Myeloma 2013-What we know-What we don’t know and what we don’t know we

don’t know.

Sergio A. Giralt, MDChief, Adult Bone Marrow Transplant Service

Division of Hematologic OncologyDepartment of Medicine

Memorial Sloan-Kettering Cancer CenterNew York, New York

Disclosures

• Grant Support– Celgene– Millenium– Onyx

• Honoraria– Celgene– Millenium– Onyx– Novartis– Sanofi/Genzyme

• Most important I am a transplanter

Initial PresentationInitial Presentation

• 45-year-old woman • Presents with proteinuria. • Normal Physical• Laboratory findings

– Hemoglobin 11 gm/dl normal iron stores– Total proteinuria 5.82 g/day– Bence Jones protein (BJP) 3.6 g/day– Hypogammaglobulinemia– Albumin 3.9 g/dL – β2-microglobulin 4.7 mg/L– Creatinine 1.7 mg/dl – No paraprotein peak but kappa light chain 120000 with lambda light

chain at 0.01– Kappa/lambda ratio=12000000

• Bone marrow biopsy – Cellularity 80% with 25% plasma cells– Cytogenetics 46, XX, inversion 9 (p11;q13)

• FISH no abnormalities• Skeletal survey: extensive lytic bone disease with healing fractures

of left 7th and the 8th ribs• MRI of the spine: diffuse hyper-intense homogenous signal on STIR

sequence• MRI of the pelvis: diffuse marrow infiltrative changes due to

myeloma• Comorbidities: Diabetic on metformin, no history of coronary artery

disease or other comorbidities

Multiple Myeloma: AnalysisMultiple Myeloma: Analysis

3 decades

Myeloma

M0 M1 M2 M3 M4 M5 M6 M7

Hyperdiploidy

t(6:14)SC Pre Pro Early Mid SHM ICS PC

t(14;16)

t(4:14)

t(11;14)

Images courtesy of Raphael Fonseca, MD.

Multiple Myeloma Treatment LinesMultiple Myeloma Treatment Linesaa

Induction Consolidation

Front-line treatment

Maintenance

Maintenance

Rescue

Relapsed

IMID:Thal-LenProteosome Inhibitor: Bor-Car

Steroids: Dex-PredAlkylator: Cyclo-Mel

Anthracycline: LipoDnr-Adr

SCT

ObservationIMID:Thal-Len

Proteosome Inh-BorSteroids:Dex-Pred

IMID:Thal-Len-PomProteosome Inh:Bor-Car

Steroids: Dex-PredAlkylators:Mel-Cy-Benda

Investigational

aTransplant eligible patients.Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant;

Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin.NCCN, 2009.

IS THERE AN OPTIMAL INDUCTION REGIMEN?

What we know…

Protocol GIMEMA 26866138-MMY-3006Protocol GIMEMA 26866138-MMY-3006VTD vs TD incorporated into double ASCT for MMVTD vs TD incorporated into double ASCT for MM

RANDOMIZATION

INDUCTION• VEL-THAL-DEX

TRANSPLANTATION• MEL 200• MEL 200

CONSOLIDATION• VEL-THAL-DEX

MAINTENANCE• DEX

INDUCTION• THAL-DEX

PBSC COLLECTION• CTX

CONSOLIDATION• THAL-DEX

RESPONSE TO PRIMARY THERAPYRESPONSE TO PRIMARY THERAPY

% of patients% of patients

RESPONSERESPONSEVTDVTD

(n=129)(n=129)

TDTD(n=127)(n=127) P valueP value

CR+nCRCR+nCR 3636 99 <0.001<0.001

VGPRVGPR 6060 2727 <0.001<0.001

< PR< PR 77 2020 0.0030.003

ProgressionProgression 00 5.55.5 0.0080.008

EBMT criteria (with added nCR and VGPR categories)

RESPONSE (CR+nCR) TO PRIMARY THERAPY RESPONSE (CR+nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIESACCORDING TO GENETIC ABNORMALITIES

27

32

43

47

0

10

20

30

40

50

60

%

13 t(4;14)

P=0.06 P=0.1

43

47

4

8

0

10

20

30

40

50

60

%

13 pos t(4;14) pos

P<0.001 P=0.002

neg pos neg pos

VTD VTD vs TD

VTD VTD

TD

GIMEMA: Results

• Secondary endpoints– PFS

– OS• 96% (VTD) vs 91% (TD); P = .2

• Primary endpoint: CR + nCR (VTD vs TD as induction therapy)

Cavo M, et al. ASH 2008. Abstract 158.

Response, %VTD

(n = 226)TD (n = 234)

P Value

CR + nCR 32 12 < .001

≥ VGPR 62 29 < .001

≥ PR 94 79 < .001

Progression 0 4.7 .001

Modified EBMT and Uniform Criteria (nCR and VGPR categories) 0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30

Mos

2-yr rates

P = .009

VTD (n = 226): 90%TD (n = 234): 80%

Meta-analysis

Phase II Study of Len, Bortezomib, and Dex (RVD) in Newly Diagnosed MM (Richardson et al)

• Pts• 35 enrolled in phase II; median age 59 (22-86) yrs; • ISS Stage II/III 54%/11%

• Dose • Lenalidomide 25 mg/d, d 1-14 in 21 day cycle• Bortezomib 1.3 mg/m2 d 1, 4, 8, 11• Dexamethasone 20 mg day of and after bortezomib• Aspirin and antiviral prophylaxis

• Safety• Grade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality

Response n = 35 evaluable

CR/nCR 52%

< VGPR 74%

ORR (≥PR) 100%

• Results• At 19 mos of follow-up, TTP, PFS, At 19 mos of follow-up, TTP, PFS, and OS have not been reachedand OS have not been reached• Median stem cell collection in 15/35 Median stem cell collection in 15/35 patients: 4.4 x 106 CD34+ cells/kgpatients: 4.4 x 106 CD34+ cells/kg

Newly Diagnosed MM

Kaplan-Meier analyses of treatment outcomes.

Kumar S et al. Blood 2012;119:4375-4382

©2012 by American Society of Hematology

Stem Cell CollectionStem Cell Collection

• After 4 cycles of RVD she achieves a VGPR with kappa light chains reduced to 10 and lambda light chains recovered to 0.1.

• Her marrow reveals 4% kappa restricted plasma cells.

• MRI demonstrates significant resolution of infiltrative images.

• She agrees to proceed to stem-cell collection and transplantation.

OPTIMAL MOBILIZATION STRATEGYOPTIMAL MOBILIZATION STRATEGY

What we know…

Effect of Lenalidomide Duration of Therapy on Stem Cell Collection

Effect of Lenalidomide Duration of Therapy on Stem Cell Collection

Paripati H. Leukemia. 2008;22:12821284.

CD

34+

Co

un

t (C

ells

µl-1

)

5

10

15

20

25

30

35

0

1

2

3

4

5

6

7

8

9C

D34

+ C

ou

nt

(in

Mil

lio

ns)

0 0

0.5

2

1.5

4

2.5

6

3.5

8

4.5

Day

s

05

101520253035

404550

Per

cen

tag

e

Mean Peripheral BloodCD34+ Count

Total CD34+ Cellscollected

(Mean x 106 cells Kg-1)

Mean number ofdays of collection

Percentage of patientswho failed

first collection

Lenalidomide Therapy Other Induction Therapies

n=16

n=40 n=40

n=40n=18

n=18

P value = 0.0002 P value=0.0025 P value = 0.07 P value = 0.0011

Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization

Utilizing Plerixafor

Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization

Utilizing Plerixafor

• Plerixafor + G-CSF– N = 60 patients with myeloma frontline

mobilization: 20 patients & CUP: 40 pts– Median CD34 collected 5.6 x 106 CD34/kg– 87% collected ≥ 2 x 106 CD34/kg– 63% collected ≥ 5 x 106 CD34/kg– Up front pts: 100% (≥ 2) & 95% (≥ 5)– CUP pts: 80% (≥ 2) & 48% (≥ 5)

Micallef I, et al. Haematologica. 2009;94(suppl 2):0718; Tarantolo S, et al. Biol Blood Marrow Transplant. 2009;15(2 suppl 2):91.

What we don’t knowWhat we don’t know

• Is VRD superior to VTD or CyBorD?• Should the goal be ‘X” number of cycles and

proceed to SCT or should patients continue induction until best response?

