The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans.

Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962-11/30/1965), medium (12/1/1965-12/31/1970), or low (1/1/1971-5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

The Association of Agent Orange (AO) Exposure with Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) Progression: A Population-based Study of Vietnam War Era Veterans.

Background: Herbicide and pesticide exposure (e.g., agent orange [AO]) is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Monoclonal gammopathy of undetermined significance (MGUS) is the precursor state to MM; however, not all patients with MGUS progress to MM. It is unclear whether AO exposure increases the risk of progression of MGUS to MM. Purpose: We aimed to determine the association between AO exposure and progression to MM in a nation-wide study of U.S. Veterans with MGUS. Patients and Methods: This is a population-based cohort study of Vietnam Era Veterans diagnosed with MGUS. A natural language processing (NLP) algorithm was used to confirm MGUS and progression to MM. The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Veterans who served during the Vietnam War Era from 1/9/1962-5/7/1975 and were diagnosed with MGUS between 10/1/1999-12/31/2021 were included. We excluded patients with missing BMI values, progression within 1 year after MGUS diagnosis date, non-IgG or IgA MGUS, or birth years outside of the range of the AO exposed group, and race other than Black and White. AO exposure and service during 1/9/1962-;5/7/1975 and stratified according to TCDD exposure levels by three time periods: 1/9/1962-11/30/1965 (high), 12/1/1965-12/31/1970 (medium), or 1/1/1971-5/7/1975 (low). The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Results: We identified 10,847 Veterans with MGUS, of whom 7,996 had AO exposure. Overall, 7.4% of MGUS patients progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, AO exposure from 1/9/1962-11/30/1965, high TCDD exposure, was associated with an increased risk of progression (adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. Conclusions: In patients with MGUS, the high Agent Orange exposure time period is associated with a 48% increased risk of progression to multiple myeloma. This suggests that patients with MGUS and prior Agent Orange exposure or occupational exposure to TCDD (eg. Agricultural workers) may require thorough screening for plasma cell dyscrasias.

Continuous Elotuzumab, Pomalidomide, and Dexamethasone Maintenance Following Second Autologous Transplantation for Multiple Myeloma: Results of a Prospective Phase 2 Multicenter Trial.

Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after upfront AHCT. Retrospective studies have suggested a significant benefit of incorporating maintenance therapy post-AHCT2, but prospective data on specific regimens are lacking. The purpose of this study was to investigate the use of elotuzumab, pomalidomide, and dexamethasone (EPd) as salvage therapy prior to and maintenance after AHCT2 for relapsed multiple myeloma. This prospective single-arm phase II trial investigating the use of EPd in combination with AHCT2 in patients with relapsed multiple myeloma was conducted at 2 academic centers in North America. The primary outcome was 1-year progression-free survival (PFS). Twenty-five patients were enrolled on the study. Sixteen patients received EPd induction; six patients (38%) progressed during salvage therapy and were removed from the trial prior to AHCT2. Following a planned safety analysis, the protocol was amended, and EPd induction was removed from the study schema. An additional 9 patients underwent induction off-study and were enrolled on trial for AHCT2 and EPd maintenance. A total of 18 patients underwent AHCT2 and received EPd maintenance. Two patients discontinued treatment because of toxicity, one attributed to elotuzumab and the other to pomalidomide. The 1-year PFS was 72%, and the median PFS was 19 months. The study was closed early owing to poor accrual; 6 patients remained on therapy at time of analysis. EPd maintenance after AHCT2 was safe and tolerable. The 1-year PFS and median PFS were similar to values in previous retrospective reports of outcomes following AHCT2. Further studies are needed to define the optimal use of and protocol for AHCT2 in fit patients with relapsed multiple myeloma.

Venous Thromboembolism Risk in Patients With Newly Diagnosed Multiple Myeloma Treated with Carfilzomib or Bortezomib in Combination With Lenalidomide and Dexamethasone.

