live from new orleans multiple myeloma · 3. jakubowiak a. imw2013: abstract 010 4. san miguel,...

Multiple Myeloma

Jo Caers CHU Liège

Live from New Orleans

1. Smoldering MM

2. Elderly patients

3. Transplant eligible patients

4. Relapsing patients

5. Plasma cell leukemia

6. New agents

3’5’10’5’5’

5’

33’20 minutes myeloma2 minutes from prof Verhoef5 minutes from prof Bosly3 minutes from dr Mazure1.5 minutes from prof Berneman30 sec from prof Beguin

=

1. Smoldering MM

2. Elderly patients

3. Transplant eligible patients

4. Relapsing patients

5. Plasma cell leukemia

6. New agents

V Rajkumar, IMF satellite symposium

Ultra High risk - treat as myeloma≥ 60% BMPCFLC ratio ≥ 100≥ 1 MRI focal lesion

High risk - clinical trials

abnormal immunophenotypeabnormal FLC ratio≥ 3 g M-protein & ≥ 10% BMPC

Low risk: observe

V Rajkumar, IMF satellite symposium

8 cycles CRd Combination Therapy

Carfilzomib 20/36 mg/m2,

day 1, 2, 8, 9, 15, 16

Lenalidomide 25 mg/day, day 1-21

Dexamethasone 20/10 mg

day 1, 2, 8, 9, 15, 16, 22, 23

SD o

r b

ette

r?

24 cycles Rev Extended Dosing

Lenalidomide 10 mg/day, day 1-21

• Each cycle is 28 days

• Stem cell harvest after >4 cycles of CRd for patients <70-75 yrs

• C1D1/2 – Carfilzomib dose is 20 mg/m2

• C1- 4 – Dex dose is 20 mg, C5- 8 – Dex dose is 10 mg

Study open for high-risk smoldering

myeloma pts >18 years old

Landgren, et al. ASH abstract #1939

Phase II trial for high-risk SMM: carfilzomib/revlimid/dex

nCR/CR/sCR 8% 58% 83% 100%

Landgren, et al. ASH abstract #1939

Mean

M-s

pik

e (

d/d

L)

11/12 (92%) are MRD negative by 8-color flow cytometry of the bone marrow

1. Smoldering MM

2. Elderly patients3. Transplant eligible patients4. Relapsing patients5. Plasma cell leukemia6. New agents

5 year overall survival by age

< 65 yrs > 65 yrs

2006-2010 73% 56%

2001-2005 63% 31%

S Kumar, ASH 2012, # 3865

Fit

Karnofsky ≥80%/Charlson index=0

Unfit Frail

Karnofsky 60%-80%Charlson index ≤2

Karnofsky < 60%Charlson index >2

MV Mateos, ASH 2013, educational session

Fit


Unfit Frail



Alkylator-based comb

MPT x9cVMP x9c CyBorD x9c

Bz biweekly the 1st cycle and weekly thereafter; Bz SQ.Thal doses up to 200mgLen full dosesCy at 500 mg/m2 days 1, 8, 15Melph full dosesDex low doses: 40 mg weekly

Non Alkylator-based comb

VTP x9cRVd x9cRd until DP

MV Mateos, ASH 2013, educational session

ORR PFS (2 yr) OS ( 2yr)

Rd 220 75% 49 % 80%

MPR 217 63% 55 % 84%

CPR 222 80% 55 % 84%

Palumbo et al. ASH 2013:abstract 536

Fit


Unfit Frail



Bz weekly since the beginning; Bz SQ.Thal doses not superior to 100mg.Len 25 mg daily in Ld, but 15 mg in RVDCy 300 mg/m2 days 1, 8, 15.Melph reduced doses: 6-7 mg/m2

Dex reduced doses: 20 mg weekly


MPT x9cVMP x9c CyBorD x9c


VTP x9c/Vd x 9cRVD x9cLd until DP

Fit


Unfit Frail



Bz weekly since the first cycle; Bz SQ.Thal doses not superior 50mg.Len dose of 10-15 mgCy dose of 50 mg dailyAvoid melph and dex


CyTPCyBorP


VpLd until DP

ORRPFS

(median) OS ( 1yr)

VP 51 67% 14 m 80%

VMP 50 63% 16 m 80%

VCP 51 80% 16 m 82%

Larocca et al. ASH 2013:abstract 539

Progression Free Survival


1310 patients (650 CRD vs 660 CTD) 1058 patients (531 CRDa vs 527 CTDa)

Pawlyn C et al. ASH 2013:abstract 540

CRD Induction: Median age 61 y (range 28-75)

Cy(500 mg po D1, 8), Len (25 mg po 1-21), dex (40 mg po D1-4, 12-15)

CRDa Induction : Median age 74 y (range 51-89)

Tx: Cy(500mg po D1, 8), Len(25mg D1-21), dex (20mg po D1-4, 15-18)

CRD

(n = 444)

CRDa

(n = 335)

ORR

(≥PR)84% 73%

CR 17% 17%

VGPR 44% 36%

PR 23%) 20%

• CRD Med N of Cycles 5Dose reduction 61%

• CRDa Med N of Cycles 6Dose reduction 74 %

• 3/4 toxicities for CRD/CRDa:

neutropenia 21% vs 32%,thrombocytopenia 5.1% vs 9.9%.

Pawlyn C et al. ASH 2013:abstract 540

1. Moreau P et al. ASH 2013:abstract 1933

2. Bringhen S et al. ASH 2013: abstract 685

3. Jakubowiak A. IMW2013: abstract 010

4. San Miguel, NEJM, 2008

Carf-MP1

Phase 1/2

Carf-Cydex2

Phase 1/2

Carf-Rd3

Phase 1/2VMP (VISTA)

Patients (N) 69 5423

≥ 65 years344

ORR (%) 87 100 100 74

≥VGPR (%) 51

77 (64%

CR/nCR, 23%

sCR)

87 (≥nCR 83%,

sCR 61%)41 (CR33%)

Safety

profile G3: PN: 1%No PN

G3-4: PN 13% (all

grades 1/2)

Grade 3-4 PN:

13%

Phase 3 CMP vs VMP - Carf-Rd vs Rd

• Rev/Dex untill progression will probably be one of the first line therapies and replace thalidomide based therapies.

• Velcade is currently the other option• Role of melphalan ?

• Doublet or triplet ?

• New agents are arriving in this setting

1. Smoldering MM2. Elderly patients

3. Transplant eligible patients4. Relapsing patients5. Plasma cell leukemia6. New agents

Novel agents

Induction

therapy

Autograft

1 ± 2Consolidation Maintenance

Novel agents

Induction

therapy

1. Lokhorst HM, et al. Haematologica. 2008;93:124-7. 2. Rajkumar SV, et al 2008 J Clin Oncol 26:2171-77. 3. Harousseau JL, et al 2010 J Clin Oncol 28:4621-

4629. 4. Rajkumar SV, et al Lancet Oncol 2010; 11: 29–37. 5. Sonneveld P, et al J Clin Oncol 2012; 30:2946-55. 6. Cavo M, et al Lancet 2010; 376: 2075–85.

7. Reeder CB, et al. Blood. 2010; 115:3416-7. 8. Richardson et al. Blood 2010;116:679-686. 9. Jakubowiak AJ, et al Blood. 2012 30;120:1801-9. 10. Palumbo A,

et al. Blood. 2012;120:[abstract 730]. 11. Kumar S, et al . Blood. 2012;120:[abstract 332]. 12. Kumar S, et al. Blood 2012 119: 4375-82.

