Long-Term Outcome of Autologous Followed by Nonmyeloablative Allografting from HLA-Identical Sibling for Multiple Myeloma (MM).
Authors: Rotta Marcello , Storer Barry , Sahebi Firoozeh , Shizuru Judith A. , Benedetto Bruno , Lange Thoralf , McSweeney Peter A. , Pulsipher Michael A. , Hari Parameswaran , Maziarz Richard T. , Agura Edward D. , Chauncey Thomas , Appelbaum Frederick R. , Sorror Mohamed L. , Bensinger William , Sandmaier Brenda M. , Storb Rainer F. , Maloney David G. 
Published: October 2019

Abstract
BACKGROUND: Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) as consolidation following high dose therapy with autologous HCT is a promising treatment for MM. Low early transplant mortality and high response rates were described in small patient (pts) cohorts with limited follow-up (FU). Here we report on the outcome of pts with HLA-identical siblings treated with this tandem auto/allo approach after a median FU of 5 year.
PATIENTS: Pts with stage II-III MM (n=102) were treated with tandem auto/nonmyeloablative allografting at 8 centers between August 1998 and August 2005. Median age was 55(range 32–71) years. Median number of prior treatments was 1(1–2), and median number of prior cycles of treatment was 6 (2–18). Median time between initiation of treatment and autografting was 13(2–118) months and 73/102 (72%) pts initiated their tandem HCT within 10 months of initial therapy. Median time between auto and allo HCT was 80(40–281) days. Autologous HCT conditioning was with melphalan 200 mg/m2 and allogeneic conditioning with 2Gy total body irradiation (TBI) alone (n=75, 73%) or with 2Gy TBI plus fludarabine 90 mg/m2 (n=27, 23%). Post allografting immunosuppression was with mycophenolate mofetil (MMF) and cyclosporine (n=91, 89%) or MMF and tacrolimus (n=11, 11%). Sixty-seven pts (66%) had chemoresponsive disease and 35 (34%) were refractory. The disease status at allo HCT included complete remission (CR, 29 pts, 28%), partial remission (PR, 38 pts, 37%), refractory (RD, 27pts, 26%) or progressive disease (PD, 8pts, 8%).
RESULTS: 101/102 pts had sustained donor engrafment. Forty one (41%) and 8 pts (8%) experienced grade 2 to 4 and 3 to 4 acute graft-versus-host-disease (GVHD); 70 pts (69%) had extensive chronic GVHD. Median FU post-allografting was 5(0.75–8.66) years. The overall response rate was 94%, with 64 (63%) and 32 pts (31%) achieving CR and PR respectively. Median time to progression was 4 years. Median progression-free survival (PFS) was 3 years while 5-year estimated PFS was 35%. Median overall survival (OS) has not been reached. Three and 5-year estimated OS were 75% and 63% respectively. Cumulative incidence of nonrelapse mortality (NRM) at 100 days, 1 and 5 year were 1%, 13% and 19% respectively. Most of the NRM (89%) was related to GVHD and/or infection. In the subset of 73 pts who initiated their tandem HCT within 10 months from initial therapy, the estimated OS and PFS at 3 and 5-years were 80% and 55%, 69% and 40% respectively. In univariate analysis refractory or progressive disease at allo HCT was associated with higher risk of relapse (p=0.004) and relapse plus NRM (p<0.0001).
CONCLUSION: Long-term disease control and GVHD and its complications remain key issues to address following tandem auto/nonmyeloablative allogeneic HCT. Comparison with tandem autologous HCT awaits results of the BMT-CTN 0102 and similar trials.