1. Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know.
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. Disclosures Grant Support Honoraria Most important I am a transplanter
Celgene
Millenium
Onyx
Honoraria
Novartis
Sanofi/Genzyme
Most important I am a transplanter

3. Initial 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 with lambda light chain at 0.01
Kappa/lambda ratio=

4. 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

5. Multiple Myeloma: Analysis
Hyperdiploidy
t(6:14) SC
Pre
Pro
Early
Mid
SHM
ICS PC
t(14;16)
t(4:14)
t(11;14) M0 M1 M2 M3 M4 M5 M6 M7
Myeloma
3 decades
Images courtesy of Raphael Fonseca, MD. 5

6. Multiple Myeloma Treatment Linesa
Front-line treatment
Maintenance
Relapsed
Induction
Consolidation
Maintenance
Rescue
SCT
Observation
IMID:Thal-Len
Proteosome Inh-Bor
Steroids:Dex-Pred
IMID:Thal-Len-Pom
Proteosome Inh:Bor-Car
Steroids: Dex-Pred
Alkylators:Mel-Cy-Benda
Investigational
IMID:Thal-Len
Proteosome Inhibitor: Bor-Car
Steroids: Dex-Pred
Alkylator: Cyclo-Mel
Anthracycline: LipoDnr-Adr
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. 6

7. Is there an optimal induction regimen?
What we know…
Is there an optimal induction regimen?

8. Protocol GIMEMA 26866138-MMY-3006 VTD vs TD incorporated into double ASCT for MM
RANDOMIZATION
INDUCTION
VEL-THAL-DEX
TRANSPLANTATION
MEL 200
CONSOLIDATION
MAINTENANCE
DEX
THAL-DEX
PBSC COLLECTION
CTX

9. RESPONSE TO PRIMARY THERAPY
% of patients
RESPONSE
VTD
(n=129) TD
(n=127)
P value
CR+nCR 36 9
<0.001
³ VGPR 60 27
< PR 7 20
0.003
Progression
5.5
0.008
EBMT criteria (with added nCR and VGPR categories)

10. RESPONSE (CR+nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIES
VTD
VTD vs TD
P=0.06
P=0.1
P<0.001
P=0.002
VTD
VTD TD
neg
pos
neg
pos
13 pos
t(4;14) pos
13
t(4;14)

11. Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
GIMEMA: Results
Primary endpoint: CR + nCR (VTD vs TD as induction therapy)
Secondary endpoints
PFS OS
96% (VTD) vs 91% (TD); P = .2
1.0
Response, %
VTD (n = 226)
TD (n = 234)
P Value
CR + nCR 32 12
< .001
≥ VGPR 62 29
≥ PR 94 79
Progression
4.7
.001
Modified EBMT and Uniform Criteria (nCR and VGPR categories)
0.8
0.6
0.4
2-yr rates
VTD (n = 226): 90%
0.2
TD (n = 234): 80%
P = .009
0.0 5 10 15 20 25 30
Mos
Cavo M, et al. ASH Abstract 158. 11

12. Meta-analysis

13. Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy
Newly Diagnosed MM
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
Results
At 19 mos of follow-up, TTP, PFS,
and OS have not been reached
Median stem cell collection in 15/35
patients: 4.4 x 106 CD34+ cells/kg
Response n = 35 evaluable
CR/nCR
52%
< VGPR
74%
ORR (≥PR)
100%
Safety
Grade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality

14. Kaplan-Meier analyses of treatment outcomes.
Kumar S et al. Blood 2012;119:
©2012 by American Society of Hematology

15. Stem 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.

16. Optimal mobilization strategy
What we know…
Optimal mobilization strategy

17. Effect of Lenalidomide Duration of Therapy on Stem Cell Collection
Lenalidomide Therapy
Other Induction Therapies
P value =
P value=0.0025
P value = 0.07
P value = 35 9
4.5 50
n=40 8
n=40
n=18 8 45 30 40 7
3.5 25
n=18
n=40 35 6 6 30 20 5
2.5
n=16
Days
Percentage 25
CD34+ Count (Cells µl-1)
CD34+ Count (in Millions) 15 4 4 20 3
1.5 10 15 2 2 10 5 1
0.5 5
Mean Peripheral Blood
CD34+ Count
Total CD34+ Cells
collected
(Mean x 106 cells Kg-1)
Mean number of
days of collection
Percentage of patients
who failed
first collection
Paripati H. Leukemia. 2008;22:

18. 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 ;15(2 suppl 2):91.

19. What 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?

20. Stem 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?

21. Role of sct in the era of imids and proteosome inhibition
What we don’t know…
Role of sct in the era of imids and proteosome inhibition

22. BENEFIT OF AUTOGRAFTING FOR MYELOMA
Figure 2
BENEFIT OF AUTOGRAFTING FOR MYELOMA
Koreth et all BBMT
Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions
Source: Biology of Blood and Marrow Transplantation 2007; 13: (DOI: /j.bbmt )

23. 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

24. IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates)
Randomize, stratification ISS & FISH
VRD x 3
Induction
VRD x 3
CY (3g/m2) MOBILIZATION
Goal: 5 x106 cells/kg
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
Collection
Melphalan 200mg/m2* + ASCT
VRD x 5
Consolidation
VRD x 2
Maintenance
Lenalidomide 12 mos
Lenalidomide 12 mos
SCT at relapse
MEL 200 mg/m2 if <65 yrs,
≥65 yrs 140mg/m2

25. 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. 25

26. Progression Free Survival
49.4% Reduced Risk of Progression
Median follow-up 26 months
2-years PFS
MPR
MEL200
54%
73%
Median PFS
Not reached
25.26 mos
0.00
0.25
0.50
0.75
1.00 5 10 15 20 25 30 35 40 45
Patients (%)
Months
HR 0.506
P =
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; PFS, progression free survival; HR, hazard ratio; mos, months

27. Conclusions MPR MEL200 P value CR 20% 25% P=0.55
24 months % % P=0.0002
OS @ 24 months % % 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
MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation

28. E4A03: Landmark Analysis at Median Follow-up of 36 mo
431 patients alive
at 4 cycles
Off therapy
n=183
Primary therapy
beyond 4 cycles
n=248
no transplant
N=93
(median age 68)
Transplant
n=90
(median age 57) Ld
n=140
(median age 66) LD
n=108
(median age 65)
Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages , January 2010 28 28

29. Outcomes in pts Age <65
Progression Free Survival
Overall Survival

30. What 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?

31. FUNCTIONAL ASSESSMENT

32. Aging Heterogeneity Community Dwelling, Healthy Age 82
Community Dwelling, Frail
Ages 19, 82, 23
Community Dwelling, Typical
Institutionalized, Frail
Ages 84,81

33. Transplant-related Mortality after Autologous Hematopoietic Cell Transplantation for Malignant Diseases by HCT-CI,
100 20 40 60 80 90 10 30 50 70
Incidence, %
Years 15 5 25
p<0.001
HCT-CI ³ 3 (n=2,388)
HCT-CI=1-2 (n=2,813)
HCT-CI=0 (n=5,185)
Xz12_56.ppt

34. 100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation According to Performance Score and Disease Indication
P<0.001
P<0.001
100 day mortality ,%

35. Rate of SCT in US according to Age Costa et al ASH 2012
<50 years
50-64 years
≥ 65 years
Figure 1

36. Randomized Phase II LD/HD CD34

37. In 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.

38. Post sct therapies

39. Both have a 10/10 sibling donor available.
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.

40. PRIMARY ENDPOINT : 3yr Progression Free Survival
BMT CTN 0102 Study Schema
Multiple Myeloma
meeting
eligibility criteria
HLA typing of all patients
with siblings
*Biologic assignment occurred when HLA-typing results were available after enrollment.
High-dose melphalan (200 mg/m2)
+ autologous PBSC transplant
Biologic assignment*
Eligible HLA-matched
sibling donor
No eligible HLA-matched
sibling donor
60 to 120 days
Non-myeloablative conditioning
TBI 200 cGY
allogeneic PBSC transplant
High-dose melphalan (200 mg/m2)
+ autologous PBSC transplant
Randomization†
† Randomization occurred once patients were assigned to auto-auto
Observation
Thalidomide
Dexamethasone
x12 months.
PRIMARY ENDPOINT : 3yr Progression Free Survival 40

41. 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

42. Number of Myeloma Cells Rate of molecular CR with HDT is 5%
Monitoring Disease CR Definition Does Matter With Regards to Depth of Remission
1 × 1012
At diagnosis
Number of Myeloma Cells
Partial response – 50% reduction in M protein
Near complete remission – immunofixation positive only
Complete remission – immunofixation negative
Nonquantitative ASO-PCR
1 × 108
Quantitative ASO-PCR flow cytometry
1 × 106
MRD
1 × 104
Rate of molecular CR with HDT is 5%

43. 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 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