BACKGROUND: Multiple myeloma (MM), as well as some treatments for MM, increase the risk of venous thromboembolism (VTE). Prior literature suggests carfilzomib, lenalidomide, and dexamethasone (KRd) may have a higher incidence of thromboembolic events compared with bortezomib, lenalidomide, and dexamethasone (VRd). We aimed to evaluate VTE risk with KRd induction compared to VRd at a large academic medical center in the United States. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed MM presenting at a single institution. Patients were followed for objectively diagnosed VTE events for 6 months following the start of induction therapy. RESULTS: A total of 209 patients were included, with 69 (33%) receiving KRd and 140 (67%) receiving VRd. Overall, 18 patients (9%) had a VTE event, with 5 (7%) in the KRd cohort and 13 (9%) in the VRd cohort (P = .80). Treatment with KRd was not associated with an increased risk of VTE compared to VRd (HR 0.74; 95% CI 0.26-2.08; P = .57). CONCLUSION: In this cohort, KRd was not associated with an increase in VTE risk compared to VRd, contrary to prior literature.

Phase I-II Trial of Early Azacitidine after Matched Unrelated Donor Hematopoietic Cell Transplantation.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). The hypomethylating agent azacitidine (AZA) has been shown to be effective in preclinical and clinical studies for the prevention of acute GVHD (aGVHD). We sought to determine the maximum tolerated dose (MTD) of AZA when given on days 1 to 5 of a 28-day cycle for 4 cycles, starting on day +7 after allo-HCT, as well as its impact on aGVHD and chronic GVHD (cGVHD), relapse, and overall survival (OS) in patients undergoing matched unrelated donor allo-HCT. This study was a single-arm, single-center, open-label phase I-II study with a total of 15 and 38 patients enrolled in the phase I and II portions of the trial, respectively. A standard 3+3 study design was used in phase I, and all patients in phase II received AZA at the MTD determined in phase I. The MTD of AZA starting at day +7 post-transplantation was 45 mg/m2. Phase II of the study was halted after enrolling 38 of the planned 46 patients following an interim analysis that suggested futility. Overall, AZA at 45 mg/m2 exhibited a side effect profile consistent with prior reports and had a minimal impact on engraftment. The cumulative incidence of clinically significant aGVHD by day +180 was 39.9% (95% confidence interval [CI], 22% to 53.7%). The incidence of all-grade cGVHD was 61.4% (95% CI, 40.3% to 75%). At 1 year, OS was 73.7% (95% CI, 60.9% to 89.1%), and the disease relapse rate was 11.4% (95% CI, .2% to 21.3%). Our results suggest that early post-allo-HCT AZA has limited efficacy in preventing aGVHD and cGVHD but could have a beneficial effect in preventing disease relapse.

Acute Graft-versus-Host Disease: An Update on New Treatment Options.

Acute graft-versus-host disease (GVHD) occurs in approximately 50% of patients and remains a primary driver of non-relapse and transplant-related mortality. The best treatment remains prevention with either in vivo or ex vivo T-cell depletion, with multiple strategies used worldwide based on factors such as institution preference, ability to perform graft manipulation, and ongoing clinical trials. Predicting patients at high risk for developing severe acute GVHD based on clinical and biomarker-based criteria allows for escalation or potential de-escalation of therapy. Modern therapies for treatment of the disease include JAK/STAT pathway inhibitors, which are standard of care in the second-line setting and are being investigated for upfront management of non-severe risk based on biomarkers. Salvage therapies beyond the second-line remain suboptimal. In this review, we will focus on the most clinically used GVHD prevention and treatment strategies, including the accumulating data on JAK inhibitors in both settings.

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34+ hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 106 CD34+ cells kg-1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34+ HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.

Evaluation of the Simplified Score to Predict Early Relapse in Multiple Myeloma (S-ERMM) in the MMRF CoMMpass study.

BACKGROUND: Zaccaria and colleagues recently proposed a new risk score to identify patients at high risk for relapse within 18 months of diagnosis (ER18), the Score for Early Relapse in Multiple Myeloma (S-ERMM). We performed external validation of the S-ERMM using data from the CoMMpass study. PATIENTS AND METHODS: Clinical data was obtained from the CoMMpass study. Patients were assigned S-ERMM risk scores and risk categories by the three iterations of the International Staging System (ISS): ISS, R-ISS and R2-ISS. Patients with missing data or early mortality in remission were excluded. Our primary endpoint was the relative predictive ability of the S-ERMM versus other risk scores for ER18 as assessed by area-under-the-curve (AUC). RESULTS: 476 patients had adequate data to assign all four risk scores. 65%, 25% and 10% were low, intermediate and high risk by S-ERMM. 17% experienced ER18. All four risk scores stratified patients by risk for ER18. S-ERMM (AUC: 0.59 [95% CI 0.53-0.65]) was similar to R-ISS (0.63 [95% CI 0.58-0.69]) and statistically inferior to ISS (0.68 [95% CI 0.62-0.75]) and R2-ISS (0.66 [95% CI 0.61-0.72]) for prediction of ER18. Sensitivity analyses were performed and did not significantly impact results. CONCLUSION: The S-ERMM risk score is not superior to existing risk stratification systems for predicting early relapse in NDMM and further studies are needed to identify the optimal approach.

The Dynamics of Financial Toxicity in Multiple Myeloma.

INTRODUCTION/BACKGROUND: People with multiple myeloma are at risk for financial toxicity due to the high cost of treatment and prolonged treatment duration. However, little data exist regarding financial toxicity among people with myeloma. PATIENTS AND METHODS: In this study, a cohort of 135 patients were recruited from an ongoing observational trial to complete the Comprehensive Score for financial Toxicity (COST). Participants were sent follow-up surveys at 3, 6, and 12 months. RESULTS: The median age was 68 years; the majority were non-Hispanic whites (88%), male (63%), held a college degree (61%), and had left the workforce (70%). The median time from myeloma diagnosis was 28 months. The median COST score was 27; 48% of participants had a score below 27 and considered to have financial toxicity. The only characteristic associated with financial toxicity was a college degree. After controlling for other covariates, those with a college education were 69% less likely to have financial toxicity. Of the 108 participants who completed a follow-up survey, 34% reported changes in their financial toxicity status at a subsequent time point. Transitioning from not having financial toxicity to having financial toxicity was more common than the reverse. CONCLUSION: Because financial toxicity is a dynamic process, which patients are experiencing it at any given time is difficult to predict. Focusing the research agenda on improved detection and intervention may be warranted.

A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation.

Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.

A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease.

A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).

Letermovir Discontinuation at Day 100 After Allogeneic Stem Cell Transplant Is Associated With Increased CMV-Related Mortality.

Letermovir is approved by the Food and Drug Administration for cytomegalovirus (CMV) prophylaxis in CMV seropositive recipients of allogeneic stem cell transplantation (alloSCT) up to day 100. Letermovir use up to day 100 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) at 24 weeks and an overall mortality benefit as far as 48 weeks after transplantation. We report data on csCMVi incidence beyond 24 weeks and overall survival (OS) beyond 48 weeks and outcomes for patients who had a prior alloSCT, are CMV seronegative with seropositive donor (D+/R-), or are high risk (defined as those receiving haploidentical transplants, mismatched transplants, T-cell-depleted grafts, umbilical cord blood transplants, prednisone ≥1 mg/kg or equivalent steroid use, or the use of 2 or more immunosuppressants). Additionally, risk factors for CMV-related mortality and possible extended duration of letermovir are reported. This is a single-center, retrospective cohort study of 333 alloSCTs with CMV seropositive donors or recipients performed at Siteman Cancer Center and Barnes-Jewish Hospital from January 2016 to June 2019. The primary endpoint of csCMVi at day 180 was 19.46% with letermovir and 39.13% without letermovir (P < .0001). The secondary endpoints are as follows: day 100 csCMVi was 8.1% with letermovir and 34.8% without (P < .0001), day 365 csCMVi was 24.8% with letermovir and 41.3% without (P = .001). Our multivariate analyses demonstrated that exposure to letermovir was associated with improved OS (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.25-0.77), nonrelapse mortality (HR 0.50; 95% CI 0.27-0.94) and CMV-related mortality (HR 0.40; 95% CI 0.16-0.95) during day 0 to day 99 but worse CMV-related mortality during day 180 to day 364 (HR 3.19; 95% CI 1.29-7.92). Patients with serum IgG levels <400 mg/dL at day 100, high-risk transplants (P = .004), post-transplantation cyclophosphamide (PTCy; P = .001), and mismatched-unrelated donors (MMUD; P = .02) experienced increased CMV reactivation. The CMV D+/R- cohort demonstrated no difference in CMV reactivation overall (P = .19), but the subset receiving PTCy showed decreased reactivation with letermovir (P = .03). Discontinuation of letermovir at day 100 leads to increased incidence of late CMV reactivation and CMV-related mortality. Letermovir use in CMV recipient seropositive alloSCT may need to be extended. Serum IgG levels <400 mg/dL at day 100 was associated with increased CMV reactivation. Patients with subclinical CMV viremia before transplantation, high-risk transplants, PTCy, or MMUD had decreased CMV reactivation with letermovir. Although there was no difference in CMV reactivation in the CMV D+/R- cohort, the subset treated with PTCy for acute graft-versus-host disease prophylaxis had decreased CMV reactivation with letermovir.

Mouse models of graft-versus-host disease.

Transplantation of allogeneic hematopoietic stem and progenitor cells (allo-HCT) allows for cure of life-limiting malignant and non-malignant hematologic diseases. Crossing the human leukocyte antigen (HLA) barrier, however, comes at the cost of graft-versus-host disease (GVHD), a life-threatening syndrome mediated in part by the same donor T-lymphocytes that eliminate malignant cells. Acute GVHD occurs in the skin, gut, and/or liver in 25-55% of patients with a mortality rate of 15-40%, while chronic GVHD develops in 30-65% of patients who survive at least 3 months following allo-HCT and is highly debilitating in its extensive form, with a 30-50% 5year mortality rate stemming in part from immune dysregulation and opportunistic infections. Knowledge gaps remain in understanding the pathogenesis and in developing novel and effective treatments for the acute and chronic GVHD, which have distinct biology and yet are both treated with front line systemic corticosteroids. Novel and informative mouse models remain the primary means by which these diseases are studied and drugs initially developed prior to testing in humans. In this chapter, we describe allo-HCT mouse models and protocols using these mouse models by which to study acute and chronic GVHD with the goal of improving prevention and therapy.

Safety analysis of patients who received ruxolitinib for steroid-refractory acute or chronic graft-versus-host disease in an expanded access program.

Outside of clinical trials and before commercial availability for acute and chronic graft-versus-host disease (GVHD), the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was available to US patients with steroid-refractory GVHD through an open-label, multicenter expanded access program (EAP) sponsored by Incyte Corporation. To assess the safety of ruxolitinib, data on serious adverse events (SAEs) reported among patients in the EAP were collected. Patients ≥12 years old who received allogeneic hematopoietic cell transplantation for a hematologic malignancy and developed any-grade acute or chronic steroid-refractory GVHD received ruxolitinib at a starting dose of 5 mg twice daily (BID; acute GVHD) or 10 mg BID (chronic GVHD). At data extraction (May 8, 2020), 60 patients with acute GVHD and 549 with chronic GVHD were enrolled. In the acute and chronic GVHD cohorts, 41 (68.3%) and 186 (33.9%) patients, respectively, had ≥1 SAE. Sepsis (8.3%) and respiratory failure (6.7%) were the most common SAEs in the acute GVHD cohort, and pneumonia (4.9%), sepsis (3.8%), and lung infection (3.5%) in chronic GVHD. Infection SAEs were reported in 23.3% and 20.0% of patients with acute and chronic GVHD, respectively. Overall, these safety findings demonstrate the tolerability of ruxolitinib in steroid-refractory GVHD.

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia.

Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA-haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.