High Response Rates to Bortezomib-Dexamethasone Followed by Donor Lymphocyte Infusions in Patients with Multiple Myeloma Relapsing After Allogeneic Stem Cell Transplantation: Results of a Multicentric Prospective Phase II Study

Patients with multiple myeloma (MM) relapsing or progressing after allogeneic stem cell transplantation (alloSCT) have limited therapeutic options. Donor lymphocyte infusions (DLI) are used to exploit the graft-versus-myeloma effect, and pilot studies have shown that cytoreduction before DLIs could increase their efficacy. These patients are often chemo-refractory or frail, so the new drugs are an attractive option in this setting. Based on experimental and pilot studies showing the high efficacy of bortezomib in alloSCT relapse of MM, we designed a prospective multicenter study to treat these patients with 3 cycles of bortezomib-dexamethasone (VD) followed by escalating doses of DLIs (VD-DLI). The primary objective was the efficacy in terms of response as defined by IMWG criteria. Secondary objectives were to assess the incidence of GVHD, the incidence of graft failure, the progression free survival (PFS), the overall survival (OS), and the safety.

Patients with relapsing or progressive MM after alloSCT were enrolled. Treatment consisted of three 21-day cycles with bortezomib 1.3mg/sqm/day iv at days 1, 4, 8, 11, and oral dexamethasone 20mg/day at days 1–2, 4–5, 8–9, 11–12, followed by 4 DLIs at escalating cell doses administered every 6 weeks. The DLIs started from 5×10^6 CD3+/kg cell dose for HLA-identical sibling donors, or 5×10^5 CD3+/kg for mismatched siblings, matched unrelated (MUD), or haploidentical donors. For every patient, the cell dose was escalated by 0.5 Log at each DLI until a maximum of 1×10^8 CD3+/kg and 1×10^7 CD3+/kg dose at the fourth DLI for HLA identical and alternative donors, respectively. DLIs were stopped anytime in case of acute GVHD, or if patients achieved >=CR after at least 2 DLIs. A safety interim analysis was run after the enrollment of the first 10 patients. Here we presented the final analysis of the study.

Nineteen patients were enrolled at 4 Italian transplant centers between 2007 and 2010. Sixteen patients had ISS stage I MM, two had ISS stage II, and one had ISS stage III MM. FISH data were not available. Median patients' age was 58 years (range, 34–68 years), 8 patients were female. Patients had been treated with a median of 2 lines of therapy (range, 2–5 lines): all the patients had received at least one autologous transplant, 10 had received thalidomide, 4 patients had received bortezomib and none of them was bortezomib-refractory. Two patients had grade (G) 1 peripheral neuropathy (PN) owing to previous treatments. Fifteen alloSCT donors were HLA identical siblings, 3 were MUD and one was haploidentical. One patient received one VD, one 2 VD, and 17 patients all the 3 planned VD. Two patients received one DLI, 1 patient 2 DLIs, 6 patients 3 DLIs, and 8 patients 4 DLIs. The median follow-up of the 15 (79%) surviving patients is 22 months (range, 12.5–55 months). Overall response rate (ORR) to VD was 63%: 3 patients achieved PR, 7 patients VGPR, 1 patient CR and 1 sCR; patients with SD were 5. The 17 patients receiving VD and DLIs had a 71% ORR, with 1 patient achieving PR, 7 patients achieving VGPR, 2 patients CR and 2 sCR; disease was stable in 4 patients. Twelve patients (63%) eventually progressed at a median time of 8.7 months (range, 1–22 months). Progression-free survival was 47% at one year and 33% at both 2 and 3 years of follow-up (median PFS, 12 months). Overall survival was 90% at 1 year and 79% at both 2 and 3 years of follow-up (median not reached). The incidence of aGVHD was 18% (3 patients: 2 had grade 1 and one grade 2). Five patients (29%) had limited cGVHD, none had extensive cGVHD. None of the patients experienced graft failure. During VD, 2 patients experienced G2 hematologic toxicity (thrombocytopenia). PN occurred in 5 patients (26%): 4 patients had G2 PN, and one patient had G3 PN. Other extra-hematologic toxicities more than G2 occurred only in one patient (G3 infection event). During DLI there were no >G2 hematologic or extra-hematologic toxicities. There were no treatment-related mortalities.

This prospective study shows that VD-DLIs is feasible, well tolerated, and it can offer a high remission rate to patients with MM relapsed or refractory after alloSCT. Interestingly, the PFS and OS curves show a plateau, suggesting the achievement of a response more prolonged respect to the series previously published, relative to the non allotransplant setting. [protocol EudraCT number: 2006-004815-24]. Supported by Janssen-Cilag.

Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma.