Myeloma and Transplant

Sergio A Giralt, MDChief, Adult Bone Marrow Transplant Service

Division of Hematologic OncologyDepartment of Medicine

Memorial Sloan-Kettering Cancer CenterNew York, New York

Tale of Two Cases• 56-year-old female with

symptomatic myeloma– Multiple lytic lesions– M peak 2.5 gms/dl IgA

lambda– Creatinine

1.5 mg/dL– Marrow plasmacytosis

50%– β2M

6 g/dL– Cytogenetics by FISH del

13 and 17p-

• 56-year-old female with symptomatic myeloma– Multiple lytic lesions– M peak 2.5 gms IgA

lambda– Creatinine

1.5 mg/dL– Marrow plasmacytosis

50%– β2M

2 gm/dL– Cytogenetics

diploid

Impact of Chromosomal Abnormalities on Survival Outcomes in MM

ISS = International Staging System.Avet-Loiseau et al, 2009.

IMWG AnalysisGenetic Abnormalities

4-Year Estimated OSMinus vs. Plus Abnormality

Log Rank p-value

Any 73% vs. 57% < .0001

t(4;14)ISS1ISS2ISS3

64% vs. 36%81% vs. 52%63% vs. 30%44% vs. 22%

< .0001< .0001< .0001< .007

Del(17)ISS1ISS2ISS3

68% vs. 44%81% vs. 64%68% vs. 42%48% vs. 28%

< .0001< .020

< .0001< .020

a. ISS1 or ISS2, normal FISH 193/610 deaths (76%)a vs. b < .0001a vs. c < .0001b vs. c < .0001

b. ISS1 + abnormal FISH/ISS3 + normal FISH

140/252 deaths (52%)

c. ISS2 or ISS3 + abnormal FISH 146/196 deaths (32%)

Questions

Is there a preferred induction therapy?1. Thalidomide/dexamethasone2. Lenalidomide/dexamethasone3. Bortezomib/dexamethasone4. Doublet vs Triplet vs Quadruplet (IMiD®/bortezomib/

dexamethasone +/- alkylator)

Is the consolidation therapy the same for both?1. Auto vs allo vs late SCT

Role of maintenance therapy1. All patients – high risk-only non CR patients

VTD vs TD Induction → ASCT: Efficacy

Efficacy*VTD

(n = 236)TD

(n = 238) p-value

InductionORR≥ nCR≥ VGPR

93%26%61%

79%9%

28%

<0.0001<0.0001<0.0001

Double ASCT ≥ nCR≥ VGPR

52%79%

41%64%

0.010.0004

Consolidation ≥ nCR≥ VGPR

59% 82%

43% 67%

0.00090.0005

PFS 30 months 76% 58% 0.009

OS Median Not reached 0.6*≥ nCR and ≥ VGPR by central assessment.

Cavo M et al. Blood. 2009;114:Abstract 351.

VTD vs TD Induction → ASCT: PFS in Poor-Prognosis Subgroups

VariableHazard ratio

(95% CI) p-value

Del(13q) 0.554 (0.308–0.997) 0.04

t(4;14) ± Del(17p) 0.454 (0.210–0.979) 0.04

LDH >190 U/L 0.573 (0.353–0.930) 0.02

Age >60 years 0.460 (0.231–0.915) 0.02

Cox Regression Analysis

Cavo M et al. Blood. 2009;114:Abstract 351.

Siegel D et al. Proc ASH 2010;Abstract 38.

Outcomes in pts Age <65After Len/Dex Induction

LD = lenalidomide + high-dose dexamethasone

Ld = lenalidomide + low-dose dexamethasone

1 yr 2 yr 3 yr

N Events Survival Prob N Events Survival

Prob N Events Survival Prob

No Early Transplant

All 141 9 0.94 141 17 0.88 141 26 0.78

LD 65 7 0.89 65 12 0.82 65 13 0.79

Ld 76 2 0.97 76 5 0.93 76 13 0.78

Early Transplant

All 68 0 1.00 68 4 0.94 68 4 0.94

LD 38 0 1.00 38 2 0.95 38 2 0.95

Ld 30 0 1.00 30 2 0.93 30 2 0.93

Is It Time For A New 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

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

Tale of Two CasesHigh Risk

• 56-year-old female with symptomatic myeloma

– Multiple lytic lesions

– M peak 2.5 gms IgA-lambda

– Creatinine 1.5 mg/dL

– Marrow plasmacytosis 50%

– β2M 6 g/dL

– Cytogenetics by FISH del 13 and 17p-

• After 4 cycles of induction and autologous SCT consolidation paraprotein peak is still 0.1 gms/dl

• She has an HLA identical donor

• You would now recommend

• 1) Allo SCT

• 2) 2nd Autograft

• 3) Maintenance lenalidomide

• 4) Observation

• 5) Maintenance thalidomide

Tale of Two CasesStandard Risk

• 56-year-old female with symptomatic myeloma– Multiple lytic lesions– M peak 2.5 gms IgA

lambda– Creatinine

1.5 mg/dL– Marrow plasmacytosis

50%– β2M

2 gm/dL– Cytogenetics

diploid

• After 4 cycles of induction and autologous SCT consolidation paraprotein peak is 0 gms/dl. IFE is negative

