Search

Purpose: Prognostic Immunophenotyping in Myeloma Response (PRIMeR) is an ancillary study of minimal residual disease (MRD) assessment for multiple myeloma by next-generation multiparameter flow cytometry (MFC). Patients were enrolled on a three-arm randomized control trial (Blood and Marrow Transplants Clinical Trials Network 0702 Stem Cell Transplant for Myeloma in Combination of Novel Agents [STaMINA]; ClinicalTrials.gov identifier: NCT01109004)., Methods: Four hundred and thirty-five patients consented to the MRD panel, which included 10 monoclonal antibodies measured via six-color MFC. MRD was measured at baseline/preautologous hematopoietic cell transplant (BL/preAutoHCT), premaintenance (PM), and 1 year (Y1) after AutoHCT with a sensitivity of 10 -5 to 10 -6 . The primary objective was to assess MRD-negative (MRD neg ) at 1 year after AutoHCT and progression-free survival and overall survival (PFS/OS)., Results: Similar to the STaMINA results, at a median follow-up of 70 months, there was no significant difference in PFS/OS by treatment arm in the PRIMeR patients. MRD neg at all three time points was associated with significantly improved PFS, and MRD neg at Y1 had significantly longer OS. Multivariate analysis of PFS, adjusting for disease risk and treatment arm, demonstrated hazard ratios (HRs) in MRD-positive patients compared with MRD neg patients at BL, PM, and Y1 of 1.55 ( P = .0074), 1.83 ( P = .0007), and 3.61 ( P < .0001), respectively. Corresponding HRs for OS were 1.19 ( P = .48), 0.88 ( P = .68), and 3.36 ( P < .001). Patients with sustained MRD neg or who converted to MRD neg by Y1 had similar PFS/OS., Conclusion: To our knowledge, this first, prospective US cooperative group, multicenter study demonstrates that MRD neg at Y1 after AutoHCT with lenalidomide maintenance is prognostic for improved 6-year PFS and OS. Serial MRD measurements may direct trials to test how further therapy may improve long-term PFS and OS.

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically., (© 2024. The Author(s).)

Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602; P = 0.045] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning [P = 0.028] but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL; P = 0.046]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

T-cell responses to minor histocompatibility antigens (mHAs) mediate graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation. Therapies that boost T-cell responses improve allogeneic hematopoietic cell transplant (alloHCT) efficacy but are limited by concurrent increases in the incidence and severity of GVHD. mHAs with expression restricted to hematopoietic tissue (GVL mHAs) are attractive targets for driving GVL without causing GVHD. Prior work to identify mHAs has focused on a small set of mHAs or population-level single-nucleotide polymorphism-association studies. We report the discovery of a large set of novel GVL mHAs based on predicted immunogenicity, tissue expression, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT data set of 3231 alloHCT DRPs. The total number of predicted mHAs varied by HLA allele, and the total number and number of each class of mHA significantly differed by recipient genomic ancestry group. From the pool of predicted mHAs, we identified the smallest sets of GVL mHAs needed to cover 100% of DRPs with a given HLA allele. We used mass spectrometry to search for high-population frequency mHAs for 3 common HLA alleles. We validated 24 predicted novel GVL mHAs that are found cumulatively within 98.8%, 60.7%, and 78.9% of DRPs within DISCOVeRY-BMT that express HLA-A∗02:01, HLA-B∗35:01, and HLA-C∗07:02, respectively. We confirmed the immunogenicity of an example novel mHA via T-cell coculture with peptide-pulsed dendritic cells. This work demonstrates that the identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD., Competing Interests: Declaration of interests P.L.M. has received honoraria from and participated in advisory boards for Bristol Myers Squibb, Bluebird, Celgene, Janssen, Juno, Karyopharm, Magenta Therapeutics, Oncopeptides and Takeda. B.R.B serves on advisory boards for Magenta Therapeutics and BlueRock Therapeutics; receives research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Pharmaceuticals Corp., and Carisma Therapeutics, Inc.; and is a co-founder of Tmunity Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Spatial heterogeneity is a common phenomenon in metastatic solid tumors and an evolving concept in multiple myeloma (MM). The interplay between malignant plasma cells (PCs) and the microenvironment has not yet been analyzed in MM. For this purpose, we performed bone marrow aspirates and imaging-guided biopsies of corresponding lesions in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. PCs were isolated and subjected to whole-exome sequencing (WES). Non-PCs were studied with next-generation flow (NGF) and T-cell receptor sequencing (TCRseq) to analyze the connection between malignant and nonmalignant cells in the bone marrow and in lesions. Although we observed a strong overlap from WES, NGF, and TCRseq in patients with intramedullary disease, WES revealed significant spatial heterogeneity in patients with extramedullary disease. NGF showed significant immunosuppression in RRMM compared with NDMM as indicated by fewer myeloid dendritic cells, unswitched memory B cells, Th9 cells, and CD8 effector memory T cells but more natural killer and regulatory T cells. Additionally, fewer T-cell receptor (TCR) sequences were detected in RRMM compared with NDMM and healthy individuals. After induction therapy, TCR repertoire richness increased to levels of healthy individuals, and NGF showed more regulatory T cells and myeloid-derived suppressor cells, regardless of depth of response. Clinical significance of imaging-guided biopsies of lesions was demonstrated by detection of monoclonal PCs in patients without measurable residual disease (MRD) in aspirates from the iliac crest as well as identification of secondary primary malignancies in MRD- patients. Furthermore, site-specific clones with different drug susceptibilities and genetically defined high-risk features were detected by our workflow., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hypoxic conditions preserve the multipotency and self-renewing capacity of murine bone marrow and human cord blood stem cells. Blood samples stored in sealed blood gas tubes become hypoxic as leukocytes metabolize and consume oxygen. Taken together, these observations suggest that peripheral blood stem cell (PBSC) samples stored under airtight conditions become hypoxic, and that the stem cells contained may undergo qualitative or quantitative changes. This study aimed to determine the effect of storage for 8 hours in a sealed system on PBSC samples. Granulocyte colony-stimulating factor-mobilized PBSC samples were collected prospectively from 9 patients with myeloma or amyloidosis prior to apheresis, followed by measurement of CO 2 , O 2 , hydrogen ion (pH), lactate, and glucose concentrations in the blood and immunophenotyping of stem cell and multipotent progenitor cell populations before and after 8 hours of storage in sealed blood collection tubes. Blood concentrations of O 2 and glucose and pH measurements were significantly decreased, whereas concentrations of CO 2 and lactate were significantly increased after storage. Significantly higher concentrations of CD34 + cells (552 ± 84 cells/10 6  total nucleated cells [TNCs] versus 985 ± 143 cells/10 6  TNCs; P = .03), CD34 + CD38 - cells (98 ± 32 cells/10 6  TNCs versus 158 ± 52 cells/10 6  TNCs; P = .03), CD34 + CD38 + cells (444 ± 92 cells/10 6  TNCs versus 789 ± 153 cells/10 6  TNCs; P = .03), and CD34 + CD38 - CD45RA - CD90 + cells (55 ± 17 cells/10 6  TNCs versus 89 ± 25 cells/10 6  TNCs; P = .02) were detected after 8 hours of storage. The changes in concentrations of CD34 + CD38 + cells and CD34 + cells were inversely associated with the change in glucose concentration (P = .003 and P < .001, respectively) and positively associated with the change in lactate concentration (P = .01 and P <.001, respectively) after 8 hours of airtight storage. Storage of PBSC samples in a sealed, airtight environment is associated with microenvironmental changes consistent with hypoxia and increased concentrations of immunophenotypically defined stem cells. These results may have clinical implications with regard to the collection and processing of stem cell products and warrant confirmation with functional and mechanistic studies., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The definition of multiple myeloma (MM) was updated in 2014, with the intent to enable earlier treatment and thereby avoid appearance of end-organ damage at progression from smouldering multiple myeloma (SMM) to MM. The purpose of this study was to investigate to which extent the development of end-organ damage at progression to MM was reduced under the updated guidelines. In this prospective observational cohort study (ClinicalTrials.gov Identifier: NCT01374412), between 2014 and 2020, 96 SMM patients prospectively underwent whole-body magnetic resonance imaging (wb-MRI) and serological follow-up at baseline and every 6 months thereafter. A total of 22 patients progressed into MM during follow-up, of which seven (32%) showed SLiM-criteria only but no end-organ damage. Four (57%) of the seven patients who progressed by SLiM-criteria only progressed with >1 focal lesion (FL) or a growing FL, and three (43%) due to serum free light-chain-ratio ≥100. Fifteen (68%) out of 22 patients who progressed still suffered from end-organ damage at progression. The updated disease definition reduced the proportion of SMM patients suffering from end-organ damage at progression to MM by one third. wb-MRI is an important tool for detection of SMM patients who progress to MM without end-organ damage., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma. Here we provide a comprehensive summary of these workshop presentations., Competing Interests: Conflict of interest statement S.A.H. has served as a consultant for Bristol Myers Squibb/Celgene, Genentech, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, SecuraBio, and Takeda and has received research funding from Oncopeptides. F.A. is listed as an inventor on US patent US20170258898A1: “Versikine for inducing or potentiating an immune response”. A.K.A. has a pending US patent for the TME-targeting nanoparticles. G.B. has served as a consultant for Karyopharm. M.B. has received institutional research funding from Celgene/Bristol Myers Squibb, Cerecor, Cellularity, Janssen, MedImmune, Millennium Pharmaceuticals, and C4 Therapeutics. L.C. has received laboratory service contract funding from Ionis Pharmaceuticals. H.G. has received sponsorship for her PhD tuition fees from the Binding Site Ltd. S.G. has received research funding from Bristol Myers Squibb. J.H. has received honoraria from Janssen; has served on advisory boards for Adaptive Biotechnologies, Amgen, AXXESS Network, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Oncotracker, Sanofi, and Skyline; and serves on an independent data safety monitoring board for Janssen. S.K. is an employee of Bristol Myers Squibb and holds stock in the company. M.C.P. has served as a consultant for Bristol Myers Squibb and Amgen and has received research support from Kite Pharma, Novartis, Janssen, GSK, Crispr, and Bristol Myers Squibb. N.S. has received research funding from Celgene/Bristol Myers Squibb, Janssen, bluebird bio, Sutro Biopharma, Teneobio, Poseida, Nektar, and Precision Biosciences and has served as an advisor for GlaxoSmithKline, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite Pharma, Karyopharm, Oncopeptides, and CSL Behring. M.S. is a cofounder and owner of Sarya, LLC. B.R.S. is a holder of patents pertaining to this work. E.L.S. has served on scientific advisory boards for Bristol Myers Squibb, Novartis, and Chimeric Therapeutics and as a consultant for Secura Bio; has licensed patents/royalties from BMS and Sanofi; and has received research funding from BMS. R.V. is an employee of Janssen. S.Z.U. has received research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; has received consulting fees from Abbvie, Amgen, Bristol Myers Squibb, Celgene, EdoPharma, Genentech, Gilead, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDx, Takeda, and TeneoBio; and has received speaking fees from Amgen, Celgene, Janssen, and Takeda. P.L.M. has served as a consultant for bluebird bio, Bristol Myers Squibb, Celgene, Juno, Fate Therapeutics, Hikmo, Janssen, Juno, Karyopharm, Magenta Therapeutics, Novartis, Oncopeptides, Sanofi, Starton Therapeutics, and Takeda. The other authors have no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown., Methods: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival., Results: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65)., Conclusions: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.)., (Copyright © 2022 Massachusetts Medical Society.)

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Recent advances in the diagnosis and management of multiple myeloma (MM) have improved patient outcomes. This progress in our understanding of MM has resulted in continuous suppressive therapy concepts, including induction, high dose chemotherapy with autologous stem cell transplantation (ASCT), consolidation, and maintenance therapy. The foundation of maintenance therapy has been with lenalidomide. Other novel immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and targeted monoclonal antibodies have also contributed to this evolution., Areas Covered: This review summarizes the outcomes from phase II/III trials with long-term lenalidomide maintenance therapy alone or in combination with other agents in post-ASCT and non-transplant settings for newly diagnosed patients with MM. We review recent data considering a combination with newer medications and ongoing trials. We also review the optimal duration, MRD negativity rate, and safety and tolerability aspects of lenalidomide maintenance therapy. This review aims to present the current and emerging clinical evidence that supports using lenalidomide as a backbone for maintenance therapy in patients with MM., Expert Opinion: There is increasing evidence to support lenalidomide as the backbone of combination therapy in the maintenance setting.

Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease., (© 2022. The Author(s).)

Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications., Competing Interests: Declaration of interests NSR reports grants and consulting fees from Bristol Myers Squibb–Celgene, Bluebird Bio, Amgen, Janssen, GlaxoSmithKline, Caribou Biosciences, and Immuneel; and personal fees from Research to Practice, Karyopharm, Takeda, Amgen, and Janssen, outside the submitted work. SKK reports grants and consulting fees from Bristol Myers Squibb–Celgene, Takeda, Abbvie, Roche, and Janssen; grants from Medimmune, Tenebio, and Carsgen; and personal fees from Oncopeptides, Beigene, and Antengene, outside the submitted work. SL reports personal fees from Celgene, Janssen, Takeda, Novartis, Bristol Myers Squibb, GlaxoSmithKline, and Amgen, outside the submitted work. TM reports personal fees from GlaxoSmithKline; and grants from Sanofi, Janssen, and Amgen, outside the submitted work. MAG reports personal fees from Abbvie, Celgene, Akcea, i3Health, Prothena, Research to Practice, Alnylym, Ambry Genetric, Amgen, Janssen, Celgene, Aurora Bio, Ionis, Karyopharm, and Sanofi; and grants from Pfizer, outside the submitted work. PH reports grants and personal fees from Bristol Myers Squibb, Takeda, Amgen, Janssen, and Legend Biotech, outside the submitted work. HL reports personal fees from Janssen, Bristol Myers Squibb–Celgene, and Seattle Genetics; and grants and personal fees from Amgen and Takeda, outside the submitted work. JLK reports grants from Abbvie; personal fees from TG Therapeutics and Incyte; and grants and personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. ADC reports personal fees from Bristol Myers Squibb–Celgene, Janssen, Takeda, AstraZeneca, Genentech–Roche, Oncopeptides, and Seattle Genetics; grants from Novartis; and grants and personal fees from GlaxoSmithKline, outside the submitted work. LG reports personal fees from Amgen, Takeda, Novartis, Bristol Myers Squibb, Janssen, and Sanofi, outside the submitted work. ET reports personal fees from Bristol Myers Squibb; grants and personal fees from GlaxoSmithKline, Janssen, and Sanofi; and grants, personal fees, and consulting fees from Amgen, Genesis Pharma, and Takeda, outside the submitted work. RN reports personal fees from Takeda, Amgen, Celgene, Janssen, Karyopharm, GlaxoSmithKline, and Bristol Myers Squibb, outside the submitted work. NL reports consulting fees from AbbVie, Takeda, and Omeros; and grants from Omeros and Alnylam, outside the submitted work. ME reports grants from Amgen, Bristol Myers Squibb, Janssen, Takeda, Sanofi, and GlaxoSmithKline, outside the submitted work. AB reports personal fees from BeiGene, Sanofi Genzyme, Pharmacyclics, and Karyopharm, outside the submitted work. AC reports personal fees from Bristol Myers Squibb, Karyopharm, Sanofi, Oncopeptides, Antengene, GlaxoSmithKline, Secura Bio, and Shattuck Labs; grants from Pharmacyclics; and grants and personal fees from Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Seattle Genetics, and Millenium–Takeda, outside the submitted work. BL reports personal fees from Karyopharm, Bristol Myers Squibb, Janssen, and GlaxoSmithKline; grants from Cellectar; and grants and personal fees from Amgen, outside the submitted work. JR reports personal fees from Bristol Myers Squibb, Takeda, Karyopharm, Oncopeptides, AstraZeneca, Adaptive Biotechnologies, Janssen, Secura Bio, and Sanofi, outside the submitted work. JSM reports personal fees from Amgen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Takeda, Sanofi, Roche, GlaxoSmithKline, Abbvie, Karyopharm, and SecuraBio, outside the submitted work. KCA reports personal fees from Amgen, Pfizer, Janssen, AstraZeneca, Precision Biosciences, Windmill, Mana, Starton, Raqia, Oncopeptides, and C4 Therapeutics, outside the submitted work. PLM reports personal fees from BlueBird Biotech, Bristol Myers Squibb, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Takeda, and Medscape; grants from Celgene; and non-financial support from Sanofi, outside the submitted work. NCM reports personal fees from Bristol Myers Squibb, Oncopeptides, Janssen, Amgen, Novartis, Takeda, Abbvie, and C4 Therapeutics, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0-18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM., (© 2021 Wiley Periodicals LLC.)

Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that β2 adrenergic receptor (β2-AR) expression on MDSCs increases with tumor growth and that the β2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that β2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that β2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The fifth annual Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma was conducted as one of the American Society of Hematology Annual Meeting Scientific Workshops on Thursday December 3, 2020. This workshop focused on four main topics: (1) integrating minimal residual disease into clinical trial design and practice; (2) the molecular and immunobiology of disease evolution and progression in myeloma; (3) adaptation of next-generation sequencing, next-generation flow cytometry, and cytometry by time of flight techniques; and (4) chimeric antigen receptor T-cell and other cellular therapies for myeloma. In this report, we provide a summary of the workshop presentations and discuss future directions in the field., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Poor physical functioning is associated with adverse outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Analytic tools to predict mortality in alloHCT recipients include the HCT Comorbidity Index (HCT-CI) based on comorbidities and the Disease Risk Index (DRI) based on disease and disease status. We developed and replicated a risk model for overall survival (OS), early mortality (ie, death from any cause at or before day +100), initial hospital length of stay (LOS), and percentage of inpatient days within the first year post-alloHCT. In this study, we incorporated a physical therapy (PT) assessment with the HCT-CI and DRI to improve outcome predictions. The well-defined and feasible measure of functional status for assessing risk includes (1) the number of sit-to-stands performed in 30 seconds, (2) performance of 25 step-ups on the right/left side with (3) oxygen saturation recovery and (4) heart rate recovery, (5) weight-bearing ability, (6) assistance with ambulation, (7) motor and grip strength, (8) sensory and coordination impairment (eg, self-reported peripheral neuropathy, imbalance), (9) self-reported pain, and (10) limited endurance (ie, inability to complete step-ups and/or sit-to-stands). Our training cohort (TC) included 349 consecutive alloHCT recipients at Roswell Park treated between 2010 and 2016 and a subsequent replication cohort (RC; n = 163) treated between 2016 and 2019. Four of the 10 metrics-self-reported pain, limited endurance, self-reported neuropathy, and <10 sit-to-stands in 30 seconds-were identified as significant predictors and were included in the multivariable models with the HCT-CI and DRI to create a new risk index (HCT-PCDRI: HCT-physical, comorbidity, and DRI) for outcomes. Models were tested in the RC. Shorter OS was associated with self-reported pain, limited endurance, higher HCT-CI, and higher DRI. At a median follow-up of 34 months, the 3-year OS based on the HCT-PCDRI was 30% for the very-high-risk group, 54% for the high-risk group, 49% for the intermediate-risk group, and 80% for the low-risk group. The number of patients identified as very high risk increased from 55 using HCT-CI alone to 120 with the new HCT-PCDRI, whereas the number in the low-risk group decreased from 91 to 45. Early mortality and a higher percentage of inpatient days within the first year post-alloHCT (a proxy for poor quality of life and high healthcare utilization) were associated with self-reported pain, higher HCT-CI, and higher DRI. A shorter initial LOS (ie, initial low healthcare utilization) was associated with performance of >10 sit-to-stands in 30 seconds, no self-reported neuropathy, and lower HCT-CI. These PT metrics combined with the HCT-CI and DRI created the HCT-PCDRI, which resulted in more patients being categorized accurately as high risk versus low risk. The HCT-PCDRI results