• Is “response adapted” therapy appropriate?• Is there a role for carfilzomib based induction?• Should anybody be chemomobilized in the era of

plerixafor?

Stem Cell TransplantationStem Cell Transplantation

• She collects 10 million CD34 cells per kg over 3 days and is ready to be admitted for high dose melphalan and autologous stem cell transplantation.

• She asks what is it going to be like and does she really need a SCT?

ROLE OF SCT IN THE ERA OF IMIDS AND PROTEOSOME INHIBITION

ROLE OF SCT IN THE ERA OF IMIDS AND PROTEOSOME INHIBITION

What we don’t know…

Figure 2

Source: Biology of Blood and Marrow Transplantation 2007; 13:183-196 (DOI:10.1016/j.bbmt.2006.09.010 )

Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions

BENEFIT OF AUTOGRAFTING FOR MYELOMAKoreth et all BBMT

Early-vs-Late SCT Study?

m

A

A

mm

A

A

AA

Risk profile

Optimalinductionregimen

Maintenance

COLLECT HD THERAPY + SCT

HARVEST AND HOLDSCT UPON RELAPSE

IFM/DFCI 2009 StudyNewly Diagnosed MM Pts (SCT candidates)

VRD x 3

VRD x 2

VRD x 5

Lenalidomide 12 mos

Melphalan 200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg

VRD x 3

CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg

Randomize, stratification ISS & FISH

Collection

Lenalidomide 12 mosSCT at relapse

MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140mg/m2

http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1

Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following

Lenalidomide/Dexamethasone (Ld) Induction

Primary end point: PFS

RANDOMIZE

Lenalidomide: 25 mg, days 1–21Low-dose Dex:40 mg, days 1, 8,15, 22 q 28 days ×4

Consolidationn=402

<65 years RANDOMIZE

Nomaintenance

Maintenancelenalidomide: 10 mg/d, Days 1–21q 28 days until relapse

Palumbo A et al. Blood. 2009;114:Abstract 350.

MPR (n=202)Melphalan: 0.18 mg/kg/d, days 1–4Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21q 28 days ×6

Tandem MEL200 ASCT

stem cells mobilized with cyclophosphamide + G-CSF

Median follow-up 26 months

Progression Free Survival

HR 0.506

P = 0.0002

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; PFS, progression free survival; HR, hazard ratio; mos, months

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20 25 30 35 40 45

2-years PFS

MPR

MEL200

54%

73%

Median PFS

Not reached

25.26 mos

Pat

ien

ts (

%)

Months

49.4% Reduced Risk of Progression

MPR MEL200 P value

CR 20% 25% P=0.55

PFS @ 24 months 54% 73% P=0.0002

OS @ 24 months 87% 90% P=0.19

Less G3-4 hematologic toxicity in MPR arm (P<0.001)

Less mucositis and infections in MPR arm (P<0.001)

No difference in term of early deaths

Significantly longer PFS after ASCT (P<0.001)

Longer follow up is needed to assess OS

Conclusions

MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation

eastern cooperative oncology groupeastern cooperative oncology group

E4A03: Landmark Analysis at Median Follow-up of 36 mo

Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages 29 - 37, January 2010

431 patients alive at 4 cycles

Off therapy at 4 cycles

n=183

Primary therapy beyond 4 cycles

n=248

no transplantN=93

(median age 68)

Transplant n=90

(median age 57)

Ldn=140

(median age 66)

LDn=108

(median age 65)

eastern cooperative oncology groupeastern cooperative oncology group

Outcomes in pts Age <65

Progression Free Survival Overall Survival

What we don’t knowWhat we don’t know

• Should everybody be collected upfront?– How much?

• Who should undergo upfront SCT?– All patients?– Only those with suboptimal response?

What is suboptimal?– PR– VGPR– Near CR

– Who is truly transplant ineligible?– What about low risk patients in CR?

• What role does risk stratification play in deciding therapies?

