This document describes outcomes from an ambulatory allografting program for high-risk multiple myeloma patients. 71 patients received tandem autologous stem cell transplants followed by a non-myeloablative allogeneic stem cell transplant. Results showed acceptable toxicity and transplant-related mortality. Higher CD3 cell doses in the allograft were associated with better donor chimerism and outcomes. Achieving a complete or stringent complete response after transplantation correlated with improved progression-free and overall survival. Upfront tandem transplants in high-risk patients showed similar or better survival compared to upfront autologous transplant alone in standard-risk patients.

1. Outcomes of an Ambulatory Allografting
Programme for Adverse Risk Multiple
Myeloma
Prof Andrew Spencer
Myeloma Research Group,
Division of Blood Cancers,
Alfred Hospital & Monash University,
Melbourne, Australia

2. 1970
1975
1980
1985
1990
1995
2000
2005
2010
2015
0
250
500
750
1000
1250
1500Deaths NHL
Acute Myeloid Leukaemia
Multiple Myeloma
MDS
CLL
HL
CML
ALL
UNMETTHERAPEUTIC NEED IN MM & AML

3. 0%
25%
50%
75%
100%
0 10 20 30 40 50
Time (months)
Multiple myelomaOverall Survival
Almost 25% of Australian MM patients die
within 2 years of diagnosis.Conversely,
a similar proportion are expected to survive
> 10 years reflecting marked heterogeneity
in disease biology
0
200
400
600
800
1000
1200
Caseaccrual
27mar2013 13nov2013 3jul2014 19feb2015 9oct2015 27may2016
Date

4. Moreau P et al. JCO 2014;32:2173-2180
Overall survival for 1,601 patients with lactate
dehydrogenase, International Staging System, and
cytogenetic data available.
Death within 2 years from progressive MM
• Stage 3 ISS
• LDH > normal
• Adverse FISH*
Adverse FISH = t(4;14) and/or 17p-

5. Benjamin Hebraud et al. Blood 2015;125:2095-2100

6. Transplant period and
stem cell source
TRM at 6 months (%) TRM at 2 yrs (%)
1983-93
BM
38 46
1994-1998
BM
21 30
1994-1998
PBSC
25 37
From EBMT registry. Br.J Haematol 2001; 113(1):209
UnacceptableTRM with MAB allografting

7. RIC vs MAB comparison
• EBMT data, 320 RIC vs 196 MABTx between 1998 & 2002
• RIC patients were older 51yrs vs 45yrs with more progressive disease (28%
vs 21%) and more priorASCT (76%Vs 11%)
• RIC patients had longer time to transplant and more received PBSC.
• NRM at 2yrs, RIC vs MAB=24% vs 37% (p=.002).
• OS=38.1% vs 50.8% (ns), PFS=18.9% vs 34.5% (p=.001).
• On multivariate analysis RIC associated with reduction in NRM (HR-0.5), but
increased relapse (HR-2)
Blood 2007;109(8)

8. Tandem Transplant vs RIC Allograft
(a) OS (b) PFS (c) relapse/progression (d) NRM
BMT 2015; 50, 802-807

9. TandemASCT-NMA
• Tandem Auto-NMA. Related or unrelated donors. Age to 70
years.
• Upfront (de novo MM) and deferred (relapsed) patient groups.
• At least PR prior to NMA SCT with no evidence of disease
progression.
• Strict eligibility criteria for upfront treatment – at least 2 of the
following:
 Stage 3 ISS
 FISH – 17p-, t(4;14), 1q+
 High LDH
 Abnormal cytogenetics
 PCL/EMD
 Suboptimal induction response – IMID or PI-based.
At diagnosis

10. • Fludarabine 48mg/m2 PO days -4 to -2.
• 2Gy TBI day 0.
• Cell dose 2 x 106 CD34/kg.
• Cyclosporin/MMF.
• Ciprofloxacin – Neut <0.5.
• No anti-fungal/CMV prophylaxis – weekly Q-PCR CMV.
• PCP/VZV prophylaxis.
FludarabineTBI protocol
Registrar review - HOC thrice weekly
Consultant review dedicated MM clinic - weekly
First NMA January 2008

11. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Patient and Disease Characteristics
Upfront tandem
ASCT/NMA HSCT
Deferred tandem
ASCT/NMA HSCT
Overall
Number of Patients 33 38 71
Patient Age, median (range) 52 (22-66) 56 (32-67) 55 (22-66)
Patient Gender (M/F) 16/17 26/12 42/29
Donor:
Sibling
Unrelated
11
22
16
22
27
44
Disease Status at HSCT:
AT ALLOHSCT
CR
VGPR
PR
SD
PD
11
7
14
1
0
13
2
17
5
1
24
9
31
6
1
Days ASCT to alloHSCT, median(range) 98 (63-318) 92.5 (50-336) 96 (50-336)

12. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Day 30 and Day 100 Admission Data
Upfront
tandem
ASCT/NMA
HSCT
Deferred
tandem
ASCT/NMA
HSCT
Overall
Number of Patients 33 38 71
Outpatient Transplants 29 33 62 (87%)
ADMISSIONS WITHIN 30 DAYS #
Admissions
#
Admissions
#
Admissions
Nil Admissions 14 13 27
Median (Days) 10 8 9
Range (Days) (1-71) (1-26) (1-71)
REASON FOR ADMISSION:
Elective Admission (Inpatient transplants) 3 5 8
Fevers/Infection 3 6 9
Infusion Reaction/Observation 4 9 13
Fever of Unknown Origin / noninfective 6 4 10
GVHD 3 4 7
Other
Median # days per admission:
7
7.5 (1-68)
6
5.5 (1-15)
13
ADMISSIONS WITHIN 100 DAYS #
Admissions
#
Admissions
#
Admissions
Nil Admissions 13 7 20
Median (Days) 14 9 11
Range (Days) (1-120) (1-34) (1-120)
REASON FOR ADMISSION:
Elective Admission (Inpatient transplants) 3 5 8
Fevers/Infection 7 13 20
Infusion Reaction/Observation 4 9 13
Fever of Unknown Origin /noninfective 8 6 14
GVHD 5 6 11
Other 9 9 18

13. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Day 30 and Day 100 Admission Data
Upfront
tandem
ASCT/NMA
HSCT
Deferred
tandem
ASCT/NMA
HSCT
Overall
Number of Patients 33 38 71
Outpatient Transplants 29 33 62 (87%)
ADMISSIONS WITHIN 30 DAYS #
Admissions
#
Admissions
#
Admissions
Nil Admissions 14 13 27
Median (Days) 10 8 9
Range (Days) (1-71) (1-26) (1-71)
REASON FOR ADMISSION:
Elective Admission (Inpatient transplants) 3 5 8
Fevers/Infection 3 6 9
Infusion Reaction/Observation 4 9 13
Fever of Unknown Origin / noninfective 6 4 10
GVHD 3 4 7
Other
Median # days per admission:
7
7.5 (1-68)
6
5.5 (1-15)
13
ADMISSIONS WITHIN 100 DAYS #
Admissions
#
Admissions
#
Admissions
Nil Admissions 13 7 20
Median (Days) 14 9 11
Range (Days) (1-120) (1-34) (1-120)
REASON FOR ADMISSION:
Elective Admission (Inpatient transplants) 3 5 8
Fevers/Infection 7 13 20
Infusion Reaction/Observation 4 9 13
Fever of Unknown Origin /noninfective 8 6 14
GVHD 5 6 11
Other 9 9 18

14. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Outcomes
ENGRAFTMENT POST NMA HSCT
Upfront tandem
ASCT/NMA HSCT
Deferred tandem
ASCT/NMA HSCT
Overall
NEUTROPHILS>0.5x109
/L
Median 0 16.5 11
Range (0-25) (0-26) (0-26)
Never below 17 (52%) 12 (32%) 26 (41%)
NEUTROPHILS>1.0x109
/L
Median 21 20 20
Range (0-35) (0-85) (0-85)
Never below 3 (9%) 3 (8%) 6 (8%)
PLATELETS>20x109
/L
Median 0 0 0
Range (0-11) (0-17) (0-17)
Never below 32 (97%) 34 (89%) 36 (93%)
PLATELETS>50x109
/L
Median 0 0 0
Range (0-18) (0-18) (0-18)
Never below 25 (76%) 28 (74%) 53 (75%)
GVHD
GVHD
GVHD Upfront tandem
ASCT/NMA HSCT
Deferred tandem
ASCT/NMA HSCT
Overall
ASCT/NMA HSCT ASCT/NMA HSCT
AGVHD
Nil 17 19 36
Grade I 8 5 13
Grade II 2 10 12
Grade III 4 3 7
Grade IV 2 1 3
% Grade II_IV 24% 37% 31%
CGVHD
Nil 11 20 31
Limited 2 5 7
Extensive 16 6 32
Not evaluable 4 7 11

15. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Outcomes
OUTCOMES Upfront Tandem
ASCT/NMA
HSCT
Deferred
Tandem
ASCT/NMA
HSCT
Overall
NUMBER OF PATIENTS 33 38 71
BEST DISEASE RESPONSE POST ALLOHSCT
CR/sCR 18 20 38
VGPR 2 3 5
PR 2 4 6
SD 3 1 4
PD 5 7 12
Not yet achieved 3 3 6
PROGRESSION 13 (39%) 17 (45%) 30 (42%)
TRANSPLANT RELATED MORTALITY
CAUSE OF DEATH
Primary Disease
GVHD
Infection
6
4
4
2
2
10
1
1
8
13
5
4
14
3

16. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Comparison of Overall and Progression Free Survival
0.00
0.20
0.40
0.60
0.80
1.00
OverallSurvivalProbability
0 2 4 6 8 10
Years post ASCT
Deferred Tandem ASCT/NMA HSCT
Upfront Tandem ASCT/NMA HSCT
Overall Survival - Upfront versus Deferred Tandem ASCT/NMA HSCT
SURVIVAL OUTCOME UPFRONT TANDEM
ASCT/NMA HSCT
DEFERRED TANDEM
ASCT/NMA HSCT
OVERALL SURVIVAL % %
3 YEARS 66 62
5 YEARS 61 53
PROGRESSION FREE SURVIVAL
3 YEARS 42 44
5 YEARS 34 33
0.00
0.20
0.40
0.60
0.80
1.00
ProgressionFreeSurvivalProbability
0 2 4 6 8 10
Years post ASCT
Deferred Tandem ASCT/NMA HSCT
Upfront Tandem ASCT/NMA HSCT
Progression Free Survival - Upfront versus Deferred Tandem ASCT/NMA HSCT

17. TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Cumulative Incidence of Progression and Non relapse Mortality
Non-relapse Mortality
Upfront versus Deferred Tandem ASCT/NMA HSCT
CUMULATIVE INCIDENCE UPFRONT TANDEM
ASCT/NMA HSCT
DEFERRED TANDEM
ASCT/NMA HSCT
CI OF PROGRESSION % %
3 YEARS 38 49
5 YEARS 46 60
NON RELAPSE MORTALITY
3 YEARS 20 7
5 YEARS 20 7
Cumulative Incidence of Progression-
Upfront versus Deferred Tandem ASCT/NMA HSCT

18. UPFRONT TANDEM ASCT/NMA HSCT (HR MM) vs UPFRONT
ASCT (SR MM)
Comparison of Overall and Progression Free Survival
0.00
0.20
0.40
0.60
0.80
1.00
ProgressionFreeSurvival
0 2 4 6 8 10
Years
Upfront ASCT
Upfront tandem ASCT/NMA HSCT
Progression Free Survival - Upfront Tandem ASCT/NMA vs Upfront ASCT
SURVIVAL OUTCOME
UPFRONT TANDEM
ASCT/NMA HSCT
UPFRONT ASCT
OVERALL SURVIVAL % %
3 YEARS 66 77
5 YEARS 61 67
PROGRESSION FREE SURVIVAL
3 YEARS 42 49
5 YEARS 34 24
0.00
0.20
0.40
0.60
0.80
1.00
OverallSurvival
0 2 4 6 8 10
Years
Upfront ASCT
Upfront Tandem ASCT/NMA HSCT
Overall Survival-Upfront Tandem ASCT/NMA HSCT versus Upfront ASCT

19. Endpoint Factor HR (CI) p value
PFS Prior lines (>3 vs 1-3) 4.76 (2.07-10.96) 0.0002
ISS (3 vs 1-2) 2.97 (1.17-7.55) 0.02
Best response post tandem
(<CR vs CR vs sCR)
4.17 (2.37-7.36) <0.0001
OS
Best response post tandem
(<CR vs CR vs sCR)
5.54 (2.67-11.5) <0.0001
CD3 cell dose (<3 or ≥3 x 108/kg
)
1.42 (1.21-1.67) <0.0001
Risk of
progression
Prior lines (>3 vs 1-3) 3.00 (1.28-7.04) 0.01
Best response post tandem
(<CR vs CR vs sCR)
3.10 (1.52-6.35) 0.002
SIGNIFICANT FACTORS ON MULTIVARIATE ANALYSIS
n = 59, median F/U 48 months

20. N = 33
p = 0.0004
OS BASED ON BEST RESPONSE POST-NMA

21. EuroFlow 8-colour MRD1
1Detects 1 in 105 clonal PCs

22. 30 60 90 180
85
90
95
100
Days post allo-HSCT
Mean%
Dynamics of CD3+
Donor Chimerism in a cohort (n = 54)
Days post-NMA
CD3 DOSE vs CHIMAERISM TO DAY+180

23. CD3 DOSE vs OUTCOME
OS
PFSNRM

24. cGvHD vs CD3cell dose
cGvHD REQUIRING ONGOING TREATMENT

25. 0.00
0.20
0.40
0.60
0.80
1.00
0 2 4 6 8 10
Years
NMA 2008-Nov 2015
NMA Dec 2015-September 2016
Overall Survival
TANDEM ASCT/NMA HSCT IN MULTIPLE MYELOMA
Overall Survival – upfront plus deferred

26. Summary
 Tandem ASCT-NMA is feasible and safe in an ambulatory
setting.
 OS for high risk NDMM and RRMM at 5 years of 61% and
53%, respectively, are higher than that achievable with
conventional therapy.
 GvHD and relapse remain major obstacles warranting
further study.
 Sustained MRD negativity would suggest the likelihood of
long-term disease control in a significant proportion of
patients

27. Conclusion
Tandem ASCT-NMA should be considered for
appropriately selected MM patients with a HLA
matched donor in the era of novel therapies

28. Acknowledgements
Myeloma Programme
Dr Anna Kalff
DrTrishWalker
Dr Jay Hocking
Dr Krystal Bergin
Daniela Klarica
John Coutsouvelis
SCT Programme
Dr Sharon Avery
Dr Sush Patil
A/Prof David Curtis
Dr Anish Puliyayil
Jenny Muirhead
Dr Tongted Das – chimaerism
Tina Pham - CTU
Gerri Bollard – CTU
Dr Susan Morgan - MRD
Geelong Hospital
A/Prof Phil Campbell
Dr David Kipp