Outcomes of Unrelated Cord Blood Transplantation in Patients with Multiple Myeloma a Eurocord, CBC-Cellular Therapy & Immunobiology Working Party and Chronic Malignancies Working Party-EBMT Study

Although outcomes for multiple myeloma (MM) have improved with the use of drugs such as bortezomib, thalidomide, lenalidomide and autologous stem cell transplantation (ASCT), it remains an incurable disease. Allogeneic stem cell transplantation (AlloSCT) is not a standard therapy for MM, but it potentially provides a graft versus myeloma effect.  The use of reduced-intensity conditioning (RIC) and the autologous-allogeneic tandem transplantation have broadened the use of AlloSCT in patients (pts) with MM. Nevertheless, relapse incidence (RI) after AlloSCT remains high and investigation of this procedure in MM population is warranted.

To date, few published reports describe outcomes of unrelated cord blood transplantation (UCBT) in MM pts. We retrospectively analyzed 95 pts, 85 with MM and 10 with Plasma cell leukemia, who underwent UCBT in EBMT centers from 2001 to 2013. Median follow-up was 41 (range 3.6-96) months. The Immunoglobulin (Ig) subtype was IgG in 41% of pts. Out of the 45 pts with available cytogenetic data, 32 had abnormal karyotypes including 11 with high risk alterations (e. g. t(4,14) and del17p).  Eighty-two pts received proteasome inhibitors or immunomodulatory drugs before UCBT. The median age at UCBT was 53 years (yrs) and 36% of pts was at stage III ISS. Fifty-one pts were male (54%) and 53% of pts were CMV positive. Thirty-six pts (38%) received a single UCBT and 59 (62%) a double UCBT (dUCBT); 89 pts (96%) received at least one previous ASCT, 26 (30%) had a tandem auto-auto transplant while 18 (21%) had an auto-allotransplant. For those 18 pts, the median time between auto and UCBT was 3.4 (2-8) months. Disease status at UCBT was 1^st complete remission (CR) in 10 pts, 2^nd CR in 10 pts, very good partial response (VGPR) in 20 pts, partial response (PR) in 37 pts, stable or progressive disease in 14 pts and missing data in 4 pts. The majority of pts (85%, n=77) received a RIC and 17 a myeloablative conditioning. Among RIC, 78% of pts received cyclophosphamide+fludarabine+Total Body Irradiation (TBI) (2-6 Gy) and 23% received anti thymocyte globulin (ATG). Median number of infused total nucleated cells (TNC) was 3.3 x10⁷/kg (0.8-7.82). Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 97±3% at 60 days and 72±5% at 180 days after UCBT with a median time for achievement of 20 and 33 days, respectively. Among 7 pts who failed neutrophil engraftment, 4 died in a median time of 21 months after UCBT and 2 underwent ASCT.  CI of 100-day acute GvHD grade II-IV and grade III-IV was 41±5% and 16±4% respectively; aGVHD was lower in pts who received ATG (18% vs 48%, p=0.02) and in those who did not receive TBI (15% vs 49% p=0.0008). CI of chronic GVHD (cGVHD) at 2 years was 22±4%, (median time 188 days, 5/23 pts had extensive cGvHD). CI of cGVHD was higher after dUCBT (30% vs 9%, p=0.015). CI of relapse at 3 years was 47±5% and it was higher in chemoresistant MM (75% vs 45%, p=0.05). Non relapse mortality (NRM) at 3 years was 29±5%.  ATG use, myeloablative conditioning and TBI were associated with higher incidence of NRM, in the univariate analysis. Sixty-three pts died: 30 of relapse and 33 of transplant related causes (infections, n=16, GvHD, n=5 and others causes, n=12). The 3-yr progression free survival (PFS) and overall survival (OS) were 24±5% and 40±5%, respectively. In multivariate analysis, the use of ATG was associated with decreased incidence of aGVHD (HR=0.16, 95%, CI=0.03-0.78, p=0.023), higher incidence of NRM (HR=6.9, 95% CI 2.06-23.38, p=0.002), decreased OS (HR=5.53, 95% CI=2.35-12.98, p<0.001) and decreased PFS (HR=3.39, 95% CI=1.50-7.67, p=0.003). Pts with good cytogenetic risk had lower RI (HR=0.28, 95% CI=0.09-0.88, p=0.03) and better OS (HR=0.35, 95% CI=0.145-0.82, p=0.016) and PFS (HR=0.38, 95% CI=0.16-0.89, p=0.027). cGVHD as time dependent variable was associated with higher PFS and OS (HR=2.64, 95% CI=1.33-5.25, p=0.006, and HR=2.43, CI=1.15-5.1, p=0.02,  respectively). Three pts received maintenance with lenalidomide after UCBT.

These results show that UCBT may be beneficial in approximately 25% of MM pts.  The main reason of transplant failure is probably the relatively high risk of relapse in pts heavily pretreated and with high disease burden. UCBT progress might be obtained with better patient selection.  The role of immunomodulatory drugs as maintenance therapy after UCBT needs to be further investigated in well-designed protocol for improving UCBT outcomes.