ASCT for AL Seok Jin Kim 07-12-2011

Untreated AL amyloidosis : Median survival 10-14 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

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 100-140mg/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

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%

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

Median overall survival : Cardiac involvement + vs. - : 7.6 yrs vs. 3.4 yrs P < 0.0001 : 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

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

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

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

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

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

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

ASCT for AL Improved outcome with reduced TRM Efficacy of Melphalan 100-140mg/m2 is highly questionable New conditioning with novel agents Frontline treatment with novel agents? Delayed or consolidation ASCT?