FUNCTIONAL ASSESSMENT

32

Aging Heterogeneity

Community Dwelling, Typical

Institutionalized, FrailAges 84,81

Community Dwelling, Healthy

Age 82

Community Dwelling, FrailAges 19, 82, 23

Xz12_56.ppt

Transplant-related Mortality after Autologous Transplant-related Mortality after Autologous Hematopoietic Cell Transplantation for Hematopoietic Cell Transplantation for

Malignant Diseases by HCT-CI, 2007-2009Malignant Diseases by HCT-CI, 2007-2009

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

Incid

en

ce,

%

Years

0 15 305 252010

HCT-CI=1-2 (n=2,813)

HCT-CI=0 (n=5,185)

HCT-CI3 (n=2,388)

p<0.001

100-Day Mortality by HCT-CI After Autologous 100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation Hematopoietic Cell Transplantation

According to Performance Score and Disease According to Performance Score and Disease IndicationIndication

10

0 d

ay m

ort

ality

,%

P<0.001 P<0.001

Rate of SCT in US according to AgeRate of SCT in US according to AgeCosta et al ASH 2012Costa et al ASH 2012

<50 years 50-64 years ≥ 65 years

Figure 1

0

1

2

3

4

5

6

Baseline Conditioning Regimen

Day of Transplant

Nadir of WBC Hospital Discharge

30 days post BMT

Mea

n of

5 M

ost S

ever

e S

ympt

oms

Time

Symptom Severity by CD34 Positive Cells Infused

4 - 6x10^6 CD34 Cells/Kg

10 - 15x10^6 CD34 Cells/Kg

Randomized Phase II LD/HD CD34Randomized Phase II LD/HD CD34

In my humble opinionIn my humble opinion

• High dose melphalan is one of the most active agents in myeloma today– 30-40% CR– 24 months median remission duration without maintenance– Name another agent with similar single agent activity– It is also cost-effective

• With stem cell support it can be given safely to older patients with comorbidities.

• Thus not planning for it’s use upfront is similar to telling a patient I am never going to use bortezomib or lenalidomide during your disease course because “I don’t like it” or I don’t believe in it”.

• Whether early or late, once twice or more times it remains an active agent that can be extremely effective in all stages of the patients disease journey.

POST SCT THERAPIESPOST SCT THERAPIES

Tales of Two Cases

Case 1• 55-year-old female presents

with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L

• Workup reveals– 30% plasma cells– Cytogenetic diploid– IgA kappa peak of 3.2– β2M of 3.0

• Receives 4 cycles of Bz/Thal/Dex

• Followed by Auto SCT on day 60 documented stringent CR

Case 2• 55-year-old female presents

with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L

• Workup reveals– 30% plasma cells– Cytogenetic t(4;14)– IgA kappa peak of 3.2– β2M of 3.0

• Receives 4 cycles of Bz/Thal/Dex

• Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dL

Both have a 10/10 sibling donor available.

Multiple Myelomameeting

eligibility criteria

High-dose melphalan (200 mg/m2) + autologous PBSC transplant

60 to 120 days

No eligible HLA-matched sibling donor

Non-myeloablative conditioningTBI 200 cGY

allogeneic PBSC transplant

High-dose melphalan (200 mg/m2) + autologous PBSC transplant

ObservationThalidomide

Dexamethasone x12 months.

Biologic assignment*

Eligible HLA-matched sibling donor

Randomization†

PRIMARY ENDPOINT : 3yr Progression Free Survival

BMT CTN 0102 Study SchemaBMT CTN 0102 Study Schema

HLA typing of all patients with siblings*Biologic assignment

occurred when HLA-typing results were available after enrollment.

† Randomization occurred once patients were assigned to auto-auto

1st Autologous Transplant

N=710

No Sibling DonorAuto-Auto

N=484

Sibling DonorAuto-Allo

N=226

High RiskN=48

Standard Risk

N=189

Standard Risk

N=436

High RiskN=37

Main groups compared

Monitoring DiseaseCR Definition Does Matter With Regards to Depth of

Remission

Rate of molecular CR with HDT is 5%

At diagnosis

Partial response – 50% reduction in M protein

Near complete remission – immunofixation positive only

Complete remission – immunofixation negative

Nonquantitative ASO-PCR

Quantitative ASO-PCRflow cytometryMRD

1 × 104

1 × 106

1 × 108

1 × 1012N

um

ber

of

Mye

lom

aC

ells

Summary

• High dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive disease

• Current therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around 3.5-4 years.

• Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden