1. ASCT for AL
Seok Jin Kim

2. Untreated AL amyloidosis
: Median survival months from diagnosis
Introduction of HDM/ASCT in the 1990s
: CR rates 16-67%, organ response 25-45%
A major issue of HDM/ASCT
: Potential for high treatment-related mortality due to underlying organ dysfunction

3. Methods 421 patients from 1994 to 2008
Excluded diseases: MM (≥ 30% of BM PC, n=16), other B-cell LPD (n=16), inadequate f/up (n=1)
Mel 200mg/m2 : standard conditioning
Mel mg/m2 : > 65 years, LVEF 40-45%, stem cell 2-2.5×106/kg, poor performance status
Median f/up: 4 years for entire cohort, 6.3 years for surviving patients

6. Hematologic relapse in CR patients
: n =40, 28%, estimated median time to relapse 12.7 years
cf. 2.7 years in non-CR patients
Organ response (improvement in at least one involved organ) in hematologic CR
: n = 114, 78.6%
Organ response in patients failed to achieve CR
: 39.1%

7. Survival outcome Median EFS in non-CR: 2 yrs
: number of organ involvement and abnormal serum FLC at diagnosis
 Predictor of EFS
Serum FLC was excluded from analysis
Event: hematologic or organ disease progression, initiation of additional treatment, death

8. Median overall survival
: Cardiac involvement + vs. - : 7.6 yrs vs. 3.4 yrs P <
: Previous treatment + vs. - : 5.6 yrs vs. 6.4 yrs P = 0.28
Mortality for 16 years of ASCT program
: 234 (55.5%) of 421 patients died

9. Day-100 all-cause mortality
7%, 11/157
12.1%, 32/265
Cohort 1
: From 8 March 1996 to 31 December 2005
Cohort 2
: From 6 January 2006 to 1 December 2009
All deaths were considered treatment
related through day-100
No patients have been lost to follow-up
Apheresis was with growth factor only
without chemotherapy priming
Amyloid 2011 Jun

10. Of the 10 subjects enrolled, one was removed from the study prior to treatment because of cardiac arrhythmias during stem cell collection that precluded HDM/SCT. This patient subsequently underwent orthotopic heart transplantation followed by HDM/SCT.
Haematologica 2011 Dec

11. Conditioning for ASCT Peripheral blood stem cell collection
G-CSF alone
Minimum of 2.5 x 106 CD 34+ cells/kg
Bortezomib 1 mg/m2
D -6, D -3, D +1, and D +4
High dose melphalan 140 or 200 mg/ m2
In two divided doses on D -2 and D -1
Depending upon age and co-morbidities
Melphalan  Bortezomib > Bortezomib  Melphalan
: Bortezomib may up-regulate the anti-apoptotic protein myeloid cell
leukemia 1 (MCL-1)
Pre-clinical and phase I/II data have suggested that the optimal timing of administration of a single dose of bortezomib is 24 hours after melphalan

12. Results Hematologic responses
89% of treated subjects (n=8/9)
CR (6/9, 67%)
By intention-to-treat, hematologic response 80% (n=8/10)
No hematologic relapses at a median follow-up of 23 months (range, 18-31)
Organ response at 1 year
78% of treated patients (n=7/9)
6 with renal and 1 with hepatic response
All subjects are alive and well after a median follow-up of 29 months from the time of diagnosis

13. Results No treatment-related mortality The median times to recovery
D +14 after SCT, respectively.
Toxicity
G4 mucositis (n = 1)
G3 renal failure not requiring dialysis (n = 1)
G3 infectious complications
Enterococcus UTI
Clostridium difficile colitis
Influenza A pneumonia

14. Conclusions This pilot study is small in highly select patients
The CR rate of 67% of treated patients compares favorably with that of 40% seen in melphalan alone
There may be additive or synergistic activity of Bortezomib and melphalan
Bortezomib senstitizes myeloma cells to DNA-damaging agents such as melphalan, and overcomes chemoresistance.
It acts upon the bone marrow microenvironment
Inhibiting nuclear factor-κB activation in bone marrow stromal cells
Leading to a reduction in interleukin-6 production
Enhanced apoptosis of myeloma cells

15. ASCT for AL Improved outcome with reduced TRM
Efficacy of Melphalan mg/m2 is highly questionable
New conditioning with novel agents
Frontline treatment with novel agents?
Delayed or consolidation ASCT?