• She has an HLA identical donor

• You would now recommend• 1) Allo SCT • 2) 2nd Autograft• 3) Maintenance lenalidomide• 4) Observation• 5) Maintenance thalidomide

Tandem AutHCT with or without Maintenance Tandem AutHCT with or without Maintenance Therapy (auto-auto) versus Single AuHCT Followed Therapy (auto-auto) versus Single AuHCT Followed

by HLA Matched Sibling Non-Myeloablative by HLA Matched Sibling Non-Myeloablative Allogeneic HCT (auto-allo) for Patients with Allogeneic HCT (auto-allo) for Patients with

Standard Risk Multiple Myeloma: Results from the Standard Risk Multiple Myeloma: Results from the BMT-CTN 0102 TrialBMT-CTN 0102 Trial

Amrita Krishnan, Marcelo Pasquini, Marian Ewell, Edward A. Stadtmauer, Edwin Alyea III, Joseph Antin, Raymond Comenzo, Stacey Goodman,

Parameswaran Hari, Robert Negrin, Muzaffar Qazilbash, Scott Rowley, Firoozeh Sahebi, George Somlo, David Vesole, Dan Vogl, Daniel Weisdorf,

Nancy Geller, Mary M. Horowitz, Sergio Giralt, David Maloney

On behalf of the Blood and Marrow Transplant Clinical Trials Network

1st Autologous Transplant

N = 710

No Sibling DonorAuto-AutoN = 484

Sibling DonorAuto-AlloN = 226

High Risk

N = 48

Standard Risk

N = 189

Standard Risk

N = 436

High Risk

N = 37

Main groups compared

Progression-Free SurvivalProgression-Free Survival Overall Overall SurvivalSurvival

Prob

abili

ty, %

100

0

20

40

60

80

90

10

30

50

70

Auto/Allo, 43% @ 3yr

Auto/Auto, 46% @ 3yr

p-value = 0.67 p-value = 0.19

Auto/Allo, 77% @ 3yr

Auto/Auto, 80% @ 3yr 100

0

20

40

60

80

90

10

30

50

70

0 6 12 18 24 30 36 42 48

436 424 406 395 370 348 305 107 79189 183 167 160 156 143 124 43 27

Survival Outcomes after the First Transplant: Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Auto-Auto vs. Auto-Allo: Intent-to-Treat AnalysisIntent-to-Treat Analysis

Months 0 6 12 18 24 30 36 42 48# at risk:Auto/Auto 436 395 348 292 242 213 178 54 42Auto/Allo 189 165 138 117 105 89 71 23 16

With permission from Krishnan A et al. Proc ASH 2010;Abstract 41.

Cumulative Incidence of Chronic GVHD Cumulative Incidence of Chronic GVHD after Allogeneic Transplantafter Allogeneic Transplant

Incid

en

ce,

%

Months0 12 24 48

100

0

20

40

60

80

90

10

30

50

70

6 18 30 36 42

Chronic GVHD @1 year 47% (95% CI: 39.2%, 55.6%)Chronic GVHD @ 2 years 54% (95% CI: 46.0%, 62.8%)

Chronic GVHD and disease progression/relapse*

Absent 1.00

Present 0.41 (0.24-0.70) 0.001

* Chronic GVHD treated as time-dependent covariate and adjusted for disease status at transplant.

With permission from Krishnan A et al. Proc ASH 2010;Abstract 41.

MaintenanceLenalidomide × 3 yrs

MaintenanceLenalidomide × 3 yrs

CTN Studies for Myeloma: STaMINA Trial

• Age <70• At least 3 months of systemic therapy• 3–9 months from start of therapy• Autologous PBSC graft of > 4 × 106 CD34 cells/kg

Melphalan 200 mg/m2

Auto HCT

Melphalan 200 mg/m2 Auto HCT

Bortezomib/Dex/Lenalidomide × 4 cycles

Randomize

MaintenanceLenalidomide × 3 yrs

Principal investigators:A. Krishnan G. Somlo E. Stadtmauer

Summary

• Who should be considered for autologous stem cell transplant?

– All patients with symptomatic myeloma except: the frail, those unable or unwilling to do so.

• How should a patient be transplanted?

– Preferably on a clinical trial. Off protocol probably bortezomib induction (double vs triple based on risk category) for 2-4 cycles. Stem cell collection followed by mel 200 mg/m2 followed by maintenance lenalidomide if not in CR.

• When should they be transplanted?

– As part of initial therapy preferably, although salvage SCT is being more extensively explored.

• With what should they be transplanted?– Autologous stem cells, although the role of allografting as upfront

therapy should continue to be explored in young high risk patients.

Copyright © 2011 Research To Practice. All rights reserved.

What is your preferred induction regimen for a younger transplant-eligible patient with multiple myeloma (MM)?

4%

2%

1%

45%

15%

15%

9%

8%

0% 10% 20% 30% 40% 50%

Other

CyBorD

VdoxD

RVD

VTD

VD

Rd

RD

Copyright © 2011 Research To Practice. All rights reserved.

Should post-transplant lenalidomide maintenance be used?

24%

27%

44%

4%

0% 10% 20% 30% 40% 50%

Yes

Yes, usually

Yes,sometimes

No

Copyright © 2011 Research To Practice. All rights reserved.

What Clinicians Want to Know

A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical

Management of Select Hematologic Cancers

Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois

Faculty

Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD

ModeratorNeil Love, MD

Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek