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Abstract: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, ∼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population., (© 2024 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.)

Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd)., Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials., Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%)., Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen., Competing Interests: DW: honoraria: Amgen, Antengene, Bristol Myers Squibb/Celgene, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda. SL: advisory board: Janssen, GSK, Takeda, Sanofi, Oncopetide, Pfizer, Regeneron; research funding: Zentalis, Sanofi; member of the board of directors and shareholder: Caelum Biosciences. MB: consultancy: Pfizer, AbbVie; advisory boards: Janssen Research, Bristol Myers Squibb/Celgene, Sanofi-Genzyme. OB, DV, CZ: employment and equity holders: Karyopharm. EC: employment: Clalit Health Services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. These studies were supported by research funding from Karyopharm Therapeutics, Inc. Medical writing and editorial assistance was funded by Karyopharm Therapeutics, Inc. Karyopharm had the following involvement in the study: study design, collection, analysis, writing, editorial assistance and submission of the article., (Copyright © 2024 White, Schiller, Madan, Lentzsch, Chubar, Lavi, Van Domelen, Bentur and Baljevic.)

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.

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.

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors., Competing Interests: AB – Research: Janssen, Advisory Board: Janssen, Speakers Bureau: Karyopharm, Janssen, CurioScience. CW and TM are employees of Karyopharm. MB - Parexel. Advisory Boards: Janssen Research, BMS/Celgene, Sanofi-Genzyme., (Copyright © 2023 Binder, Walker, Mark and Baljevic.)

Background: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options., Patients and Methods: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs., Results: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications., Conclusion: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients., Competing Interests: Acknowledgments Karyopharm funded the study and provided selinexor supply. Sharon Furman-Assaf, supported by funding from Karyopharm, provided drafts and editorial assistance to the authors during the preparation of this manuscript. This work was supported by Karyopharm Therapeutics Inc. Karyopharm Therapeutics was the sponsor of this study and was responsible for study design, the collection of data, analysis of data, interpretation of data, writing of the report, and the decision to submit the paper for publication. The corresponding author had full access to all data and had the final responsibility for the decision to submit for publication with the agreement of all other authors., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To design and implement "handshake rounds" as an antibiotic stewardship intervention to reduce inpatient intravenous (IV) antibiotic use in patients with hematologic malignancies., Design: Quasi-experimental analysis of antibiotic use (AU) and secondary outcomes before and and after handshake rounds were implemented., Setting: Quaternary-care, academic medical center., Patients: Hospitalized adults with hematologic malignancies receiving IV antibiotics., Methods: We performed a retrospective review of a preintervention cohort prior to the intervention. A multidisciplinary team developed criteria for de-escalation of antibiotics, logistics of handshake rounds, and outcome metrics. Eligible patients were discussed during scheduled handshake rounds between a hematology-oncology pharmacist and transplant-infectious diseases (TID) physician. Prospective data were collected over 30 days in the postintervention cohort. Due to small sample size, 2:1 matching was used to compare pre- to and postintervention AU. Total AU in days of therapy per 1,000 patient days (DOT/1,000 PD) was reported. Mean AU per patient was analyzed using Wilcoxon rank-sum test. A descriptive analysis of secondary outcomes of pre- and postintervention cohorts was performed., Results: Total AU was substantially lower after the intervention, with 517 DOT/1,000 PD compared to 865 DOT/1,000 PD before the intervention. There was no statistically significant difference in the mean AU per patient between the 2 cohorts. There was a lower rate of 30-day mortality in the postintervention cohort and rates of ICU admissions were similar., Conclusions: Conducting handshake rounds is a safe and effective way to implement an antibiotic stewardship intervention among high-risk patient population such as those with hematologic malignancies., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2023.)

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D-RVd/RVd induction, high-dose therapy and ASCT, D-RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D-RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D-RVd patients and 15.7% of RVd patients; grade 2-4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D-RVd versus RVd patients (305 days vs 119 days). Anti-thrombosis prophylaxis use was similar between arms (D-RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D-RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti-thrombotic prophylaxis use was suboptimal., (© 2022 Janssen Scientific Affairs, LLC. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti-B-cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti-BCMA-targeted chimeric antigen receptor-T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA-antibody-drug conjugate therapy. We observe that X-containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients' prior anti-BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X-based regimens following broader anti-BCMA therapy., Competing Interests: Muhamed Baljevic ‐ Consultancy: BMS/Celgene, Cardinal Health; Sanofi‐Genzyme. Advisory Boards: Oncopeptides, Janssen Research, Karyopharm, BMS/Celgene, Sanofi‐Genzyme. Speaker: NCCN, CurioScience, AJH. Cristina Gasparetto ‐ Leadership: Celgene. Consulting or Advisory Role: Abbvie/Genentech; Celgene; GlaxoSmithKline; Janssen; Karyopharm Therapeutics; Sanofi. Speaker: GlaxoSmithKline; Karyopharm Therapeutics; Sanofi. Travel, Accommodations, Expenses: Celgene; Karyopharm Therapeutics. Gary J. Schiller ‐ clinical research support from KaryopharmSascha A. Tuchman ‐ Consulting: Caelum, Sanofi, Shattuck Labs, Janssen; Research support: Karyopharm, Sanofi, Caelum, Janssen. Natalie S. Callander ‐ Research Funding: Cellectar. Suzanne Lentzsch ‐ Leadership: Caelum Biosciences. Stock and Other Ownership Interests: Caelum Biosciences. Consulting or Advisory Role: Abbvie/Genentech; Amgen; Caelum Biosciences; Celularity; GlaxoSmithKline; Janssen; Sanofi; Sorrento Therapeutics; Takeda. Speaker: Clinical Care Options/NCCN; PeerView. Research Funding: Karyopharm Therapeutics; Sanofi. Patents, Royalties, Other Intellectual Property: Patent 11‐1F4 mAb for use in AL Amyloidosis. Travel, Accommodations, Expenses: Janssen. Jorge Monge ‐ Consultancy for BMS, Research funding from Karyopharm Therapeutics. Rami Kotb ‐ Research funding: Merck, Sanofi. Ownership/Share holder: Karyopharm. Honoraria: Celgene/BMS, Janssen, Takeda, Amgen, Sanofi, Merck, Pfizer. Nizar J. Bahlis ‐ Consultancy and advisory board: BMS/Celgene, Janssen, Pfizer, Amgen, Genentech, Sanofi, Karyopharm. Research funding: PfizerDarrell White‐ Amgen, Antengene, Celgene/BMS, Forus, GSK, Janssen, Karyopharm, Sanofi, Takeda: honoraria, consultancyChristine I. Chen ‐ Consulting or Advisory Role ‐ Abbvie; AstraZeneca; Bristol‐Myers Squibb; Gilead Sciences; Janssen; Novartis; Research Funding ‐ Gilead Sciences. Heather J. Sutherland ‐ Honoraria ‐ Amgen; Bristol‐Myers Squibb; Celgene; Genzyme; Janssen; Takeda. Consulting or advisory role ‐ Amgen; Bristol‐Myers Squibb; Celgene; Janssen; Sanofi; Takeda. Sumit Madan ‐ Speaker bureau: Janssen, BMS Ad hoc advisory board/consultancy: Janssen, Takeda, Oncopeptide, Pfizer. Richard LeBlanc‐ Consultancy/advisory board: BMS Canada; Janssen Inc.; Amgen Canada; Takeda Canada; Sanofi Canada. Michael Sebag ‐ Honoraria: Amgen; Bristol‐Myers Squibb; Celgene; Janssen‐Ortho; Karyopharm Therapeutics; Novartis; Takeda. Research funding: Janssen. Patents, Royalties, Other. Intellectual Property: Patent but with no associated royalties or profit. Christopher P. Venner ‐ Honoraria: Amgen; Bristol‐Myers Squibb; GlaxoSmithKline; Janssen; Sanofi; Takeda. William I. Bensinger ‐ Speakers bureau: Janssen, BMS, Amgen, Takeda, SanofiDane R. Van Domelen, Ohad S. Bentur, and Chris Zhang are employees of Karyopharm Therapeutics. Andrew DeCastro, Jatin J. Shah, and Michael G. Kauffman are former employees of Karyopharm Therapeutics. Sharon Shacham is a former employee of Karyopharm Therapeutics and holds patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide‐containing nuclear transport modulators and uses and holding pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide‐containing nuclear transport modulators and uses. Brea Lipe ‐ Consultant for BMS, Janssen, GSK., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM)., Methods: The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m 2 ) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib., Results: Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m 2 , and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months., Conclusions: Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM., (© 2021. The Author(s).)

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

Muhamed Baljevic, MD, considers the role of autologous stem cell transplantation for light chain amyloidosis in a peer perspective accompanying an article by Iuliana Vaxman, MD, and Angela Dispenzieri, MD.

Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted., Competing Interests: Cristina Gasparetto: No conflict of interest; Suzanne Lentzsch: research funding—Karyopharm and Sanofi; patents, royalties, other intellectual property—Caelum Bioscience; stock and other ownership interests—Caelum Bioscience, Mesoblast, Magenta, and Kadmon; consulting or advisory role—Caelum Bioscience, Sorrento, Janssen, and Celularity; Gary Schiller: research funding: AbbVie, Agios, Actinium, Ambit, AMGEN, ARIAD, Astellas, Leukemia & Lymphoma Society, BioMed Valley Discoveries, Inc., Bluebird Bio, Bristol‐Myers Squibb, Boehringer‐Ingleheim, Celator, Celgene, Cellerant, Constellation Pharmaceuticals, CTI BioPharma Corp., Forma, Cyclacel, Daiichi Sankyo, Deciphera, The California Institute for Regenerative Medicine (CIRM), Gamida Cell Ltd., GILEAD, Incyte, Janssen, Karyopharm, Kite Pharma, Inc., Mateon, MedImmune, Millennium, National Marrow Donor Program, National Institute of Health: National Cancer Institute, Novartis, Onconova, Onyx, Pfizer, PharmaMar, Sangamo, Stemline Therapeutics, Inc., National Marrow Donor Program, Tolero, Trovagene, University of California Davis, and University of California San Diego‐ UCHMC; stock and other ownership interests—Amgen, Bristol‐Myers Squibb, Pfizer, and Johnson and Johnson; consulting or advisory role—Incyte, Elevate Bio, AbbVie, ONO UK, Novartis, Evidera, Agios, AstraZeneca, National Institute of Health: National Cancer Institute, and Federal Drug Administration; speakers' bureau—Agios, Amgen, Astellas, Bristol‐Myers Squibb, Celgene, Sanofi‐Genzyme, Incyte, Janssen, Jazz, Kite (gilead)‐Yescarta, Pharmacyclics, and Stemline; Natalie Callander: research funding—Cellectar; Sascha Tuchman: research funding—Celgene, Karyopharm, Amgen, Janssen, and Sanofi; consulting or advisory role—Oncopeptides, Celgene, Karyopharm, Caelum, and Sanofi; honoraria—Celgene, Karyopharm, Caelum, and Sanofi; speakers' bureau—Celgene; Christine Chen: No conflict of interest; Darrell White: consulting or advisory role: Amgen, Antengene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda; honoraria—Amgen, Antengene, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda; Rami Kotb: research funding—Merck and Sanofi; stock and other ownership interests—Karyopharm; consulting or advisory role—Celgene/BMS, Janssen, Amgen, Takeda, Sanofi, and Merck; Heather Sutherland: honoraria: Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, and GlaxoSmith Kline; Michael Sebag: consulting or advisory role—Janssen and Karyopharm; Muhamed Baljevic: consulting or advisory role—Celgene Corporation, Cardinal Health, Putnam Associates, Gerson Lehrman Group, Inc., and AlphaSights; honoraria—Karyopharm Therapeutics Inc. clinical trial internal review committee member and NCCN Hematologic Malignancies Congress panelist; William Bensinger: research funding—BMS, Acetylon, Amgen, Janssen, Regeneron, and Sanofi; consulting or advisory role—Regeneron and BMS; speakers' bureau—Amgen, Janssen, BMS, Sanofi, and GSK; travel, accommodations, and expenses: Amgen, Janssen, BMS, Sanofi, and GSK; Richard LeBlanc: consulting or advisory role—Celgene Canada, Janssen Inc., Amgen Canada, Takeda Canada, Sanofi Canada; speakers' bureau—Celgene Canada, Janssen Inc., and Amgen Canada; Chris Venner: honoraria—Celgene, Johnson & Johnson, Amgen, Sanofi, and Takeda; Nizar Bahlis: research funding—received research support from Celegen and BMS; honoraria—Janssen, Celgene/BMS. Amgen, Takeda, Karyopharm, Sanofi, and GSK; Heidi Sheehan: employee and stockholder in Karyopharm Therapeutics; Jean‐Richard Saint‐Martin: employee and stockholder in Karyopharm Therapeutics; Dane Van Domelen: employee and stockholder in Karyopharm Therapeutics; Kazuharu Kai: employee and stockholder in Karyopharm Therapeutics; Jatin Shah: Executive Vice President, CMO, and stockholder in Karyopharm Therapeutics; Sharon Shacham: President, CSO, and stockholder in Karyopharm Therapeutics; Michael Kauffman: CEO and stockholder in Karyopharm Therapeutics; Brea Lipe: research funding—Amgen and Cellectar; consulting or advisory role—BMS, Janssen, and Abbvie., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells in vitro , and with the proteasome inhibitor bortezomib in vivo . IVIgG inhibited the growth of all cell lines tested, induced G 1 cell cycle arrest, and suppressed pro-tumor cytokines including Interleukin (IL)-6, IL-8, and IL-10. Genomic and proteomic studies showed that IVIgG reduced tumor cell HSP70-1 levels by suppressing the ability of extracellular HSP70-1 to stimulate endogenous HSP70-1 promoter activity, and reduced extracellular vesicle uptake. Preparations of IVIgG were found to contain high titers of anti-HSP70-1 IgG, and recombinant HSP70-1 reduced the efficacy of IVIgG to suppress HSP70-1 levels. Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib's activity in bortezomib-resistant myeloma cells. Moreover, IVIgG reduced transfer of extracellular vesicles (EVs) to cells, and blocked transfer of bortezomib resistance through EVs. Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter., (Copyright © 2020 Jones, Singh, Shirazi, Wan, Wang, Wang, Ha, Baljevic, Kuiatse, Davis and Orlowski.)

