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

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

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: 83-93 157 108 65 32 12 2 94-98 100 28 0

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

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

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

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)

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

(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

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

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

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

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

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

DLI following RIC Retrospective analysis from 8 European centers Response to DLI n = 63 patients PR 12 (19%) CR 12 (19%) Total 24 (38%)* * ± Comparable to DLI following myeloablative Allo-SCT NWCJ Van De Donk et al. BMT 2006

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

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

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

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

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

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

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

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

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)

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)

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