Bortezomib Consolidation after Nonmyeloablative Allogeneic Stem Cell Transplantation Leads to a High Incidence of Immunophenotypic Complete Response in Young and/or High-Risk Multiple Myeloma Patients
Authors: LeBlanc Richard , Ahmad Imran , Terra Rafik , Landais Séverine , Sebag Michael , Lemieux-Blanchard Emilie , Bambace Nadia M. , Bernard Lea , Cohen Sandra , Delisle Jean-Sebastien , Kiss Thomas , Lachance Silvy , Roy Denis-Claude , Sauvageau Guy , Roy Jean 
Published: October 2019

Abstract
Introduction: Allogeneicstem cell transplantation (alloSCT) is the only curative modality for newly diagnosed multiple myeloma (NDMM) patients (pts). However, we have previously shown in a large cohort of 92 pts that relapse remains common (49%) and the incidence/severity of chronic GVHD is significant (79%) after tandem auto-allo SCT in NDMM pts (Ahmad et al. BMT 2016;51:529). We hypothesized that a tandem auto-nonmyeloablative (NMA) alloSCT followed by bortezomib (btz) consolidation might be safe, while decreasing both the severity/incidence of chronic GVHD and the risk of relapse in young and/or high-risk NDMM pts. In addition, we hypothesized that btz might further increase depth of responses after alloSCT.
Methods: NDMM pts with either ISS stage III, plasma cell leukemia, abnormal cytogenetics defined as t(4;14) with ISS II or III, t(14;16), t(14;20), 17p-, 1p-, or 1q+ in ≥ 10% of purified plasma cells or age ≤ 50 years with a 6/6 sibling or 8/8 unrelated donor were prospectively enrolled in this phase II trial. After a btz-based induction with ≥ partial response and autologous (A) SCT, outpatient NMA alloSCT was performed with either a conditioning of fludarabine 30 mg/m2 x 5 days and cyclophosphamide 300 mg/m2 x 5 days (sibling donor) or fludarabine 30 mg/m2 x 3 days and TBI 2Gy (unrelated donor), followed by G-CSF mobilized stem cells infusion. Acute GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. Btz 1.3 mg/m2 SC every 2 weeks was started on day +120 after alloSCT for 1 year. Bone marrow aspirates before alloSCT, before starting btz and every 3 months thereafter were prospectively collected for 2 years in order to assess the impact of btz on minimal residual disease (MRD) by a highly sensitive (≥10-5) multiparametric flow cytometry using the 8-color Euroflow protocol evaluating ≥ 10 x 106 cells/specimen. MRD negativity was defined as the detection of < 30 clonal aberrant plasma cells. Response evaluation is based on IMWG criteria including immunophenotypic complete response (iCR) defined as a stringent CR (sCR) plus a negative MRD. Immunophenotypic remission (iR) is defined as MRD negativity regardless of other disease status.
Results: As of 06/30/2016, 20 MM pts have been enrolled and 18 allotransplanted (8 siblings; 10 unrelated); median age is 54.5 (range 35-63) years. Of these pts we report: age ≤ 50 (n=6), ISS stage III (n=10) or poor risk cytogenetics (n=7; 5 with 1q+, 2 with t(4;14)). Pts received initial induction with VTD (n=7) or CyBorD (n=11), followed by ASCT (melphalan 200 mg/m2; median CD34+/kg infused: 7.2 x 106). Median times from diagnosis to ASCT and from ASCT to alloSCT were 7.0 (range: 5.3-11) and 4.8 (range: 3.0-7.0) months, respectively. All pts allotransplanted (median CD34+/kg infused: 7.4 x 106) engrafted. With a median follow-up of 282 (range: 22-562) days after alloSCT, 15 pts have received 221 of 239 (92%) planned doses of btz. Observed grade ≥3 non-hematologic adverse events include btz-induced diarrhea (n=1), herpes mucositis despite adequate prophylaxis (n=1), viral hemorrhagic cystitis (n=3) and asymptomatic EBV reactivation (n=4) requiring rituximab. In contrast, CMV reactivation was infrequent. None of the pts developed or exacerbated pre-existing peripheral neuropathies. Fifteen pts were followed ≥ 7 months after alloSCT; acute GVHD occurred in 3 pts (1 grade II; 2 grade III) and chronic in 10 (67%; 3 mild; 7 moderate). Two pts died from grade III acute GVHD. Nine pts (60%) required hospitalization for a median of 13 days (8-184). Response rates after induction, ASCT, alloSCT and btz are shown in Table 1. Most notably, depth of response improved after btz, with 6 pts (40%; 2 with 1q21, 1 with t(4;14), 2 normal and 1 unknown) in iCR and 4 pts (27%; 1 with 1q21, 2 normal and 1 unknown) in sCR. An additional 20% of pts not in iCR or sCR were in iR with negative MRD. No patient developed extramedullary disease.
Conclusions: Our major finding is a high sCR + iCR of 67% in young and/or high-risk NDMM pts following tandem auto-alloSCT and btz consolidation. Although our follow-up is still short, our results are encouraging for an eventual low relapse rate. Additionally, administration of btz 1.3 mg/m2 SC every 2 weeks starting on day +120 after alloSCT is safe and well tolerated. Finally, close monitoring of EBV should be performed prospectively in alloSCT recipients who receive a proteasome inhibitor in order to better assess the risk of viral reactivation.

Disclosures
Sebag: Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria.