Impact of the Use of Thalidomide, Lenalidomide, or Bortezomib, Compared to“standard Chemotherapy”, as “salvage” Before Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation (RIC-AT), for Relapsed Multiple Myeloma
Authors: Schmitt Anna , Tabrizi Reza , Vigouroux Stephane , Sauvezie Mathieu , Foucaud Carine , Bouabdallah Krimo , Dilhuydy marie-Sarah , Pigneux Arnaud , Leguay Thibaut , Adiko didier-Innocent , Boiron Jean-Michel , Marit Gerald , Milpied Noel-Jean 
Published: April 2020

Abstract
In the era of novel drugs, the role of RIC AT for relapsed Multiple Myeloma (MM) remains to be determined. In this retrospective study we analyzed the results of RIC AT performed in 36 patients with relapsed MM in our institution between June 1999 and August 2007. At diagnostic our population consisted of 27 males and 9 females. Twenty-eight patients had stage III, 4 patients had stage II and 4 patients had stage I DS. B2-micoglobuline was ≤ 3 mg/l in 16 patients and &gt; 3 mg/l in 11 patients. Del 13 was present in 7/18 patients evaluated. Nineteen received at least 2 HDM with autologous stem cell transplantation, 15 received only one and 2 didn’t received HDM as part of frontline treatment. The median age at time of AT was 56 years (range: 44–64). The “pre-AT” treatments consisted in “standard chemotherapy” for 13 patients and targeted treatments, represented by thalidomide or lenalidomide, or bortezomib w or wo dexamethasone in 23 patients. At the time of AT, 29 patients were responder (3 complete response (CR), 6 very good partial response (VGPR) and 20 partial response (PR)), and 7 patients were not responder (6 stable disease (SD) and 1 progressive disease (PD)). RIC regimen consisted of fludarabine associated with busulfan (n=22), treosulfan (n=2), total body irradiation (n=10), idarubicine and cytosine arabinoside (n=1) or melphalan (n=1). In addition, 25 patients received ATG as part of the conditioning. The donor was an HLA-identical sibling in 20 cases or an unrelated donor in 16 cases. GVH Prophylaxis consisted of CSA alone (n=16), CSA with MMF (n=7), or CSA with MTX (n=13). The median delay between AT and the first response evaluation was 3.8 months, 15 patients achieved CR, 3 patients achieved VGPR, 9 patients achieved PR, 2 patients were in SD and 4 in PD. Twenty one patients developed acute GVHD (grade 1–4) and 14 patients developed chronic GVHD. With a med FU of 42 months, 11 patients are alive. The 3-year event free survival (EFS) and overall survival (OS) from AT are 17, 5% (+/−7.2%) and 32% (+/− 8.3%) respectively. The causes of death were transplant-related complications in 11 patients, relapse or progression in 13 patients, and second malignancy in 1 patient. The TRM at Day 100 and Day 365 was 19 % (+/− 6.6 %) and 32 % (+/− 8%) respectively. Among the numerous factors that were evaluated for their prognostic influence, only two were significantly associated with a better OS and EFS (in univariate and multivariate analysis): the achievement of a CR or VGPR after AT (median OS: 31m vs 5; p&lt;0.0001; median EFS: 56m vs 9; p=0.005) and the occurrence of a chronic GVHD (median OS: 31m vs 9; p=0.0003; median EFS: 56m vs 21; p=0.007). The achievement of a CR or a VGPR after the RIC AT was significantly associated with the result achieved before RIC AT. In our small cohort of patients we were unable to identify factor associated with the occurrence of a cGVH. When targeted treatments were used as salvage, the rate of CR+VGPR before and after RIC AT was higher (before:35% vs 7%; after: 61% vs 31%) however, this did not turned in a significant improvement of the OS, the EFS and the TRM.
Conclusion: The disease response remains a major goal to improve the results of RIC AT in relapsed Multiple myeloma. The targeted therapies are able to improve the disease response in patients who relapse after HDM and were never treated with such drugs. However we did not document a significant improvement of the overall results of RIC AT following such salvage as compared to chemotherapy salvage.