Morie Gertz Chair Dept. of Medicine Treatment Strategies in Amyloidosis Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Amyloidosis 2010 New Diagnostic Strategies New methods of monitoring New prognostic indicators New therapies

Mel Dex for Non SCT candidates AL; Long Term F/U Palladini, G. et al. Blood 2007;110:787-788 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Mel Dex for Non SCT candidates AL 40 consecutive non SCT pts Worse outcomes related to Hi cardiac #’s 10.5 mo BJH 143:369-73

Intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with AL and severe cardiac involvement Median OS 17.5 mos; 28% mortality first 3 months Blood. 2010 Apr 7. [Epub ahead of print]

Kastritis 428 CRd AL Dex 20 d1-4 CTX 100mg/d x10 R dose escalation MTD 15 N=26 17 untreated 5/9 treated prior BTZ @dose max 9/13 responses 69% All pts 14/23 61% RR 5/23 organ responses; PFS 10 mos For renal failure Cr > 2.5 CTX 50 R 15qod RR 3/8

MDR for AL MDR AL Ph 1 dose escalation R 5→20 d1-21 M .17 mg/kg/d 1-4; D40 1-4q28 LMWH for DVT proph 26 evaluable , R 15 (DLT @20) 6 deaths CR 42%; PR 9/26 ORR 58% organ response 50% EFS 54%@2yr, OS 81%@2yr Moreau Blood 2010 in press

Mayo Clinic survival post SCT Median 94 mos.

SCT outcomes by stage N=443

Survival: Landmark analysis Cardiac Amyloidosis SCT Considering only patients surviving beyond day 100 Median OS 76 mos (95% CI; 69, NR) Follow up from SCT (mos)

Day 100 all cause mortality before & after 2006 7.0% P=0.09 12.1%

Mutivariable Survival Analysis Only Troponin p=.02 & BNP p=.008 predictive of survival

Bortezomib is active in AL Blood. 2009 Jun 4. [Epub ahead of print]

Bortezomib +/-Dex Untreated patients had a 47% CR rate. Twice weekly bortezomib (P = .041) higher response rates. Cardiac response 29% Hematologic responses were associated with a cardiac response and NT-proBNP reduction. The 1-year survival is 76%. NT-proBNP was independently associated with survival (P = .001) J Clin Oncol. 2010 Feb 20;28(6):1031-7.

C neither 3-month landmark Survival of patients according to (A) hematologic and (B) proBNP response By FLC BNP dec 30% A heme & BNP B 1 only C neither 3-month landmark Kastritis, E. et al. J Clin Oncol; 28:1031-1037 2010

Wechalekar, A. D. et al. Blood 2007;109:457-464 CTD Therapy of AL Wechalekar, A. D. et al. Blood 2007;109:457-464 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Dispenzieri, A. et al. Blood 2007;109:465-470 REV DEX for AL Dispenzieri, A. et al. Blood 2007;109:465-470 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Dispenzieri, A. et al. Blood 2007;109:465-470 REV DEX RESPONSES Dispenzieri, A. et al. Blood 2007;109:465-470 Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

MD vs MDB in Newly Diagnosed Immunoglobulin Light Chain Amyloidosis (AL) Patients Who Are Not Candidates for ASCT MD M=0.22 mg/kg/d, days 1-4 12 courses at 6-week intervals 95 Untreated AL patients; ineligible for ASCT (N = 190*) Primary endpoint: PFS at 2 years 60%80% Stratify as cardiac stage I or II MDB Arm MD + Bortezomib 1.3 mg/m2 days 1,4,8,11 95 *Eighty-six required for each arm for a=0.05 (two-sided) and b=0.80. Additional 18 patients allowed for drops-outs and ineligibles

Conclusions For patients who can be transplanted safely SCT remains a preferred option For non transplant candidates Mel Dex remains the default standard Bortezomib has clear activity but its integration into practice is not fully defined Imid therapy including CTD & MDR is being explored

Treatment of AL Transplant Eligibility Criteria “Physiologic” Age ≤ 70 years Performance Score ≤ 2 TnT < 0.06 ng/ml CrCl ≥ 30 ml/min * (unless on chronic dialysis) NYHA Class I/II* No more than 2 organs significantly involved *Selected patients may become eligible for PBSCT with cardiac and renal transplantation v1 Jan 2010 21

Treatment of AL Amyloidosis– off-study Newly Diagnosed AL Amyloidosis Transplant Eligible Transplant Ineligible SCT with Mel Mel-Dex Consider second-line therapy if: heme PR not achieved at day +100 organ progression at 6 months Treat to max response + 2 (no more than 10 cycles) Consider second-line therapy if: heme MR not seen after 4 cycles organ progression at 6 months Msmart.org v1 Jan 2010 22

Relapsed AL Amyloidosis Treatment of AL Amyloidosis– off-study Relapsed AL Amyloidosis Mel-Dex, Len-Dex, Bortezomib or Dex v1 Jan 2010

Low dose regimen or clin trial Cardiac only OHT then HDM/ASCT Cardiac stage III Multiorgan Low dose regimen or clin trial CR Obs HDM/ ASCT PR Obs or Novel Agent YES NR EARLY DIAGNOSIS, ACCURATE TYPING Eligible for ASCT ? Novel Agent Cardiac staging CR Obs NO MDex, Clin trial Non-CR Novel Agent 24

Solid Organ Transplantation Renal Transplantation and Stem Cell Transplantation Which should come first? Who is eligible?

Cardiac Transplantation