prolongation of

both PFS (HR 0.49,

95% CI, 0.41–0.58,

P<.001) and OS (HR

0.77, 95% CI, 0.62–

0.95, P = .013) with

LM vs. placebo/no

maintenance

• N=1209, median follow up 6.6 years

• OS benefit with LEN vs control: Not reached vs 86 months

− HR = 0.74; 95% CI, 0.62-0.89; log-rank P = .001

• 5 yr, 6 yr, and 7 yr OS longer with LEN

• LEN maintenance benefited all subgroups after ASCT

Attal M, et al. J Clin Oncol. 2016;34(suppl): Abstract 8001

Lenalidomide Maintenance Therapy Meta-Analysis: Updated OS

Consolidation and Maintenance Therapy Post-Transplant With Lenalidomide, Bortezomib and

Dexamethasone (RVD) in High Risk Patients

1. Stringent CR 51%, 96% VGPR

2. Median PFS 32 months

3. Three-year OS 93%

Nooka AK, et al. Leukemia. 2014;28(3)690-693.

N = 256, all patients received RVD

All received 3 drug maintenance

Minimal exposure to alkylators

Nooka AK, et al. Leukemia. 2014;28(3)690-693.

Early Versus Late Transplant in High Risk MM

P = .044; logrank

RVDx3

RVD x 2

RVD x 5

Revlimid until PD

Melphalan

200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

RVDx3

CY (3g/m2)

MOBILIZATIONGoal: 5 x106 cells/kg

Randomize

Collection

Revlimid until PD

SCT at relapse

Calibration

MRD

MRD

MRD

MR

D @

CR

MR

D @

CR

IFM/DFCI 2009; DFCI #10-106; CTN 1304

“The Determination Trial”

Newly Diagnosed MM (N = 1,360)

*Primary objective = 7-color Flow, secondary objective = molecular

P-value : p<0.0001

Negative (<10-6)

PositivePositive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Patients

without pro

gre

ssio

n (

%)

51 51(0) 51(0) 51(0) 47(3) 36(9) 26(5) 6(9) 3(0)MRD positive

80 80(0) 80(0) 80(0) 80(0) 73(3) 57(3) 33(5) 9(0)MRD neg (<10-6)

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at post-maintenance in CR patients

IFM 2009: 375 CR/sCR, 131 MRD Patients

83%

30%

Avet-Loiseau H, et al. Blood. 2015;126: Abstract 191.

P value: <.0001

Ixazomib Maintenance Following Ixazomib-Lenalidomide-Dexamethasone Induction in Untreated Multiple Myeloma

29 29

48

10

10

19

33

519

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Best response toinduction

Best response overall

sCRCRnCRVGPRPRMRSD

n = 5

n = 2

10 (48%) patients improved their response during maintenance:

2 VGPR to nCR, 5 VGPR to CR, 1 VGPR to sCR, and 2 CR to sCR

n=2

n=1

Kumar SK, et al. Blood. 2011;118.

Conclusions: Post-Transplant ConsolidationEmerging as a Key Component of Initial Treatment

Autotransplant

Initial therapy Maintenance

Consolidation


Autotransplant


Consolidation

Bortezomib1

VTD2

Lenalidomide3

RVD4

CTD5

Post-transplant consolidation

improves depths of response

(VGPR and CR)

Mellqvist UH, et al. Haematologica. 2011;96(Suppl1):S31. Cavo M, et al. Blood. 2012;120: Abstract 4210. Attal M, et al.

Haematologica. 2011;96(Suppl1):S23. Roussel M, et al. Blood. 2011;118: Abstract 1872. Sonneveld P, et al. Blood.

2012;120: Abstract 333. Adapted from: Jakubowiak AJ, Poznan 2014. EU /US Perspectives in MM.


Autotransplant


Consolidation

Bortezomib1

VTD2

Lenalidomide3

RVD4

CTD5

Post-transplant consolidation

improves depths of response

(VGPR and CR)

Benefits of Consolidation Emerging

Mellqvist UH, et al. Haematologica. 2011;96(Suppl1):S31. Cavo M, et al. Blood. 2012;120: Abstract 4210. Attal M, et al.

Haematologica. 2011;96(Suppl1):S23. Roussel M, et al. Blood. 2011;118: Abstract 1872. Sonneveld P, et al. Blood.

2012;120: Abstract 333. Adapted from: Jakubowiak AJ, Poznan 2014. EU /US Perspectives in MM.

Conclusions: Post-Transplant Maintenance

ThalidomidePFS prolonged (6/6)

OS prolonged (3/6)

LenalidomidePFS prolonged (2/2)

OS prolonged (1/2)

Bortezomib +/- ThalidomideMay contribute to

prolonged PFS (2/2)

prolonged OS (1/2)

Autotransplant


Consolidation

Adapted from Jakubowiak AJ, Poznan 2014; EU/US Perspectives in MM.

Conclusions: Post-Transplant Maintenance

ThalidomidePFS prolonged (6/6)

OS prolonged (3/6)

LenalidomidePFS prolonged (2/2)

OS prolonged (1/2)

Bortezomib +/- ThalidomideMay contribute to

prolonged PFS (2/2)

prolonged OS (1/2)

Autotransplant


Consolidation

Lenalidomide associated with increased SPM post SCT/HD Mel but OS benefit seen

USA: lenalidomide most commonly used agent based on favorable risk/benefit ratio

Updated TTP Updated OSIncludes pts crossing over

McCarthy, IMW 2013

Adapted from Jakubowiak AJ, Poznan 2014; EU/US Perspectives in MM.

Conclusions/Future Directions• New directions in prognostication / risk adapted therapy:

– Minimal residual disease measurements

PCR, Flow Cytometry, NGS

– Cytogenetic testing

CD138 selection with cytogenetic analysis

– Molecular gene expression profiling

• Disease control with less toxicity will likely result in improved

PFS and OS

• Addition of next generation novel agents

– Carfilzomib

– Anti-CD38 antibodies (DARA, ISA), anti-CS-1/SLAM F7 (ELO)

– Ixazomib

– Vaccines

– HDACIs

Conclusions/Future Directions

• Transplant eligible

– Bortezomib for 2 years following ASCT is a standard primarily

for those presenting in renal failure and those patients with

chromosome del(17p)

– Lenalidomide until PD is a standard of care following ASCT

– Second primary cancer risks is increased with lenalidomide

maintenance after HD MEL, but cumulative incidence risk of

relapse and death are worse without lenalidomide

maintenance

• Consolidation/maintenance for transplant eligible multiple

myeloma patients as part of clinical trials a key priority

• Identify target pathways for testing new agents with curative

intent (eg, checkpoint inhibition)

Thank You!!

Slide Courtesy of Phil McCarthy, MD

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Consolidation and Maintenance Therapy for Multiple Myeloma ... · Novel Agent-Containing Consolidation Therapy Improves Depth of Response and Prolongs PFS • Bortezomib monotherapy