Sequential Allogeneic Transplantation for Multiple Myeloma Patient in Early Relapse Post-Autograft
Authors: Charbonnier Amandine , Gruson Berengere , Lebon Delphine , Beaumont Marie , Merlusca Lavinia , Morel Pierre , Marolleau Jean-Pierre , Royer Bruno 
Published: November 2019

Abstract
Multiple myeloma (MM) remains mostly incurable despite novel therapeutic approaches. Allogeneic stem cell transplantation (ASCT) in MM could be the only curative treatment but is associated with a high morbidity and mortality, and relapses remain, mainly in high risk (17p deletion, (4;14) translocation, plasma cell leukemia, extramedullary disease or early relapse post-autograft).
In refractory or poor risk cytogenetic acute myeloid leukemia (AML), sequential conditioning, followed by prophylactic immunomodulation with donor lymphocyte infusion (DLI), seems improve the outcome, compared to conventional ASCT regimens.
Based on this sequential approach ASCT, we developed a sequential conditioning for MM, with a systematic immunomodulation strategy. The conditioning included melphalan 100mg/m² at day-10, followed by FB2 conditioning (fludarabine 30mg/m²/d day-6, -5,-4, -3, -2, busulphan 3.2mg/kg/d day-5, -4 and horse antithymoglobulin 2.5mg/kg/d day-3, -2). Prophylaxis of GVHD included cyclosporine and methotrexate according to ABO compatibility. This schema was proposed for young patients with early relapse after autograft (<1 year). The aim of the study was to evaluate feasibility and safety.
In the absence of GVHD, 2 cycles of bortezomib (1,3mg/m² day 1, 4, 8, 11) without steroids followed by 3 escalated doses of DLI.
Four patients received this sequential conditioning. All were low risk cytogenetic but were in early relapse post-autograft. Patients' characteristics are shown in table1. One patient received 2 autologous transplantation (patient 3). They received 2 or 3 lines of combination chemotherapy before allograft including: bortezomib (n=4), lenalidomide (n=4), pomalidomide (n=1). All of them were in partial response at time of ASCT.
All patients were grafted with peripheral blood stem cells (median dose = 8 CD34+/kg [5.44-8.15]). Only one patient received methotrexate in addition to cyclosporine for GVH prophylaxis for ABO minor incompatibility.
Two patients presented grade 3-4 acute GVHD: 1 was steroid-resistant and responded secondary to ruxolitinib, but unfortunately he died of septic shock. Patient 4 was in sCR with MRD negative 6 months post ASCT but currently presents signs of disease evolution without treatment criteria at 10 month.
Two patients didn't presented GVHD and received prophylactic schedule with bortezomib followed by escalated doses of DLI. Three doses of DLI were planned: first dose=5x106 CD3+/kg, second dose=1x107CD3+/kg and third dose=5x107CD3+/kg. Only 2 doses were administrated because patients relapsed before the third dose. Patient 3 presented limited chronic GVHD (oral lichen) after DLI2 but relapsed 11 months post ASCT. Patient 1 relapsed at 10 months: they were retreated with pomalidomide and are now alive.
In conclusion, sequential conditioning for young patients with MM in early relapse post-autograft is feasible. The addition of melphalan to the classical FB2 is safe without early toxicity (no mortality related to transplantation at day +100). 2 patients however presented severe acute GVHD. Despite the post ASCT immunomodulation, this procedure was not capable to control the disease. The optimization of conditioning procedure, the post-allograft immunomodulation and a maintenance therapy may provide a benefit to patients and, thus, requires further study.
Table 1 Table 1.

Disclosures
No relevant conflicts of interest to declare.