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Introduction : Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy and has an increasing incidence and prevalence globally, and proteasome inhibitors (PIs) form the backbone of some of our most effective regimens for all phases of this disease in fit and frail patients. Areas covered : Strong understanding of the proteasome complex is increasingly important as the rapid development of new PIs and innovative myeloma therapies complicate the use of old and new combination regimens. We focus herein on the pharmacodynamics and pharmacokinetics of the approved PIs and others in development, including their safety and efficacy in corresponding clinical studies. Expert opinion : Advancements such as the first oral PI, ixazomib, with a more convenient route of administration and improved toxicity profile led to an improved quality of life, patient compliance, and all-oral combination regimens which are efficacious for long-term management of standard and high-risk MM. Novel pan-PIs, such as marizomib, hold the promise of superior clinical activity due to irreversible targeting of all multicatalytic proteinase complex subunits. Development of clinically validated biomarkers of PI sensitivity/resistance is required to inform utilization of the most optimal and effective, rationally targeted PI treatments for all MM patients.

Multiple myeloma (MM) is the second most common hematologic malignancy with an increasing incidence and prevalence. The wide array of effective antimyeloma agents have transformed MM into a chronic condition for some patients, requiring long-term management planning. Immunomodulatory drugs and proteasome inhibitors have played a pivotal role in defining the most effective regimens for both transplantation-eligible and transplantation-ineligible subgroups. Nevertheless, recent approvals of immunotherapies in MM such as daratumumab have added another important component to combination treatments for both relapsed or refractory and newly diagnosed disease. Evolving novel therapies such as chimeric antigen receptor T cells are poised to raise the bar even further, holding a promise of effective treatment option for patients who would otherwise have limited treatment alternatives. As we continue to therapeutically exploit the essential roles of cell-mediated immune surveillance, antigen presentation, and modulation of inhibitory surface signaling, we are rapidly establishing the cornerstone role of immunotherapies in the management of all phases of MM. In this review, we will cover the spectrum of available immunotherapies approved for clinical use in MM, as well as briefly describe those in early- and late-phase development, with the focus of raising the awareness of the expanding immuno-oncology armamentarium in MM.