Pati

en

ts r

esp

on

din

g (

%)

Induction regimenAdapted, Stewart et al Blood 2009

N ORR PFS (2 yr) OS ( 2yr)

VCD 88 93% 69.9 % 92%

VRD 71 87% 67.9 % 84.6%

Progression free survival Overall survival

Kumar S et al. ASH 2013:abstract 3179

ORR 89%

≥ VGPR 62%

PFS (5 year) 42%

OS (5 year)OS standard risk

70%81%

Reeder C et al. ASH 2013:abstract 3192

1. Korde N et al. ASH 2013:abstract 538

2. Sonneveld et al. ASH 2013: abstract 688

Carf-Len-Dex1

Phase 2

Carf-Thal-Dex

Phase 1/2

Patients (N) 69 58

ORR (%) 97 94 - 100

≥VGPR (%) 89 84

nCR/CR/sCR63%

51%

Safety profileG3: PN: 1%

No PN

16%

38%

58%67%35%

48%

31%21%

47%

12% 8% 9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0

0,5

1

1,5

2

2,5

3

3,5

BL 2 4 6 8

Me

an M

-pro

tein

(g

/dL)

Cycles of CRd DeliverednCR/CR/sCR VGPR PR SD

n(%)

22/43(51)>VGPR n/N(%): 34/40(85) 34/38(89) 30/33(91)

Korde N et al. ASH 2013:abstract 538

0

5

10

15

20

25

CR/sCR nCR VGPR PR SD

Pati

en

ts

MRD Status after CRd therapy MFC

Among 27 nCR/sCR* patients

assessed by flow, all 27 are MRD

negative

CD45 V500

CD

56

PC

7

102

103

104

105

102

103

104

105

CD45 V500

CD

56

PC

7

102

103

104

105

102

103

104

105

CD45 V500

CD

19

AP

C

102

103

104

105

102

103

104

105

CD45 V500

CD

19

AP

C

102

103

104

105

102

103

104

105

Patient #7

Pre CRd: Abnormal PC’s CD19-,

CD45 dim, CD56dim+

Post CRd: Normal PC’s CD19+,

normal CD45, CD56-

MRD NEGATIVE

FLOW

POSITIVE

AFTER 8 cycles

FLOW

NEGATIVE

AFTER 8 cycles

*2 patients (1 sCR and 1 nCR) not available for interpretation

Carfilzomib 20/27mg/m2

days 1,2,8,9,15,16 of a

28 day cycle.

Thalidomide 200 mg

days 1-28 of a 28 day

cycle

Dexamethasone 40 mg

days 1,8,15,21 of a 28

day cycle

HDM

200 mg/m2

ASCT

Induction

4 cycles

Consolidation

4 cycles

Intensification

1 cycle

Carfilzomib 27mg/m2

days 1,2,8,9,15,16

of a 28 day cycle.

Thalidomide 50 mg

days 1-28 of a 28 day

cycle

Dexamethasone 40 mg

days 1,8,15,21 of a 28

day cycle

Sonneveld P et al. ASH 2013:abstract 685

Carfilzomib dose

27 mg/m2 36 mg/m2 Total

# % # % # %

Total 50 20 70

After Induction sCR/CR 9 18 3 15 12 17

≥VGPR 29 58 16 80 45 64

≥PR 46 92 19 95 65 93

After HDM sCR/CR 15 30 7 35 22 31

≥VGPR 34 68 16 80 50 71

≥PR 47 94 20 100 87 96

After Consol sCR/CR 28 56 8 40 36 51

≥VGPR 43 86 16 80 59 84

≥PR 47 94 20 100 67 96


High

Risk

Standard

Risk

All

Patients # 30 25 70

CR/sCR % 57 48 51

≥ VGPR % 90 76 84

≥ PR % 90 90 96

High Risk: t(4;14) and/or 17p- and/or add1q and/or ISS3

Standard Risk: all other Sonneveld P et al. ASH 2013:abstract 685

Novel agents

Induction

therapy

Autograft

1 ± 2

Randomization

3 x VAD 3 x PAD

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

Thalidomide

maintenance

50 mg/day for

2 years

Allogeneic

Tx

Bortezomib

Maintenance

1.3 mg/m2 / 2 weeks

for 2 years


A: VADB: PADCox LR Stratified P =0.009

N414413

F333305

A: VADB: PAD

At risk:414413

325355

228260

162186

119136

7792

4250

1317

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

A: VADB: PADCox LR Stratified

N414413

D182155

P =0.05

A: VADB: PAD

2 Jul 2013-17:13:09

At risk:414413

361375

327343

278307

249271

182193

79

101

2028

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

Randomization arm

Overall survival

goodintermediatepoor

N567327

F365322

good

intermediatepoor

At risk:567327

506321

384413

28287

20195

15113

1060

320

good

intermediate

poor

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

Progression-free survival by risk group FISH + ISS

Progression-free survival Overall survival


F286428

N468330

goodintermediatepoor

good

intermediatepoor

At risk:468330

436818

41458

35265

24192

16101

1041

311

good

intermediate

poor

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

A: VADB: PADCox LR Stratified P =0.009

N414413

F333305

A: VADB: PAD

At risk:414413

325355

228260

162186

119136

7792

4250

1317

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

A: VADB: PADCox LR Stratified

N414413

D182155

P =0.05

A: VADB: PAD

2 Jul 2013-17:13:09

At risk:414413

361375

327343

278307

249271

182193

79

101

2028

A: VAD

B: PAD

0

25

50

75

100

months0 12 24 36 48 60 72 84

Cum

ula

tive p

erc

enta

ge

Randomization arm

Overall survival

Progression-free survival Overall survival

Overall survival single vs double


Hovon

Novel agents

Induction

therapy

Autograft

1 ± 2Consolidation

– Bortezomib versus observation post auto HSCT• Mellqvist U et al Blood 2013

– VTD versus TD post tandem auto HSCT• Cavo M et al, Blood 2012, ASH 2013 abstract 2090

– VTD after auto HSCT • Ladetto M et al JCO 2010

• Leleu X et al. Leukemia 2013 ASH 2013 abstract 3221

– Lenalidomide after auto HSCT• Attal M et al, NEJM 2012

– Allogeneic Hematopoietic Stem Cell Transplant?• Krishnan A et al Lancet Oncology 2011, Gahrton G et al Blood 2013

Phase III Studies

1. Ladetto et al J Clin Oncol 2010;28:2077. 2. Cavo et al Blood. 2012;120:9-19. 3. Roussel et al Blood 2011;118:1872.

4. Attal et al New Eng J Med 2012;366:1782. 5. Leleu et al Leukemia 2013 Epub. 6. Mellqvist et al Blood 2013;121:4647-54.

Pati

en

ts r

esp

on

din

g (

%)

Consolidation regimen

Novel agents

Induction

therapy

Autograft

1 ± 2Consolidation Maintenance

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%

)

307 225 141 92 63 43 7 0Placebo307 244 208 157 121 86 27 0Lenalidomide

N at risk

0 12 24 36 48 60 72 84

Months of follow-up

Lenalidomide

Placebo

P=0.80

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

Aliv

e(%

)

307 287 276 250 227 160 52 3Placebo307 294 264 236 215 165 64 2Lenalidomide

N at risk

0 12 24 36 48 60 72 84

Months of follow-up

Lenalidomide

Placebo

CALGB 100104: Updated IFM 2005-02 updated dataBoccadoro, ASCO 2013

Poor outcome after progression ?

1. 2nd PFS = from 1st to 2nd progression

2. PFS 2 = 1st PFS + 2nd PFS

3. Survival after the 1st progression

First line Second line Third line 4 th line x th line death



Attal M et al. ASH 2013:abstract 406

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%

)

241 161 90 45 11 2Placebo165 77 26 11 1 1Lenalidomide

N at risk

0 12 24 36 48 60

Months of follow-up

Lenalidomide

Placebo

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Patie

nts

(%

)241 209 161 101 44 7Placebo165 122 67 36 7 3Lenalidomide

N at risk

0 12 24 36 48 60

Months of follow-up

Lenalidomide

Placebo

2nd PFS

1.Survival after the 1st progression

Survival after the 1st progression


2nd PFS according to treatment of 1st progression

Total

(n=614)

Placebo

(n= 307)

LEN

(n=307

)

p

Nb of 1st progression 406 241 165

Nb of treated 1st progression 369 215 154

Imid based regimen: n (%)

No of patients

Median 2nd PFS

181 (49%)

134

19 m

49

8 m 0.003

Velcade based Regimen: n (%)

No of patients

Median 2nd PFS

94 (25%)

31

8 m

63

9 m 0.28

No new agents: n (%)

No of patients

Median 2nd PFS

92 (25%)

50

30 m

42

18 m 0.06


• Triplet combinations (based on velcade) are considered standard of care.

• VCD or VTD are probably excellent induction regimens for standard-risk patients

• High-risk patients

– Consolidation and maintance with btz?

– Induction with carfilzomib?

• Consolidation

• Maintenance (under debate)

1. Smoldering MM2. Elderly patients3. Transplant eligible patients

4. Relapsing patients5. Plasma cell leukemia6. New agents

• Relapsing patients– Early treatment in high risk cytogenetics t(4;14)

and del17p#689 X Leleu

– Update from the MM03 with prolonged follow-up#408, M Dimopoulos#686, J S Miguel

• Amyloidosis (relapsing patients)– #288, G Palladini– pomalidomide 4mg/Dexamethasone

ORR 70%, VGPR+ = 37%, CR 4%

del17

p

t(4;14

)

ITT

IFM 2010-02 Pomalidomide/dex in high risk patients

ITT population

(N = 50)

del17p

(n = 22)*

t(4;14)

(n = 32)*

ORR

(≥PR)11 (22) 7 (32) 5 (16)

≥ VGPR 3 (6) 2 (9) 1 (3)

PR 8 (16) 5 (23) 4 (12.5)

SD 30 (60) 9 (41) 22 (69)

PD 7 (14) 4 (18) 5 (16)

N = 50•RRMM

•Exposed to Len

•del 17p and/or t(4;14)

•Measurable disease

•ECOG 0–2

•PNn > 1 x109/L

•Plat ≥ 75 x109/L

•Hb ≥ 8 g/dL

•CrCl ≥30 mL/min

Pomalidomide

4 mg/day, po, days 1–21 (of 28 d cycle)

Dexamethasone

40 mg, po, days 1, 8, 15, 22

Aspirin/LMWH

once daily, continuously

Until progression

Leleu X et al. ASH 2013:abstract 689

• Frontline treatment: alkylators and bortezomib

• Response rates to Lenalidomide in refractory patients is 40%

• Phase 2 trial (2 mg starting dose and increase if responses unsatisfactory) in refractory patients showed response rate of 48%.

• Treatment schedule 28-day cycles (until progression or toxicity) of

pomalidomide (3+3 dose escalation), days 1-28- 2 mg/day (3 patients), no DLT- 4 mg/day (24 patients)

dexamethasone- 40 mg/week (14 patients)- 20 mg/week (13 patients with fluid retention or arrhythmias)

prophylaxis: aspirin (or heparin), cotrimoxazole, omeprazole

Palladini et al. ASH 2013:abstract 288

Hematologic responsePatients

dFL

C d

ecr

eas

e (

%)

Best response N (%)

CR 1 (4)

VGPR 9 (33)

PR 9 (33)

Overall 19 (70)

• Median time to first response: 1.1 months• Median time to best response: 3.0 months

