High Response Rate and Improved Graft-Versus-Host Disease (GVHD) Following Bortezomib as Salvage Therapy after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation (RIC allo-SCT) for Multiple Myeloma (MM).
Authors: El-Cheikh Jean , Michallet Mauricette , Nagler Arnon , de Lavallade Hugues , Nicolini Frank E. , Shimoni Avichai , Faucher Catherine , Sobh Mohamad , Revesz Daniela , Hardan Izhar , Furst Sabine , Blaise Didier , Mohty Mohamad 
Published: October 2019

Abstract
Bortezomib has been shown to be an efficient treatment for MM. Similarly, a potent allogeneic graft-versus-myeloma effect can be induced against MM. However, despite progress in terms of transplant-related mortality, a significant proportion of patients may still relapse or progress after RIC-allo-SCT. This retrospective report describes the results of 37 MM patients who received bortezomib (1.3 or 1.0 mg/m2 intravenously, days 1, 4, 8, and 11) as a salvage therapy after progression following RIC-allo-SCT. Median age was 49 years. All patients (100%) received and failed at least one autologous stem cell transplantation prior to RIC allo-SCT. Median time between the initial diagnosis of MM and allo-SCT was 11 (range, 6–96) months. Patients were not treated in a combined autologous/allo-SCT strategy. Before bortezomib initiation, 14 patients (38%) received and failed DLI. Also, 20 patients (54%) received and failed thalidomide (because of disease progression or toxicity). Overall, 32 patients (86%) received bortezomib salvage in progressive disease, while 5 patients (14%) were in PR. Median time between allo-SCT and bortezomib initiation was 20 (range, 1–65) months. At time of bortezomib initiation, the majority of patients (n=26; 70%) did not have any symptoms of chronic GVHD, while 8 patients (22%) had some form of limited chronic GVHD, and 3 patients (8%) had extensive signs. The median number of bortezomib cycles administered was 6 (range, 1–15). Peripheral neuropathy was frequently observeded after bortezomib (n=13; 35%; 4 grade 2 and 9 grade 1). Mild thrombocytopenia not requiring platelets transfusions was observed in 9 cases (24%). Fatigue was also observed in 7 patients (19%). None of the patient had to discontinue the treatment because of a life-threatening adverse event, and no treatment-related toxic deaths were observed. In terms of GVHD, patients did not experience reactivation or worsening of GVHD symptoms. Interestingly, two patients among the three patients with extensive GVHD signs at the beginning of bortezomib experienced a significant improvement and were staged as limited chronic GVHD at last follow-up. In all, 27 patients (73%; 95%CI, 59%–87%) achieved an objective disease response after starting of bortezomib (7 CR, 7 VGPR, and 13 PR). Prior use of thalidomide and/or DLI did not influence disease response to bortezomib. There was also no difference in disease response when using bortezomib in combination or without dexamethasone. With a median follow-up of 9 (range, 3–42) months from bortezomib initiation, 25 patients (68%; 95%CI, 53%–83%) still had a sustained objective disease response (5 CR, 5 VGPR, and 15 PR). Ten patients (27%) died and 27 are still alive with a median overall follow-up after allo-SCT of 80 (range, 18–153) months. The majority of deaths were directly attributed to disease progression (n=8; 80% of all deaths). Most importantly, patients achieving an objective disease response (CR, VGPR or PR) after introduction of bortezomib enjoyed a significantly higher overall survival as compared to non-responding patients (P=0.002). Collectively, these data demonstrate that bortezomib is a safe and potentially efficient option for MM patients failing RIC allo-SCT.