were replicated in an independent cohort. Pre-alloHCT PT metrics with self-reported symptoms (pain and neuropathy) were associated with survival post-alloHCT and prolonged hospital LOS. The HCT-PCDRI scoring system for risk stratification of alloHCT recipients more accurately identifies patients at potential risk of poor outcomes. The HCT-PCDRI can be tested in <15 minutes to identify patients for intervention before or during treatment to potentially improve outcomes., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT., Methods: We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011., Findings: Using meta-analyses of both cohorts, genome-wide significant associations ( p  < 5 × 10 -8 ) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p  = 3.3 × 10 -8 ) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p  = 2.0 × 10 -8 ); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p  = 3.15 × 10 -8 ), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p  = 2.84 × 10 -8 ), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p  = 6.9 × 10 -9 ) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p  = 2.6 × 10 -8 ); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p  = 1.26 × 10 -8 ) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p  = 4.6 × 10 -9 ). Results publicly available at https://fuma.ctglab.nl/browse., Interpretation: These data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies., Funding: This project was funded by grants from the National Institutes of Health, USA., Competing Interests: PLM: Consulting: BlueBird Biotech, Bristol-Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Sanofi, Takeda; Honoraria: BlueBird Biotech, Bristol-Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Medscape, Takeda; Institutional Research Support: Celgene. MCP: Institutional Research Support: Bristol-Myers Squibb, Novartis, Kite, GlaxoSmithKline; Consulting: Amgen (institution), Bristol-Myers Squibb (personal). TH, LESC: report grants from NIH/NHLBI, grants from NIH/NCI, during the conduct of the study. EK: reports a Graduate Student Fellowship from Pelotonia Foundation. All other authors have nothing to declare., (© 2021 The Author(s).)

Background: Daratumumab is an anti-CD38 immunotherapeutic drug that has increasingly been used to treat patients with heavily pre-treated and relapsed/refractory multiple myeloma. In so doing, the detection of CD38 antigen on plasma cells by flow cytometry is impeded. We hypothesized that alternative markers can be used in place or in addition to CD38 when detecting plasma cells post-treated with daratumumab., Methods: A total of 16 alternative markers were tested using 22 bone marrow aspirates from patients with plasma cell neoplasm. The ability of selected markers to discern plasma cells from other hematopoietic cells were evaluated. The stability of tested markers when stored at 4 or 25°C after T = 0, 24, 48, and 72 h was also established. Finally, selected markers were incorporated into a panel used for monitoring multiple myeloma measurable residual disease to test their utility to identify plasma cells in the presence of daratumumab and/or elotuzumab (anti-CD319) drugs., Results: Out of the 16 tested markers, CD319, CD54, CD229, CD317, and p63 were expressed by >90% of the plasma cells. Only CD319, CD54, and CD229 achieved 100% detection sensitivity. Further analysis showed that CD319 was better than CD229 and CD54 at resolving plasma cells from background hematopoietic cells, with CD54 being the worst (resolution metric, mean ± SD: CD319 [2.04 ± 0.86]; CD229 [1.47 ± 0.45]; and CD54 [1.22 ± 0.60]). CD229 was expressed by >90% of T lymphocytes, whereas CD319 was expressed preferentially by the CD8+ T cells and less frequently in CD4+ T cells. Additionally, CD229 was found on >60% of B and NK cells, as well as minor subsets of monocytes and granulocytes. CD319 was expressed on most NK cells and a minor subset of B cells, granulocytes, and monocytes. Even though CD229 and CD319 were expressed by different leukocyte subsets, their expression levels were highest on plasma cells. The expression of CD138 on plasma cells was significantly lower after storage at 4°C, while the expression levels of CD38, CD229, and CD319 remained stable at 4 or 25°C. Using limiting dilution experiments, the treatment of cells with daratumumab severely impeded the detection of CD38 antigen on plasma cells, whereas elotuzumab treatment did not block detection of CD319 on plasma cells., Conclusions: CD319 is a suitable alternative to CD38 for identifying plasma cells. Our results showed that a panel used for monitoring multiple myeloma measurable residual disease could be modified by using CD319 alone or in combination with CD38 to detect PCs in daratumumab or elotuzumab treated patients., (© 2020 International Clinical Cytometry Society.)

Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens prior to ASCT as well as post-ASCT maintenance therapy. Randomized phase III clinical trials have helped establish lenalidomide maintenance as a standard of care. However, as nearly all patients will eventually experience disease relapse, there continues to be significant interest in developing novel maintenance strategies to improve upon lenalidomide maintenance. In this review, we summarize the available evidence for the use of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies as post-ASCT maintenance therapies as well as discuss future directions and unanswered questions in the field.

Chronic graft-versus-host disease (cGVHD) is the most common cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (alloHCT). Cutaneous cGVHD is characterized by thickening of the skin and connective tissues, causing discomfort and limited mobility. Current assessment of these skin lesions is based on physical examination of their thickening, pinchability, and movability. Optical coherence tomography (OCT) is a noninvasive, high-resolution technique using near-infrared light to interrogate tissues and image the microstructure without the use of contrast agents. We determined the applicability of OCT to human cutaneous cGVHD. Seven patients with varying degrees of cutaneous cGVHD, including 3 controls who underwent autologous HCT were prospectively examined using the cGVHD Skin (Vienna) Scale and imaged with OCT. Analysis of OCT images and clinical exams revealed that stratum corneum thickness, epidermal thickness, and depth of light transmission were correlated with cutaneous cGVHD severity in the hands, forearms, upper arms, legs, thighs, and upper back (P ≤ .03). Longitudinal OCT changes during cGVHD treatment paralleled clinical changes in the arm and upper back. OCT changes were observed in the absence of clinical changes. OCT imaging reflects the severity of cutaneous cGVHD and can be used to follow these lesions. OCT may facilitate the design of therapeutic trials in cGVHD by providing a quantitative measurement of cGVHD severity. Additional studies are needed., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients., Competing Interests: Competing interests: CC─Consultant and/or advisory board: Novartis. MLD─Consultant and/or advisory board: Celyad, Novartis; Research/license support: Atara, Celgene; Stock option: Adaptive Biotechnologies, Precision Bioscience. CD─ Consultant and/or advisory board: Evidera, Juno. JD─Consultant and/or advisory board: Unum Therapeutics, Blue Earth Diagnostics; Royalties: Wolters Kluwer. JCF─NIDDK 23 grant. MJF─Consultant and/or advisory board: Arcelex, Celgene, Nkarta, Novartis, Xenetic Bio. JLH-C─At-large board member: ASTCT; Vice Chair: Government affairs, Task force member on Immunotherapies and Palliative Care, ASH; Co-Primary Investigator: Imaging trial haplo/cord, graft failure NHLBI RO1 grant. SAG─Consultant and/or advisory board: Adaptimmune, Allogene, Cellectis, Eureka, GlaxoSmithKline, Humanigen, J&J/Janssen, Juno, Novartis, Roche, TCR2, Vertex/CRISPR Therapeutics; Grant/research support: Kite Gilead, Novartis, Servier, Vertex. KVK─Consultant or SAB: Kite/Gilead, Autolus, Juno/BMS, Celgene, Novartis, Takeda, Kiadis, Incyte, Atara, Legend, Kadmon, Helocyte; Clinical trials support (institutional): Kite/Gilead, Novartis, Atara, Allogene; Nonprofit organizations: National Marrow Donor Program (Board of Directors), ASTCT (Chair, cell therapy committee). DWL─Owner: Immchase, LLC; Consultant and/or advisory board: ACI Clinical (on behalf of Celgene), Harpoon Therapeutics, Juno Therapeutics. FLL─Scientific advisor: Kite/Gilead, Novartis, BMS/Celgene, Allogene, Wugen, Calibr, Gamma Delta Therapeutics; Consultant: Cellular Biomedicine Group Inc; Research support: Kite/Gilead. SLM─Consultant and/or advisory board: Kite, Novartis. MVM─Consultant and/or advisory board: Adaptimmune, Adaptive Biotechnologies, Argentus, BD Sciences, Bluebird Bio, Cell Signaling, Collectis (SAB), CRISPR Therapeutics, EMD Serono, Inysus, Kite, Juno, MPM, Novartis, Takeda, TCR2 (SAB), Third Rock Ventures, WindMIL (SAB); Grant/research support: CRISPR Therapeutics, Kite Gilead. PLM─Consultant and/or advisory board: BlueBird Biotech, BMS, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, MedScape, Sanofi, Takeda. SSN─Consultant and/or advisory board: Celgene, Cell Medica, Incyte, Kite/Gilead, Merck, Novartis, Pfizer, Precision Biosciences, Unum Therapeutics; Grant/research support: Acerta, BMS, Collectis, Karus, Kite Gilead, Merck, Poseida, Unum Therapeutics. TGN─Consultant on imaging: Parexel, Intrinsic Imaging; SAB on Checkpoint and Myocarditis: BMS; Consultant: H3 Biomedicine, Aprea Therapeutics. BDS─Consultant and/or advisory board: Kite Gilead, Juno/Celgene, Insysus, Novartis, Janssen; Grant/research support: ADC Therapeutics. EJS─Consultant and/or advisory board: Adaptimmune, Cellgene, Magenta, Novartis, Partner Therapeutics. DTT─Advisory board: La Roche, Amgen, Janssen, Novartis. CJT─Consultant and/or advisory board: Aptevo, Arsenal Bio, AstraZeneca, Caribou Biosciences, Century Therapeutics, Eureka Therapeutics, Humanigen, Juno/BMS, Kite/Gilead, Myeloid Therapeutics, Nektar Therapeutics, Novartis, Precision Biosciences, T-CURX; Stock options: Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Arsenal Bio, Myeloid Therapeutics; Grant/research support: Juno/BMS, Nektar Therapeutics, AstraZeneca. SA, MRB, JNB, TJF, EM, and TW─Nothing to disclose. SITC staff: AK, BL, LL and SMW─Nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies have reported a beneficial effect from cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (alloHCT) on immune reconstitution. We determined the CMV antigenemia level associated with increased CMV antigen-specific T cells (CASTs) at day +100 and decreased CMV reactivation after day +100. CMV reactivation and CASTs were measured with CMV antigenemia and CMV-specific major histocompatibility complex multimers. The analysis consisted of 775 CAST measurements obtained before and 30, 100, and 365 days post-alloHCT from 327 consecutive patients treated between 2008 and 2016. Detectable CASTs correlated with recipient (P < .0001) and donor (P < .0001) CMV seropositivity pre-alloHCT. CMV reactivation before day +100 was associated with a higher proportion of patients who achieved ≥3 CASTs/µL by day +100 (61% with versus 39% without reactivation, P < .001). In alloHCT recipients at high risk for CMV reactivation (R + D ± ) with a maximum of grade II acute graft-versus-host-disease, reactivating CMV before day +100 and achieving ≥3 versus <3 CASTs/µL at day +100 was associated with reduced CMV reactivation from day +100 to +365 (27% versus 62%, P = .04). This protective effect was observed with low-level but not high-level CMV reactivation (<5 versus ≥5/50,000 polymorphonuclear leukocytes + pp65, respectively). These findings suggest low-level CMV reactivation may be beneficial and that treatment may be delayed until progression. These findings will need validation in prospective clinical trials using CMV PCR and antigenemia assays., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. All rights reserved.)