Nonmyeloablative conditioning can establish durable and stable engraftment with acceptable transplantation-related mortality (TRM) and excellent disease control in various hematologic malignancies, including multiple myeloma.1,2  We evaluated donor lymphocyte infusions (DLIs) given in 8 European transplantation centers for relapsed (n = 48) or persistent (n = 15) myeloma following nonmyeloablative allogeneic stem cell transplantation (allo-SCT). Twenty-four (38.1%) of 63 patients responded to DLI: 12 (19.0%) with a partial response (PR) and 12 (19.0%) with a complete response (CR). The median follow-up time after DLI of the 43 (68.3%) patients still alive was 14.0 months (range, 3.0-50.7 months). Nine patients relapsed from DLI, 5 from PR, and 4 from CR. Median progression-free survival after DLI was 27.8 months (range, 1.2-46.2+ months) and median overall survival, 23.6 months (range, 1.0-50.7+ months). Twenty (31.7%) patients have died, 13 (20.6%) from progressive disease and 7 (11.1%) from TRM. Acute graft-versus-host disease (GVHD)3  occurred in 24 (38.1%) patients, and chronic GVHD4  occurred in 27 (42.9%) patients.

DLI following nonmyeloablative allo-SCT is a valuable strategy for relapsed or persistent disease, although major drawbacks remain: the graft-versus-myeloma (GVM) effect of DLI seems inextricably bound up with the occurrence of GVHD, and durable remissions are restricted to a minority of patients who achieve CR. Still, survival after DLI in this study was remarkably long, probably due in part to the fact that 15 (83.3%) of 18 patients not responding to (n = 16) or relapsing (n = 2) after DLI were sensitive to additional treatment with bortezomib and thalidomide (Table 1). All 7 patients treated with bortezomib administered according to the Richardson et al scheme5  responded, including 2 patients with a very good partial response (VGPR). Six of 9 patients achieved a PR after treatment with thalidomide (100-300 mg daily), and 2 of 2 patients receiving both drugs achieved CRs that are still ongoing at 8 and 19 months (Table 1). Two patients received bortezomib after treatment failure to thalidomide; one of these patients achieved CR. One patient received thalidomide after treatment failure to bortezomib and achieved PR (Table 1). In 2 patients treated with thalidomide, a transitory flare up of GVHD was observed (1 skin, 1 skin and liver).

Table 1.

Efficacy of bortezomib and thalidomide in DLI-refractory patients


Patient

Stem cell source

No. DLIs (maximum T-cell dose, T cells/kg)

Interval DLI next therapy, mo

Reason to add treatment

Next therapy

Response

Response, mo

Toxicity
1   Sibling   2 (1 × 108)   5   NR to DLI   Bort 6   PR   6   No  
2   Sibling   3 (1 × 108)   4   NR to DLI   Bort 8   VGPR   8+   PNP grade 2  
3   Sibling   2 (1 × 107)   5   NR to DLI   Bort 3   PR   3   PNP grade 3; reason to stop therapy  
4   MUD   2 (1 × 107)   5   NR to DLI   Bort 8   VGPR   9   PNP grade 2  
5   Sibling   1 (1 × 107)   4   NR to DLI   Thal 100   PR   9+   GVHD grade 1; death from lung embolus  
6   Sibling   1 (1 × 107)   4   NR to DLI   Thal 200   PR   6+   GVHD grade 1  
15   Sibling   1 (1 × 106)   5   NR to DLI   Bort 8   PR   9+   PNP grade 2, dose reduction after cycle 3  
28   Sibling   1 (1 × 107)   15   Relapse from CR   Thal 100 + bort 4   CR   19+   No  
29   Sibling   1 (1 × 107)   21   Relapse from CR   Thal 100 + bort 4   CR   8+   No  
32   MUD   1 (1.3 × 107)   6   NR to DLI   Thal 100   PR   8   No  
35   MUD   2 (1 × 106)   2   NR to DLI   Thal 300   PD   NA   No  
37   Sibling   1 (1 × 106)   4   NR to DLI   Thal 100-300   PD   NA   No  
39   Sibling   2 (5 × 106)   3   NR to DLI   Thal 100-200   PR   7   No  
39   Sibling   2 (5 × 106)   10   PD after thal   Bort 4   CR   6   No  
41   MUD   1 (5 × 106)   5   NR to DLI   Thal 100   PR   24+   No  
49   Sibling   1 (1 × 106)   2   NR to DLI   Thal 200   PR   14   No  
54   MUD   1 (1 × 107)   4   NR to DLI   Bort 6   PR   6   No  
59   Sibling   2 (1 × 108)   1   NR to DLI   Thal 100   NR   NA   No  
59   Sibling   2 (1 × 108)   3   PD after thal   Bort 3   PD   NA   PNP grade 2  
63   Sibling   3 (1 × 108)   14   NR to DLI   Bort 8   MR   10   No  
63
 
