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The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma is controversial. Between 2008 and 2014 a total of 217 multiple myeloma patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multicenter clinical trial to compare alloTSCT to autologous tandem transplantation (autoTSCT) followed by 2 years of maintenance therapy with thalidomide (100 mg/day) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent a second transplant (132 allogeneic, 46 autologous). PFS at 4 years after the second transplant was 47% (95% CI: 38-55%) for alloTSCT and 35% (95% CI: 21-49%) for autoTSCT (P=0.26). This difference increased to 22% at 8 years (P=0.10). The cumulative incidences of non-relapse mortality and of relapse at 4 years were 13% (95% CI: 8-20%) and 2% (95% CI: 0.3-2%) (P=0.044) and 40% (95% CI: 33-50%) and 63% (95% CI: 50-79%) (P=0.04) for alloTSCT and autoTSCT, respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (P=0.002). Four-year overall survival was 66% (95% CI: 57-73%) for alloTSCT and 66% (95% CI: 50-78%) for autoTSCT (P=0.91) and 8-year overall survival was 52% and 50% (P=0.87), respectively. In conclusion, alloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly. This study was registered with ClinicalTrials.gov (NCT00777998).

Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy.

Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P<0.001). In multivariate analysis URD, not in complete remission (CR) at transplant or untreated, and female donor for male recipient were factors associated with increased risk whereas the use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months, respectively, for the periods analyzed. Three-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%, respectively. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and the use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning was linked to lower mortality. Mortality increased with increasing patient age but decreased in the recent cohorts. Our analysis demonstrates that aGvHD has decreased over recent decades and also that the survival rates of patients affected with aGvHD has improved.

Melphalan at a dose of 200 mg/m 2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m 2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m 2 and melphalan 140 mg/m 2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m 2 (n=245) and melphalan 200 mg/m 2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m 2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m 2 versus melphalan 140 mg/m 2 : 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m 2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m 2 and melphalan 140 mg/m 2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m 2 or melphalan 140 mg/m 2 for key transplant outcomes (NCT01362972)., (Copyright© 2018 Ferrata Storti Foundation.)

Allogeneic stem cell transplantation is a therapeutic option under dispute but nonetheless chosen with increasing frequency for patients suffering from multiple myeloma in Europe. To study possible predictors of survival, 79 patients were investigated using whole-body magnetic resonance imaging to assess the visible tumor burden before and after allogeneic stem cell transplantation. Statistical analysis of clinical and imaging parameters included Cox regression models and distribution of survival time estimates (Kaplan-Meier method). Log rank test was used to determine the prognostic impact of the presence of focal lesions on survival. A higher tumor burden according to the lesion count was associated with a shorter overall survival (univariable/multivariable Cox regression: 1 st magnetic resonance imaging P =0.028/ P =0.048; 2 nd magnetic resonance imaging P =0.008/ P =0.024). Focal infiltration pattern itself seemed to be an additional adverse prognostic factor for overall survival (2 nd MRI P =0.048), although no definite cut-off could be defined. Kaplan-Meier estimates at 60 months of follow up show a significant difference (Log rank P =0.04) for overall survival rates between patients with focal infiltration (32%) and those without (75%). Since this subgroup of patients may benefit from maintenance therapy, adoptive immunotherapy, or local interventions, whole-body imaging is an appropriate and highly recommendable diagnostic approach for detection of prognostically relevant lesions before and after treatment., (Copyright© 2018 Ferrata Storti Foundation.)

Background and Objectives: Peripheral blood stem cells (PBSC) following reduced intensity conditioning (RIC) are being increasingly used for allogeneic transplantation in multiple myeloma. The purpose of this study was to compare outcome of patients transplanted with either PBSC or bone marrow (BM) following RIC or myeloablative conditioning (MAC)., Design and Methods: Data from 1,667 patients who had received an allogeneic identical sibling donor transplant for multiple myeloma from 1994 to 2003 were analyzed. Comparisons were made between results of PBSC and BM transplants after conditioning with RIC or MAC., Results: The engraftment rate was faster with PBSC than with BM (median: 14 and 18 days for neutrophils and 15 and 25 days for platelets respectively) irrespectively of whether RIC or MAC was used. The incidence of acute graft-versus-host disease (GVHD) did not differ significantly between the groups while chronic GVHD was more prevalent in PBSC recipients irrespectively of whether they had RIC or MAC. Non-relapse mortality did not differ between PBSC and BM recipients, but was significantly higher in those treated with MAC than in those given RIC irrespectively of the cell source. The relapse/progression rate did not differ between PBSC and BM recipients, but was significantly higher in those given RIC, irrespectively of the cell source. There was no significant difference in overall or progression-free survival between patients given PBSC or BM transplants., Interpretation and Conclusions: Although transplantation of PBSC is associated with faster engraftment and more frequent chronic GVHD, overall survival, non-relapse mortality, relapse/progression and progression-free survival are similar to those following BM transplants. However both PBSC and BM transplants are associated with lower non-relapse mortality, lower response rate and higher relapse/progression if RIC is used instead of MAC.