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

2 Amyloidosis 2010 New Diagnostic Strategies New methods of monitoringNew prognostic indicators New therapies

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

4 Mel Dex for Non SCT candidates AL40 consecutive non SCT pts Worse outcomes related to Hi cardiac #’s 10.5 mo BJH 143:369-73

5 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 Apr 7. [Epub ahead of print]

6 Kastritis 428 CRd AL Dex 20 d1-4 CTX 100mg/d x10R 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

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

8 Mayo Clinic survival post SCTMedian 94 mos.

9 SCT outcomes by stage N=443

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

11 Day 100 all cause mortality before & after 20067.0% P=0.09 12.1%

12 Mutivariable Survival AnalysisOnly Troponin p=.02 & BNP p=.008 predictive of survival

13 Bortezomib is active in ALBlood Jun 4. [Epub ahead of print]

14 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 Feb 20;28(6):

15 C neither 3-month landmarkSurvival 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:

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

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

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

19 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 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= Additional 18 patients allowed for drops-outs and ineligibles

20 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

21 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

22 Treatment of AL Amyloidosis– off-studyNewly 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

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

24 Low dose regimen or clin trialCardiac 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

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

26

27

28 Cardiac Transplantation

29

30

31