Previoustreatment

Responders

Lenalidomide 6/7

Ixazomib 3/3

Palladini et al. ASH 2013:abstract 288

– REP was feasible and effective in a retrospective pilot with 14

heavily pre-treated len-dex refractory myeloma patients (van de Donk,

BJH 2010)

– However, the optimal dose of LEN with continuous oral

cyclophosphamide and prednisone has not yet been defined

Cohort Lenalidomide Cyclophosphamide Prednisone mg

1 10 100 20

2 15 50 20

3 15 100 20

4 25 50 20

5 25 100 20

All patientsn=21

LEN and BOR refractory patients

n=16

Patients with high-risk MM

by FISH analysis n=9

VGPR 33% 31% 44%

≥ PR 67% 69% 78%

≥ MR 76% 75% 89%

≥ SD 86% 88% 89%

Mean PFS 6.3 m

Mean OS 15.5 m

Nijhof I et al. ASH 2013:abstract 287

1. Smoldering MM2. Elderly patients3. Transplant eligible patients4. Relapsing patients

5. Plasma cell leukemia6. New agents

Primary Plasma Cell LeukemiaNo prior therapy18 ≤ age ≤ 70 y

Induction: PAD / VCDalternance of 4 cycles (D1=D22)

Response ≥ SD and blood PC < 1%=> Cyclophosphamide + G-CSF

=> PSC collection

Melphalan 200mg/m2 + ASCT

If response ≥ VGPR, age < 66y and donorMelphalan 200mg/m2 + ASCT n°2

Consolidation/maintenance for 12 monthsVRD / 3months

Len: 15mg D1-D21/ every other monthsReduced Intensity Conditioning-allograft

If age > 66y or no donor

PAD: Bor1.3mg/m2 +Dex 40mg ) D1 D4 D8 D11 + Doxo 30mg/m2 D4VCD: Bor1.3mg/m2 + Dex 40mg ) D1 D4 D8 D11 + Cyclophosphamide 300mg/m2 D1 D8VRD: Bor1.3mg/m2 + Dex 40mg ) D1 D4 D8 D11 + Len 15mg D1-D14RIC-allo: Fludarabin-Busulfan-Antilymphocyte serum

Design

MRD

MRD

MRD

MRD

40 patientst(4;14) in 5Del 17p in 9+ 1q in 17Loss/del p53 in 9

40 patients After induction

After ASCT

27 responses13 no responses

27 24 6 patients 2 ASCT15 patients RIC-Allo

CR 16% sCR/CR 37%

VGPR 32 % VGPR 29%

PR 44 %SD 8%

PR 22%SD 4%PD 8%

12 patients died

1 before treatment: sepsis2 during induction: sepsis2 post RIC-Allo: EBV+ relapse, toxoplasmosis (1)7 from disease progression

Royer et al. ASH 2013:abstract 761

1. Smoldering MM2. Elderly patients3. Transplant eligible patients4. Plasma cell leukemia5. Relapsing patients

6. New agents

• Monoclonal antibodies

– CD38• Daratumumab # 1986 combined with len/dex

• SAR650984 # 284 phase 1, ORR 31%

– CD138

• Indatuximab Ravtansine # 758 combined with len/dex

• Ixazomib (MLN9708)• # 535 P Richardson

Phase 1/2 combined with len/dex

ORR 94%, VGPR+ = 76%, CR/sCR 45%

• Further information:

Myeloma Beacon

• http://www.myelomabeacon.com/ash-2013-multiple-myeloma-gateway/

WEBCAST OF THE IMWG CONFERENCE SERIES "MAKING SENSE OF TREATMENT"

www.myeloma.org

Videos – webcasts from meetings – ASH2013

http://www.myelomabeacon.com/ash-2013-multiple-myeloma-gateway/

http://www.myeloma.org/

live from new orleans multiple myeloma · 3. jakubowiak a. imw2013: abstract 010 4. san miguel,...

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