Use of bortezomib in the management of chronic graft-versus-host disease among multiple myeloma patients relapsing after allogeneic transplantation

Abstract

We report on the use of bortezomib for the management of chronic graft versus host disease (cGVHD) among 8 multiple myeloma (MM) patients who relapsed after reduced-intensity conditioning (RIC) allogeneic transplantation. Five patients (62%) responded to bortezomib demonstrating anti-myeloma effect. Four patients had active cGVHD, including 3 patients with severe punctate keratopathy, at the time of bortezomib administration. All showed an improvement in their condition. This is the first report showing that bortezomib may be useful in the management of cGVHD and related ocular involvement.

We report on the use of bortezomib for the treatment of 8 MM patients who relapsed after allo-RIC. Median age was 54.5 years (range: 30–62). Relapses occurred at a median of 15 months (range: 3–33). Five patients developed an extramedullary relapse and in the remaining 3 patients an increase of monoclonal component was also observed. Two showed bone marrow infiltration > 10% plasma cells by flow cytometry while in the remaining 6 patients no infiltration was observed in the bone marrow. Prior to bortezomib, 3 patients received a mean of 3 donor lymphocyte infusions (range 2–4) at a starting dose of 1 × 10 CD3 cells/kg. Other therapeutic strategies prior to bortezomib included Tha-Cy-Dex in one patient and thalidomide as a single agent in another patient. Bortezomib was administered at conventional doses for a median of 6 cycles (range 3–12). Three patients received bortezomib alone, two in combination with dexametasone, one in combination with lyposomal doxorubicin, and two patients also received local radiotherapy to treat extramedullary relapses. Five patients (62%) responded, including 2 (25%) complete responses (CR). Both of them are in CR 8 to 12 months after treatment respectively. One out of the 3 patients who reached partial response (PR) continues in PR six months after treatment while the other two patients progressed. All 3 patients are, however, alive 6 to 43 months after relapse. Three patients (37%) did not respond to treatment. One of them is alive 3 months after relapse.

Among observed toxicity, the most secondary effects were neuropathy, affecting 5 (62%) patients. Grades III/IV thrombocytopenia were observed in 4 (50%) patients, leukopenia in 1 (12%) while 4 (50%) patients had gastrointestinal toxicity. Four patients (50%) did not receive the 8 planned cycles and required drug discontinuation due to grades III/IV neuropathy (2 patients), headache (1 patient), and grade III/IV cytopenias (1 patient).

Four patients had chronic and one acute GVHD at the time of bortezomib administration with severe punctate keratopathy in three patients. Systemic immunosupression was already stopped at the time of MM relapse in 3 patients while 1 patient was still being tapered off tacrolimus. Interestingly, in all four patients, cGVHD significantly improved.

Table 1.Patients’ characteristics and outcome.

A median of 150 days (range: 120–333 days) after bortezomib discontinuation, cGVHD continues in remission in three patients. Interestingly both symptoms and conjunctival ulcerations responded in all 3 patients with ocular involvement (Figure 1). However, in 1 of them, the punctate keratopathy has reappeared at last follow-up. The patient with aGVHD developed scleroderma at the time of bortezomib treatment. Bortezomib is a useful drug in the treatment of relapsed MM, including extramedullary involvement.1–3 We focused on the influence of bortezomib on the outcome of cGVHD. Therefore, four patients with refractory extensive (n=3) or limited (n=1) cGVHD responded to bortezomib. However, since two of these patients also received dexamethasone, GVHD response could be attributed to any of the two agents. Nevertheless, one of these patients had already received dexametasone in combination with thalidomide and cyclophosphamide and neither MM nor cGVHD had responded. For the remaining patient, cGVHD improvement could be related to both bortezomib and/or dexametasone. By contrast patient 1, who responded to bortezomib alone, had previously received prednisone in combination with tacrolimus and cGVHD had not improved. This further suggests the efficacy of bortezomib independently of the steroid administration. Improvement at the ocular level is remarkable since ocular involvement is usually very resistant to conventional treatment, including steroids.4,5 Although other chemotherapeutic agents may induce a less specific immunosupression, bortezomib modulates immune responses inducing selective apoptosis among alloreactive T cells.6,7 Interestingly, several studies have shown that NF-κB activation plays a crucial role in inflammatory eye disease. NF-κB blockade may, therefore, have an important role in the management of ocular GVHD.8 Interestingly, GVHD and graft-versus-myeloma effect are closely associated with allo-RIC. Nevertheless, myelomatous cells may escape GVM control outside bone marrow increasing the risk of extramedullary relapses even among patients who develop cGVHD.9 The efficacy of bortezomib in the treatment of extramedullary relapses and its effect on GVHD suggests it may help to control GVHD without compromising GVM. However, bortezomib must be carefully monitored after allogeneic transplantation because in this study, 62% patients developed neuropathy requiring drug discontinuation in 2 patients. Results from previous clinical studies are very limited and even contradictory. Giralt et al.10 reported that bortezomib did not worsen cGVHD in a series of 9 patients while Kröger et al. reported a mild aggravation of skin GVHD in two patients with cGVHD and in one patient with aGVHD among 18 MM patients.2

Figure 1.In patient 1, at physical examination ocular involvement improved from grade 4 and 5 keratitis prior to bortezomib to total recovery of the ocular surface after treatment. Pre-bortezomib findings: (1A) Right eye: fluorescein staining (grade 4 keratitis according to Oxfod scale); (1B) Left eye: fluorescein staining (grade 5 keratitis); post-bortezomib findings: (2A) Right eye. No fluorescein staining (grade 0); (2B) Left eye. No fluorescein staining (grade 0); (2C) right eye and (2D) Left eye: anterior segment biomicroscopy; no hyperemia, no keratitis, no epithelial defects.

Although this is a short series of patients, it is the first report showing that bortezomib may be useful in the management of cGVHD, and its related ocular involvement.