Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus, the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review, we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document, we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem autologous HCT, post-HCT maintenance therapy, and the role of allogeneic HCT for patients with MM.

Acute myeloid leukemia is the most common indication for an allogeneic hematopoietic cell transplant. The introduction of reduced intensity conditioning has expanded the recipient pool for transplantation, which has importantly made transplant an option for the more commonly affected older age groups. Reduced intensity conditioning allogeneic transplantation is currently the standard of care for patients with intermediate or high-risk acute myeloid leukemia and is now most often employed in older patients and those with medical comorbidities. Despite being curative for a significant proportion of patients, post-transplant relapse remains a challenge in the reduced intensity conditioning setting. Herein we discuss the studies that demonstrate the feasibility of reduced intensity conditioning allogeneic transplants, compare the outcomes of reduced intensity conditioning versus chemotherapy and conventional myeloablative conditioning regimens, describe the optimal donor and stem cell source, and consider the impact of post-remission consolidation, comorbidities, center experience, and more intensive (reduced toxicity conditioning) regimens on outcomes. Additionally, we discuss the need for further prospective studies to optimize transplant outcomes. ABSTRACTas the backbone of most RIC regimens which also include either a reduced dose of an alkylating agent or a reduced dose of TBI. Fludarabine is generally well tolerated and synergizes well with alkylating agents to enhance inhibition of DNA repair mechanisms. 10 Multiple RIC regimens have been developed and described [12][13][14][15][16][17][18][19] (Table 1).In the late 1990s and early 2000s, the feasibility and efficacy of lower intensity conditioning regimens were demonstrated in several studies that showed successful engraftment in recipients of grafts from both related 19,20 and unrelated donors. 21,22 These regimens were also demonstrated to be a treatment modality that can be successful in older patients with hematologic malignancies. 23 McSweeney et al. described 45 patients with a median age of 56 years who had human leukocyte antigen (HLA)-identical sibling donors and relative contraindications to conventional conditioning for HCT. In these patients a conditioning regimen of TBI alone (200 cGy) produced a survival rate of >66% after a median follow-up of 417 days with a NRM rate of only 6.7%. The associated toxicities were mild, and over 50% of patients were able to have their transplant done completely in the outpatient setting. 23 This set the stage for future studies focusing on the potent immunological graft-versus-leukemia effect to induce cures as opposed to just on intensive pre-transplantation marrow ablative strategies.As the number of efficacious regimens grew, so did the number of patients for whom transplantation became a therapeutic option. Much enthusiasm has led to the widespread adoption of RIC HCT as a potentially curative option for older patients or those with comorbid disease, despite lack of supportive, prospective, randomized d...

Secondary acute myeloid leukemia (sAML) has been associated with inferior outcomes compared with de novo AML. Little is known about patient risk factors and outcomes in sAML after allogeneic hematopoietic stem cell transplantation (HCT); thus, this large systemic analysis of the European Society for Blood and Bone Marrow Transplantation registry was performed. This study included 4997 patients with sAML who received HCT from 2000 to 2016. In univariate analysis the 2-year cumulative incidence of chronic graft-versus-host disease (GVHD), relapse, and nonrelapse mortality (NRM) were 33.5% (95% confidence interval [CI], 32% to 34.9%), 33.7% (95% CI, 32.3% to 35.1%), and 27.5% (95% CI, 26.1% to 28.7%), respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) at 2 years were 44.5% (95% CI, 43% to 46%), 38.8% (95% CI, 37.4% to 40.3%), and 27.2% (95% CI, 25.9% to 28.6%), respectively. In multivariate analysis, patients receiving myeloablative regimens had decreased relapse (hazard ratio, .859; 95% CI, .761 to .97; P = .01), higher NRM (hazard ratio, 1.175; 95% CI, 1.03 to 1.341; P = .02), and no differences in OS, LFS, and GRFS compared with patients receiving reduced-intensity conditioning regimens. Active disease, adverse cytogenetics, older age, Karnofsky performance status (≤80%), ex vivo T cell depletion, other malignant hematologic diseases, and patient cytomegalovirus seropositivity were associated with inferior OS and LFS. These variables should be considered in patients with sAML in need of HCT, and further study regarding the impact of conditioning regimens on relapse is needed.

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL‐2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off‐label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia‐free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post‐HCT AML relapse has an exceedingly poor outcome, and venetoclax‐based therapy is a potent therapy option that should be studied prospectively in this setting.

, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD þ AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P ¼ 0.0027), increased risk of relapse (1-year: 59% vs 19%, P ¼ 0.01), and a trend towards decreased OS (P ¼ 0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD þ independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P ¼ 0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P ¼ 0.01). Time to relapse in patients with FLT3/ITD þ was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD þ AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse.

Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come.

In recent years, we have seen rapid expansion of chimeric antigen receptor T-cell (CAR-T) therapies in multiple malignancies. CAR-T therapy has profoundly altered the treatment landscape of non-Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. Currently available CD19 and B-cell maturation antigen-directed CAR-T therapies have shown high overall response rate and durable remissions in patients who have failed standard therapies. Multiple studies are underway exploring the role of CAR-T-cell therapy as earlier line of treatment. In high-grade B-cell lymphoma, CD19 CAR-T therapy may replace autologous hematopoietic cell transplantation as second line therapy in near future. CAR-T-cell therapy targeting novel tumor-associated antigens will help expand utility of this treatment modality in other hematological malignancies. It may also help overcome limitations of currently approved CAR-T-cell therapies. In this review, we have provided an overview of currently approved CAR-T therapies and upcoming clinical trials which may potentially impact the clinical practice.

1. FLT3 mutation status does not impact overall survival after allogeneic hematopoietic stem cell transplant. 2. Pre-emptive strategies to reduce relapse need to be investigated in FLT3 mutated patients to further improve post HCT outcomes. Background Patients (pts) with FMS like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML) have poor prognosis and are referred for early allogeneic hematopoietic cell transplant (HCT). Methods Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we evaluated 511 adult pts with de novo AML who underwent HCT during 2008-2011 to determine if FLT3 mutations (mut.) impact HCT outcomes. Results 158 (31%) pts had FLT3 mut. Univariate analysis and multivariate analysis showed increased relapse risk at 3 years(yr.) in FLT3 mut. group when compared to wild type (WT) group (38% (95% confidence intervals [CI] 30-45) vs. 28% (95% CI 24-33), P =0.04; and relative risk [RR] 1.60 (95% CI 1.15-2.22), P =0.0048). However, FLT3 mut. status was not significantly associated with non-relapse mortality, leukemia-free survival, or overall survival (OS). Though more pts in the FLT3 mut. group died from relapsed primary disease (60% vs. 46%) as compared to WT, the 3-year OS of pts was comparable 49% (95% CI 40-57) and 55% (95% CI 50-60%) P=0.20. Conclusions Our data shows that FLT3 mut. status did not adversely impact the OS after HCT and about 50% of pts with this mut. who underwent HCT were long term survivors.