Congenital factor VII deficiency is a challenging disorder to manage, as it is associated with varied genotypes that do not clinically correlate with a bleeding phenotype. Individuals with severe factor VII deficiency (FVII: c <1%) might be asymptomatic, while patients with moderate deficiency (FVII: c level >5%) may experience severe hemorrhages. In modern medicine, due to extensive routine pre-operative laboratory testing, clinically asymptomatic patients without any bleeding history might be incidentally discovered, raising clinical dilemmas. Careful consideration of bleeding versus thrombosis risk has to be made in such cases, especially in the elderly. Clinical history of no prior bleeding complications may be a reassuring factor. Minimal required replacement dosing of recombinant activated factor VII can be given peri-operatively in such situations, with close monitoring.

The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.

Telomeres are the capping ends of chromosomes that protect the loss of genetic material and prevent chromosomal instability. In human tissue-specific stem/progenitor cells, telomere length (TL) is maintained by the telomerase complex, which consists of a reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Very short telomeres and loss-of-function mutations in the TERT and TERC genes have been reported in acute myeloid leukemia, but the role of telomeres in acute promyelocytic leukemia (APL) has not been well established. We report the results for a large cohort of 187 PML/RARα-positive APL patients. No germline mutations in the TERT or TERC genes were identified. Codon 279 and 1062 TERT polymorphisms were present at a frequency similar to that in the general population. TL measured in blood or marrow mononuclear cells at diagnosis was significantly shorter in the APL patients than in healthy volunteers, and shorter telomeres at diagnosis were significantly associated with high-risk disease. For patients who achieved complete remission, the median increase in TL from diagnosis to remission (delta TL) was 2.0 kilobase (kb), and we found delta TL to be the most powerful predictor of overall survival when compared with well-established risk factors for poor outcomes in APL., Competing Interests: of Conflicts of Interest: Authors report no conflicts of interest., (© 2016 S. Karger AG, Basel.)

Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potential life-threatening clinical syndrome that results from uncontrolled activation of the immune system. Secondary HLH, more commonly observed in adult patients, is seen in the context of underlying triggering conditions. Epstein-Barr virus (EBV) has been recognized as the leading infectious cause and is associated with a poor outcome. As clinical and laboratory features of HLH could overlap with septic shock syndrome in most patients, the diagnosis of HLH, especially in adults, is the most challenging aspect of the disease that results in delayed recognition and treatment of rapidly progressive multiorgan system failure. We report a case of Hemophagocytic lymphohistiocytosis in a patient who presented with signs of septic shock syndrome and we review the literature on the topic.

Translocation t(11;17) is a well-recognized variant of acute promyelocytic leukemia (APL) and has also been identified in patients with mixed-lineage leukemia (MLL) non-APL acute myeloid leukemia. Here, we describe two patients bearing translocation t(11;17) presenting with a clinical diagnosis of de novo myelodysplastic syndrome (MDS): the first with sole karyotypic abnormality 46,XY,t(11;17)(p11.2; p13) and the second where it represented one of the two karyotypic abnormalities 46,XX,del(5)(q13q33)46,XX,del(5)(q13q33),t(11;17)(q24;q23). Molecular characterization of both cases failed to identify fusion transcripts involving MLL or PLZF-RARA and no collaborating somatic mutations commonly found among MDS patients were seen in either case, suggesting the presence of an as yet unidentified oncogenic fusion protein., (Copyright © 2012 S. Karger AG, Basel.)

The introduction of all-trans retinoic acid to anthracycline-based chemotherapy has revolutionized the prognosis of patients with acute promyelocytic leukemia (APL). The introduction of arsenic trioxide enabled the therapeutic approach of rationally targeted frontline protocols with minimal or no traditional cytotoxic chemotherapy and without compromise of previously established outstanding outcomes with anthracycline-based regimens. Although most of the current investigative efforts in APL are focused on developing potentially curative therapy without the exposure to toxicities and risks of DNA-disrupting agents, the cure rate can further be increased by implementing meticulous supportive care strategies that counter early coagulopathy-related deaths., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5(-/-) mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.

Blood vessel formation is controlled by the balance between pro- and antiangiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a vascular endothelial growth factor (VEGF)-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGM(lacZ/+)), with which we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17 to 22 hours postfertilization. Blockade of AGM activity with morpholino oligomers results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR2/flk-1, is blocked by the simultaneous injection of AGM morpholino oligomers. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the proangiogenic effects of VEGF-A.

Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.