Allogeneic Hematopoietic Stem Cell Transplantation in First Line High Risk Multiple Myeloma Patients: Evolving Strategies with the Immunomodulating Drugs.
Authors: Michallet Mauricette , Sobh Mohamad , El-Cheikh Jean , Morisset Stéphane , Sirvent Anne , Reman Oumedaly , Cornillon Jérôme , Tabrizi Reza , Milpied Noel , Harousseau Jean-Luc , Labussière-Wallet Hélène , Nicolini Franck E. , Dumontet Charles , Mohty Mohamad , Attal Michel , Blaise Didier , Moreau Philippe , Avet-Loiseau Hervé 
Published: October 2019

Abstract
Abstract 3116
We evaluated in this study the efficacy and toxicity of a pilot tandem auto-HSCT strategy followed by reduced intensity conditioning (RIC) and allogeneic HSCT with the post-allo-HSCT introduction of bortezomib and donor lymphocyte infusion (DLI) in high risk multiple myeloma (MM) patients (Group1). We compared our results to those observed after traditional tandem auto-RIC-allo-HSCT without bortezomib after allo-HSCT (Group2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the IFM previous prospective studies. Matching variables were: diagnosis date, age, gender, β2 microglobulin, cytogenetics and induction treatment, the matching ratio was 1:3.
Groups 1 & 2 included MM patients of age ≤ 65 years who previously received vincristine, doxorubicin and high-dose dexamethasone (VAD) or bortezomib plus dexamethasone (VD) as induction treatment followed by auto-HSCT. Only patients who achieved at least a partial response (PR) after auto-HSCT were included. Patients must have an HLA identical related or unrelated donor, and at least one of the following factors: β2 microglobulin level >3mg/L, del13, t(4;14) or del17p. The conditioning regimen combined fludarabine 30 mg/m2/d (d-5→d-1), busilvex IV 3.2 mg/kg/d (d-4, d-3) and ATG 2.5 mg/kg/d (d-2, d-1). GVHD prophylaxis consisted on cyclosporine A 3mg/Kg from day -1 with the addition of methotrexate at days 1, 3 and 6 in case of ABO incompatibility. In group1, by day 90 post-allo-HSCT, patients not in CR received 4 cycles of bortezomib 1.3 mg/kg (21 days cycle, on days 1, 4, 8 and 11); if the CR was not achieved, increasing doses of DLI were administered.
Allo-HSCT groups included 25 patients (12 in group1 and 13 in group2), 18 males and 7 females with a median age of 51 years [28–67], there were 15 IgG, 6 IgA and 4 light chains MM. Fourteen (56%) patients had del13, 7 (28%) del17 and 17 (68%) had β2 microglobulin level >3mg/L. Induction treatment was VAD in 16 (64%) patients and VD in 9 (36%). Twenty-one (84%) patients received high dose melphalan (200 mg/m2) while the rest received a dose of 140 mg/m2; auto-HSCT was performed after a median time of 5.5 months [3.6–15.3] from diagnosis. The median time between auto-HSCT and allo-HSCT was 3.8 months [2.5–8.5]. The stem cell source was peripheral HSC in 22 (88%) of cases and the median number of infused CD34+ cells was 6.1×106cells/Kg (range: 2–13) from 16 identical siblings and 9 HLA (10/10) matched unrelated donors. Sex matching was as follow: F→M:9, F→F:3, M→F: 4 and M→M:9 and for ABO compatibility, 18 (72%) were compatible, 1 had minor incompatibility and 6 major incompatibility. At allo-HSCT, one patient was in CR, 4 in very good partial response (VGPR) and 20 patients were in PR. The matched population included 36 controls for group1 and 39 for group2. At Day 90 after allo-HSCT, all patients engrafted, 10 patients were in CR and 15 patients were in less than CR. Nine patients in group1 received bortezomib, 3 reached a CR while the 6 others were still in PR and received increasing doses of DLI. There were 8 acute GVHD [7 grade II (3 in group1) and 1 grade III in group1] and 11 chronic GVHD [3 lim. (all in group1) and 8 ext. (1 in group 1)]. No GVHD reactivation was observed after DLI. At the last follow-up, 14 patients are alive (9 in group1 and 5 in group2), 10 patients were in durable CR1 post-allo-HSCT and 4 patients in PR after DLI; 11 patients died (3 in group1: all from progression; 8 in group2: 5 from progression and 3 from TRM). After a median follow-up of 55 months [3–142], the median OS was not reached in group1 vs. 65 months (51-NR) in its matched patients (p=0.027); and it was 96 months (49-NR) in group2 vs. 91 months (32-NR) in its matched patients (p=0.77). The median PFS was 49 months (29-NA) in group1 vs. 25 months (21–35) in its matched patients (p=0.0045); and it was 31 months (22-NR) in group2 vs. 28 months (21–40) in its matched patients (p=0.0776).
The encouraging results observed in group1, in terms of OS, PFS and toxicity are due to the introduction of IV busilvex and better ATG administration schedule in addition to the immunomodulating role of bortezomib in the elimination of the residual disease. In addition, we showed a good GVL effect after DLI with a durable stability of the disease without any important GVHD complication. According to our promising results, we should reconsider the allo-HSCT in the context of first line treatment for high risk MM patients.

Disclosures:
Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.