1. Come trattare la ricaduta di mieloma multiplo dopo trapianto allogenico di cellule emopoietiche

2. Multiple Myeloma Overview all transplants, autologous and allogeneic (period 1992-2003) N=28.887

3. Survival, BM Allogeneic transplantation in Multiple Myeloma
1.0
1.0
p<0.0001
Survival
Tx 94-98
n=223
0.8
0.8
0.6
0.6
0.4
0.4
Tx 83-93
n=334
0.2
0.2
0.0
0.0
Months 24 24 48 48 72 72 96 96
120
120
144
144
At risk:

4. Graft-Versus-Myeloma Effect: Proof of Principle
Tricot G et al. Blood 1996

5. Therapeutic options to treat relapse after allo-SCT in MM
Chemotherapy
Radiotherapy (plasmacytomas)
Donor lymphocyte infusions
Thalidomide
Bortezomib
Combinations of the previous items

6. cGVHD correlates with clinical response, suggesting the existence of a graft-versus-myeloma effect
Crawley et al. Blood 2005

7. Retrospective study
13 patients with relapsed myeloma after allo
29 DLIs
8/13 responded (4 CR, 4 PR)
Toxicities: aGVHD and cGVHD in 66% and 56% of all pts (87% and 85% of the responders)

8. Spectratyping of TCR V repertoire Orsini et al. Cancer Research 2003
Mechanisms of Post-DLI GVM: occurrence of anti-MM specific CD8+ T-cell clones
Spectratyping of TCR V repertoire
Orsini et al. Cancer Research 2003

9. (eg versus the B Cell Maturation Antigen, BCMA)
Mechanisms of Post-DLI GVM: occurrence of antibody responses to highly expressed antigens
(eg versus the B Cell Maturation Antigen, BCMA)
E= Early post-DLI serum, L= Late post-DLI serum
Bellucci et al. Blood 2004 and Bellucci e al. Blood 2005

10. The occurrence of GVHD is the major predictive factor for response to DLIs in MM
40 pts received re-induction CT (VAD, L-PAM 70, Dex) + DLIs
54 pts in relapse after allo
14 pts received DLIs
Lokhorst et al. Blood 2004

11. The occurrence of GVHD is the major predictive factor for response to DLIs in MM
5 pts obtained a CR
4 pts obtained a PR
DLI
14 pts received DLI
5 pts refractory
Lokhorst et al. Blood 2004

12. Altogether of 54 pts in relapse after allo 17% CR, 35% PR
The occurrence of GVHD is the major predictive factor for response to DLIs in MM
Altogether of 54 pts in relapse after allo
17% CR, 35% PR
57% aGVHD post-DLI, 52% cGVHD
post-DLI
Lokhorst et al. Blood 2004

13. The occurrence of GVHD is the major predictive factor for response to DLIs in MM
Lokhorst et al. Blood 2004
PFS after DLI

14. OS after DLI by deletion of cr 13
The occurrence of GVHD is the major predictive factor for response to DLIs in MM
Lokhorst et al. Blood 2004
OS after DLI by deletion of cr 13

15. DLI following RIC Retrospective analysis from 8 European centers
Response to DLI n = 63 patients
PR (19%)
CR (19%)
Total (38%)*
* ± Comparable to DLI following myeloablative Allo-SCT
NWCJ Van De Donk et al. BMT 2006

16. NWCJ Van De Donk et al. BMT 2006 Median follow-up: 23 months
DLI following RIC
Overall survival
All patients
PR + CR NR
NWCJ Van De Donk et al. BMT 2006
Median follow-up: 23 months

17. NWCJ Van De Donk et al. BMT 2006
DLI following RIC
Prognostic Factors
The only significant prognostic factors for response to DLI were the occurence of aGVHD and cGVHD
NWCJ Van De Donk et al. BMT 2006

18. DLI To Treat Myeloma Relapsing after allo: summary
30-50% Response Rate
(Few CR)
40-60% GVHD
(Mortality due to GVHD post DLI 4%)

19. STRATEGIES TO ACHIEVE BETTER RESULTS
Combination of DLI and new drugs ?

20. Thalidomide and DLI: Rationale 1
Thalidomide induces remarkable response rates between 25% and 35% for relapsed and refractory MM patients
As a single agent in newly diagnosed patients, partial remission rates of 50% were observed, which can be enhanced to 60% to 70% by concomitant therapy with Dex
Kroger et al, 2004

21. Thalidomide and DLI: Rationale 2
Besides its inhibitory effect on tumor necrosis factor- (TNF-) production and angiogenesis, thalidomide has additional mechanisms of antimyeloma activity by modulation of myeloma cell binding to bone marrow stroma
The immunologic properties of thalidomide such as potentiation of natural killer (NK) cell activity, costimulation of CD8 cells, and increase of IL-2 production make the drug a potential enhancer of immune-mediated antimyeloma response after allo
Thalidomide has been shown to be active as an immunosuppressive drug in treatment of GvHD, especially cGvHD
Kroger et al, 2004

22. Thalidomide and DLI
18 patients with progressive disease or residual disease and prior ineffective DLI after allografting:
Toxicity
weakness grade I/II (68%)
peripheral neuropathy grade I/II (28%)
no grades II to IV aGvHD was seen
Response Rate = 67% (CR=22%)
2-year estimated OS and PFS were respectively 100% and 84%
Kroger et al, 2004

23. Bortezomib after allo: Rationale 1
Bortezomib (VelcadeTM) has a very high affinity and specificity for the catalytic activity of the proteasome in the cell cytoplasm and blocks migration of NF-kB into the nucleus. Thus, the functions of NF-kB, constitutively active in MM, are inhibited
Clinical studies demonstrates that Bortezomib is active in relapsed/refractory Myeloma
Proteosome activity is also involved in T-cell functions and recent murine studies indicate that NF-kB is important in the pathophysiology of GVHD

24. Bortezomib +/- Dex after allo
Retrospective Study on 23 patients (Bruno et al 2006) who had relapsed after allo:
MAIN TOXICITIES
Thrombocytopenia (Grade 3-4)= 22% (Bortezomib), 29% (Bortezomib+Dex)
Neutropenia (Grade 3-4)= 7% (Bortezomib), 11% (Bortezomib+Dex)
Neuropathy (Grade 3-4)= 7% (Bortezomib), 22% (bortezomib+Dex)
Allergic Reaction= 7% (Bortezomib)

25. Bortezomib +/- Dex after allo
Overall response rate was 61% (14/23) with 22% (5/23) immunofixation-negative CR.
Three patients had stable disease and six progressed
(Bruno et al, 2006)

26. Conclusions
Although there is no doubt about the existence of a Graft versus Myeloma effect, it is strictly related to GVHD
The achievement of CR following Allo-SCT & DLI is the major condition for improvement and (probably) for sustained remissions
The possible role of “novel” agents in the allogeneic setting needs to be established