1. Myeloma and Transplant
Sergio A Giralt, MD
Chief, Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

2. Tale of Two Cases 56-year-old female with symptomatic myeloma
Multiple lytic lesions
M peak 2.5 gms/dl IgA lambda
Creatinine mg/dL
Marrow plasmacytosis 50%
β2M 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 mg/dL
Marrow plasmacytosis 50%
β2M gm/dL
Cytogenetics diploid 2

3. Impact of Chromosomal Abnormalities on Survival Outcomes in MM
IMWG Analysis
Genetic Abnormalities
4-Year Estimated OS
Minus vs. Plus Abnormality
Log Rank
p-value
Any
73% vs. 57%
< .0001
t(4;14)
ISS1
ISS2
ISS3
64% vs. 36%
81% vs. 52%
63% vs. 30%
44% vs. 22%
< .007
Del(17)
68% vs. 44%
81% vs. 64%
68% vs. 42%
48% vs. 28%
< .020
a. ISS1 or ISS2, normal FISH
193/610 deaths (76%)
a vs. b < .0001
a vs. c < .0001
b vs. c < .0001
b. ISS1 + abnormal FISH/ISS3 +
normal FISH
140/252 deaths (52%)
c. ISS2 or ISS3 + abnormal FISH
146/196 deaths (32%)
ISS = International Staging System.
Avet-Loiseau et al, 2009.

4. Questions Is there a preferred induction therapy?
Thalidomide/dexamethasone
Lenalidomide/dexamethasone
Bortezomib/dexamethasone
Doublet vs Triplet vs Quadruplet (IMiD®/bortezomib/ dexamethasone +/- alkylator)
Is the consolidation therapy the same for both?
Auto vs allo vs late SCT
Role of maintenance therapy
All patients – high risk-only non CR patients

5. VTD vs TD Induction → ASCT: Efficacy
p-value
Induction
ORR
≥ nCR
≥ VGPR
93%
26%
61%
79% 9%
28%
<0.0001
Double ASCT
52%
41%
64%
0.01
0.0004
Consolidation
59%
82%
43%
67%
0.0009
0.0005
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. 5

6. VTD vs TD Induction → ASCT: PFS in Poor-Prognosis Subgroups
Cox Regression Analysis
Variable
Hazard 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)
LDH >190 U/L
0.573 (0.353–0.930)
0.02
Age >60 years
0.460 (0.231–0.915)
Cavo M et al. Blood. 2009;114:Abstract 351.

7. Outcomes in pts Age <65 After Len/Dex Induction
1 yr
2 yr
3 yr N
Events
Survival Prob
No Early Transplant
All
141 9
0.94 17
0.88 26
0.78 LD 65 7
0.89 12
0.82 13
0.79 Ld 76 2
0.97 5
0.93
Early Transplant 68
1.00 4 38
0.95 30
LD = lenalidomide + high-dose dexamethasone
Ld = lenalidomide + low-dose dexamethasone
Siegel D et al. Proc ASH 2010;Abstract 38. 7

8. Is It Time For A New Early-vs-Late SCT Study?
Optimal
induction
regimen
COLLECT
HD THERAPY + SCT A A A
Maintenance A A A m m m
HARVEST AND HOLD
SCT UPON RELAPSE
Risk profile

9. stem cells mobilized with cyclophosphamide + G-CSF
Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following Lenalidomide/ Dexamethasone (Ld) Induction
Consolidation
n=402
<65 years R A N D O M I Z E R A N D O M I Z E
MPR (n=202)
Melphalan: 0.18 mg/kg/d, days 1–4
Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21
q 28 days ×6 No
maintenance
Lenalidomide:
25 mg, days 1–21
Low-dose Dex:
40 mg, days 1, 8,
15, 22 q 28 days ×4
Tandem MEL200
ASCT
stem cells mobilized with
cyclophosphamide + G-CSF
Maintenance
lenalidomide:
10 mg/d, Days 1–21
q 28 days until relapse
Primary end point: PFS
Palumbo A et al. Blood. 2009;114:Abstract 350. 9

10. Tale of Two Cases High Risk
56-year-old female with symptomatic myeloma
Multiple lytic lesions
M peak 2.5 gms IgA-lambda
Creatinine mg/dL
Marrow plasmacytosis 50%
β2M 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 10

11. Tale of Two Cases Standard Risk
56-year-old female with symptomatic myeloma
Multiple lytic lesions
M peak 2.5 gms IgA lambda
Creatinine mg/dL
Marrow plasmacytosis 50%
β2M 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 11

12. On behalf of the Blood and Marrow Transplant Clinical Trials Network
Tandem AutHCT with or without Maintenance Therapy (auto-auto) versus Single AuHCT Followed by HLA Matched Sibling Non-Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard Risk Multiple Myeloma: Results from the BMT-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

13. 1st Autologous Transplant N = 710
No Sibling Donor
Auto-Auto
N = 484
Sibling Donor
Auto-Allo
N = 226
High
Risk
N = 48
Standard
N = 189
N = 436
N = 37
Main groups compared

14. Progression-Free Survival Overall Survival
Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo:
Intent-to-Treat Analysis
Progression-Free Survival Overall Survival
100 20 40 60 80 90 10 30 50 70
100 20 40 60 80 90 10 30 50 70
Auto/Allo, 3yr
Auto/Auto, 3yr
p-value = 0.67
p-value = 0.19
Auto/Allo, 3yr
Auto/Auto, 3yr
Probability, %
Months
# at risk: Auto/Auto Auto/Allo
With permission from Krishnan A et al. Proc ASH 2010;Abstract 41.

15. Cumulative Incidence of Chronic GVHD after Allogeneic Transplant
100 20 40 60 80 90 10 30 50 70
Chronic year 47% (95% CI: 39.2%, 55.6%)
Chronic 2 years 54% (95% CI: 46.0%, 62.8%)
Incidence, %
Chronic GVHD and disease progression/relapse*
Absent
1.00
Present
0.41 ( )
0.001 6 12 18 24 30 36 42 48
Months
* 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.

16. 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
Maintenance
Lenalidomide × 3 yrs
Melphalan 200 mg/m2 Auto HCT
Maintenance
Lenalidomide × 3 yrs
Randomize
Principal investigators: A. Krishnan G. Somlo E. Stadtmauer
Bortezomib/Dex/ Lenalidomide × 4 cycles
Maintenance
Lenalidomide × 3 yrs

17. 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.

18. What is your preferred induction regimen for a younger transplant-eligible patient with multiple myeloma (MM)? 18 18

19. Should post-transplant lenalidomide maintenance be used?19 19

20. 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, :00 PM – 9:30 PM Chicago, Illinois
Moderator
Neil Love, MD
Faculty
Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD
Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek