Reduced intensity allogeneic hematopoietic stem cell transplantation is a safe and effective treatment option in high‐risk myeloma patients – a single centre experience

Abstract

Allogeneic stem cell transplantation (allo-SCT) has been extensively investigated as a potentially curative treatment strategy for myeloma. Early studies using myeloablative conditioning showed an unacceptable transplant-related mortality (TRM) of 53%, despite long-term remission rates (39%). 1 Recent improvements in transplant conditioning, graft-versus-host disease (GvHD) prophylaxis and treatment, and supportive care have seen allo-SCT for myeloma re-emerge as a viable option, in particular for young patients with high-risk disease, in whom the prognosis remains poor. 2 Despite this, newer therapeutic strategies have raised the bar for what allo-SCT would need to achieve to be seen as a useful option. 3 At our institution, we use a low-intensity fludarabine/cyclophosphamide conditioning regimen without pre-emptive T-cell depletion. This has been shown to be safe and effective in acute myeloid leukemia, 4 acute lymphoblastic leukaemia 5 and lymphoid malignancies 6 for patients over a wide age range (the latter report included 11 of the current cohort).For this study, we retrospectively collected data from myeloma patients who underwent allo-SCT. Patients received reduced intensity conditioning with fludarabine 25 mg/ m 2 /day for 5 days and cyclophosphamide 1 g/m 2 /day for 2 days, followed by infusion of stem cells from human leukocyte antigen (HLA)-matched donors. GvHD prophylaxis consisted of short-course methotrexate (5 mg/m 2 on days +3, +6 and +11), and cyclosporin (5 mg/kg on day À2 and 3 mg/kg per day thereafter, adjusted according to blood levels). Standard supportive therapy and antimicrobial prophylaxis were employed. Full details of the protocol are as previously described. 4 Myeloma was monitored with serum and urine protein electrophoresis, and latterly serum-free light chain assay. From 2007 onwards, patients received their conditioning in an ambulatory setting, with admission to the hospital ward only if medical complications arose. Details of the statistical methods are given in Supplementary Materials.All 37 patients with myeloma undergoing allo-SCT between 2000 and 2018 were included in the analysis. The majority were male (76%) with a median age at transplant of 52 years (range 31-63). International Staging System (ISS) values were recorded for 32 patients as follows: I 21Á9%, II 40Á6% and III 38Á0%. At least one high-risk cytogenetic feature (t(4:14), t(14:16),17pÀ or 1q+) was present for 57% of the cohort who had available cytogenetic analysis, consistent with a high-risk population.

Allogeneic Stem Cell Transplantation in Multiple Myeloma

“…In various studies remission status at allo-SCT was also a relevant predictor for survival with significantly longer OS and/or PFS in patients responding to induction as compared to those with progressive disease at the time point of transplantation [ 17 , 18 , 36 , 43 , 45 , 51 , 67 , 75 , 77 , 78 , 80 , 81 , 82 ]. The role of minimal residual disease (MRD)-status was analyzed in the post-transplant setting and is not conclusively clarified at this time: Achievement of MRD-negativity by flow cytometry after transplantation led to a survival benefit in a large retrospective analysis [ 76 ], whereas another trial could not prove a difference [ 82 ].…”

“…In line with a suspected higher GvM effect, occurrence of mild or moderate chronic GvHD led to a survival benefit [ 52 , 62 , 67 , 72 , 74 ]. On the contrary, the outcome was worse in patients developing severe acute GvHD, likely due to prolonged immunosuppression and increased TRM [ 52 , 71 , 73 ].…”

Donor Lymphocyte Infusion to Enhance the Graft-versus-Myeloma Effect

“…However, the dissection of the subgroup of patients who may benefit from alloSCT from those who may benefit from less toxic novel agent approaches remains crucial [52]. Limited evidence points to subgroups with high-risk MM patients, young and motivated patients [53][54][55]. Moreover, DLI application is a complex procedure, whereby many factors need to be considered (e.g., patient-oriented factors prior to application, disease-specific factors, as well as possible combinations with further therapies during and after DLI).…”

Allogeneic stem cell transplantation in multiple myeloma: is there still a place?

“…Notably, in this cohort, the development of chronic GvHD predicted longer survival. ( 50 ) Conversely, the efficacy of allo-HSCT is limited in patients who have active disease at transplantation (median PFS and OS of 6 months and 23 months, respectively) as well as in those patients with early relapse (<12 months) after first-line treatment. ( 51 – 53 ) Compared with non-transplantation approaches, an Italian retrospective study showed a potential benefit for allo-HSCT in RRMM.…”