Sibling
 
3 (1 × 108)
 
40
 
PD after bort
 
Thal 100
 
PR
 
15+
 
PNP grade 2
 

Patient

Stem cell source

No. DLIs (maximum T-cell dose, T cells/kg)

Interval DLI next therapy, mo

Reason to add treatment

Next therapy

Response

Response, mo

Toxicity
1   Sibling   2 (1 × 108)   5   NR to DLI   Bort 6   PR   6   No  
2   Sibling   3 (1 × 108)   4   NR to DLI   Bort 8   VGPR   8+   PNP grade 2  
3   Sibling   2 (1 × 107)   5   NR to DLI   Bort 3   PR   3   PNP grade 3; reason to stop therapy  
4   MUD   2 (1 × 107)   5   NR to DLI   Bort 8   VGPR   9   PNP grade 2  
5   Sibling   1 (1 × 107)   4   NR to DLI   Thal 100   PR   9+   GVHD grade 1; death from lung embolus  
6   Sibling   1 (1 × 107)   4   NR to DLI   Thal 200   PR   6+   GVHD grade 1  
15   Sibling   1 (1 × 106)   5   NR to DLI   Bort 8   PR   9+   PNP grade 2, dose reduction after cycle 3  
28   Sibling   1 (1 × 107)   15   Relapse from CR   Thal 100 + bort 4   CR   19+   No  
29   Sibling   1 (1 × 107)   21   Relapse from CR   Thal 100 + bort 4   CR   8+   No  
32   MUD   1 (1.3 × 107)   6   NR to DLI   Thal 100   PR   8   No  
35   MUD   2 (1 × 106)   2   NR to DLI   Thal 300   PD   NA   No  
37   Sibling   1 (1 × 106)   4   NR to DLI   Thal 100-300   PD   NA   No  
39   Sibling   2 (5 × 106)   3   NR to DLI   Thal 100-200   PR   7   No  
39   Sibling   2 (5 × 106)   10   PD after thal   Bort 4   CR   6   No  
41   MUD   1 (5 × 106)   5   NR to DLI   Thal 100   PR   24+   No  
49   Sibling   1 (1 × 106)   2   NR to DLI   Thal 200   PR   14   No  
54   MUD   1 (1 × 107)   4   NR to DLI   Bort 6   PR   6   No  
59   Sibling   2 (1 × 108)   1   NR to DLI   Thal 100   NR   NA   No  
59   Sibling   2 (1 × 108)   3   PD after thal   Bort 3   PD   NA   PNP grade 2  
63   Sibling   3 (1 × 108)   14   NR to DLI   Bort 8   MR   10   No  
63
 
Sibling
 
3 (1 × 108)
 
40
 
PD after bort
 
Thal 100
 
PR
 
15+
 
PNP grade 2
 

Bort n indicates that patients received an intravenous bolus of bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 for n 3-week cycles; MUD, matched unrelated donor; Thal, thalidomide; PNP, polyneuropathy; GVHD, graft-versus-host disease; NR, no response; MR, minor response; PR, partial response; VGPR, very good partial response; CR, complete response; PD, progressive disease; NA, not applicable; and No, no WHO toxicity > 1.

Response to salvage therapy was assessed according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT).3 

Several studies have shown that the novel agents bortezomib, thalidomide, and thalidomide derivatives may have strong immunemodulating effects resulting in enhancement of graft-versus-tumor reactions without stimulation of GVHD.6-8  The dissociation of GVHD and GVM is of vital importance in improving the efficacy of allo-SCT and DLI. It is therefore questionable whether DLI as a single treatment should be recommended for post-allo-SCT therapy. Our data support the initiation of studies in which novel agents such as bortezomib, thalidomide, and thalidomide derivatives are incorporated into the treatment of relapsed and persistent disease following allo-SCT, alone or in combination with (low-dose) DLI.

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