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Aim: The definition of high-risk (HR) in Multiple Myeloma (MM) is ever evolving with the discovery of new genomic abnormalities and increasing therapeutic options. There are various stratification models incorporating laboratory and genetic features with different definitions of high-risk and varied emphasis on individual risk factors. Recognized high-risk cytogenetic abnormalities (HRCA) include t(4;14), t(14;16), t(14;20), del(17p) with recent inclusion of del(1p) and gain/amplification (amp) of 1q (+1q) . In addition to del(17p), the presence of biallelic del(1p) and ≥2 HRCAs (“double-” or “triple-hit”) appear to confer poorer outcomes. A new definition proposed by the International Myeloma society (IMS) defines HR as the presence of del(17p) and/or TP53 mutation; an IgH translocation - t(4;14), t(4;16) or t(14;20) along with +1q and/or del(1p); monoallelic del(1p32) along with +1q; bi-allelic del(1p32); or β2 microglobulin ≥5.5 with normal creatinine (<1.2mg/dL). Herein, we report real-world outcomes on these HRCAs and the new IMS consensus definition of HR MM. Method: We retrospectively reviewed newly diagnosed MM patients from the Australian and New Zealand Myeloma and Related Diseases Registry across 4 Australian states. Patients with FISH and/or SNP microarray testing for IgH translocations, 1q21 (CKS1B), del(1p32) (CDKN2C) and del(17p) (TP53) were identified. Positive threshold was 30%. We used Kaplan-Meier methods to compare progression free survival (PFS) and overall survival (OS) between groups and first performed univariate analysis (UA) for each HRCA. We next analyzed patients with gain1q vs amp1q and monoallelic vs biallelic del(1p). In the final analysis, two risk groups were formed: cases meeting the new IMS-defined HR criteria were considered IMS-HR and the rest were considered standard risk (IMS-SR). Indeterminate cases with missing variables that could influence risk classification were excluded. Results: Of 839 newly diagnosed patients (pts) included, 31% had ISS (International staging system) stage 3 disease. High-risk IgH translocations t(4;14) and t(14;16) were present in 8% and 4%. Secondary HRCAs del(17p), del(1p), gain1q and amp1q were present in 9%, 14%, 30% and 11% respectively. In this cohort, 41% received ASCT. Of the transplant eligible pts, 41% received triplet therapy (PI, IMiD and corticosteroid) and 57% received PI-based induction. Of the transplant ineligible pts, 31% received triplet therapy, 47% PI-based and 19% IMiD-based therapy. Frontline Anti-CD38 antibody use was <1%. Median follow up was 35 months[m] (IQR 18-60). On UA, the risk of progression and/or death was increased with ISS III vs I, amp1q, del(17p), t(14;16), del(1p) and gain1q in descending order by hazard ratio. The risk remained significant in ISS III, del(17p), amp1q and gain1q after multi-variate analysis (MVA). The risk of death was increased with ISS III vs I, del(17p), amp1q, del(1p) and t(14;16), ISS II vs I in descending order by hazard ratio. After MVA, the risk remained significant for ISS stage III, del(17p), amp1q and t(14;16). Of the 117 pts with del(1p32), 108 had monoallelic and 9 had biallelic loss. Pts with biallelic del(1p32) had an inferior PFS (median 16.3 vs 23.2m, p<0.001) and OS (median 24.8m vs NR, p<0.001) compared to those with monoallelic del(1p32). In pts with 1q+, pts with amp1q had an inferior PFS (median 16.3 vs 27.5m, p<0.001) and OS (median 37.0m vs NR, p<0.001) vs pts with gain1q. Based on the new definition of HR myeloma - 385 pts met the criteria for IMS-HR and 216 for IMS-SR. There were 238 indeterminate cases due to missing data. The IMS-HR group had an inferior PFS (median 20.2 vs 39.7m, p<0.001) and OS (median 44.2m vs NR, p<0.001) when compared to IMS-SR. Noting that the IMS-HR group had a higher median age, poorer performance status and lower rates of ASCT use, adjusted analysis for these variables still showed an inferior PFS (aHR 1.68; 95% CI 1.30-2.16, p<0.001) and OS [aHR 1.72; 95% CI 1.21-2.44, p=0.002). Conclusion: ISS III, del(17p), amp1q are the strongest predictor of OS and PFS. Differentiating between monoallelic vs biallelic del(132p) and gain vs amp1q21 has important prognostic value. The IMS- HR definition which takes into account del(1p), “double-” and “triple-hit” disease predicts for a group of patients with a PFS of ~20 months and inferior OS, and provides a standardized approach to risk stratification in MM.

Background: Daratumumab (DARA) has demonstrated clinical benefit in multiple myeloma (MM) and is approved for the treatment of both newly diagnosed MM (NDMM) and relapsed refractory MM (RRMM). While single-center studies have shown the benefit of DARA retreatment in patients (pts) who are refractory to DARA (D-Ref), there is a lack of real-world data on the characteristics of pts who are retreated with DARA across multiple lines of treatment (LOTs). In this study, we examine DARA retreatment patterns and outcomes among pts who are D-Ref and those who are sensitive to DARA (D-Sens) after the first DARA exposure in the US real-world clinical practice. Methods: This study used the Flatiron MM Core Registry data to identify pts with MM treated with a DARA-containing regimen in ≥2 separate LOTs between November 1, 2015, and March 31, 2024. The first DARA-based LOT was defined as D1, and the second DARA-based LOT was defined as the retreatment LOT (D2). The following criteria, developed by Janssen Scientific Affairs, were used to classify pts as Dara-retreated: 1) pts treated with the same DARA-containing regimens in consecutive LOTs were classified as Dara-retreated if there was a gap of >90 days between D1 and D2, 2) pts treated with different DARA-containing regimens in consecutive LOTs were classified as Dara-retreated, 3) pts treated with DARA-containing regimens had ≥1 LOTs between D1 and D2 they were classified as Dara-retreated, regardless of whether the regimens were the same or different. Derived disease progression reported in the Flatiron data was used for this analysis. If disease progression was reported during D1, or within 60 days of discontinuing D1, the pt was considered as D-Ref, otherwise, the pt was considered as D-Sens. Kaplan-Meier (KM) analyses were conducted to evaluate duration of D2, proportion of pts not receiving subsequent treatment after D2, and progression-free survival (PFS) rates during D2. Results: Data for 201 pts retreated with DARA were identified in this analysis, 150 were D-Sens and 51 were D-Ref. In the D-Sens group, the median age at D2 initiation was 71 years, 44.0% of pts were female, 27.3% were ISS stage II and 16.0% were African American. In the D-Ref group, the median age at D2 initiation was 67 years, 45.1% of pts were female, 21.6% were ISS stage II, and 25.5% were African American. At D2 initiation, 64.7% (D-Sens) and 60.8% (D-Ref) of pts were frail, and 56.0% (D-Sens) and 52.9% (D-Ref) of pts had a Quan-Charlson Comorbidity Index of ≥3, indicating a high burden of comorbidities. About 31% of pts in both groups had high cytogenetic risk abnormalities, and about 20% had a 1q21 gain or amplification. The median time from MM diagnosis to start of D1 and to start of D2 was shorter in the D-Sens group (10.8 and 34.9 months) than in the D-Ref group (18.4 and 44.4 months). D-Sens pts were less likely to receive D1 in the third LOT or later compared to D-Ref pts (30.0% vs 45.1%). The median number of LOTs before D2 was three in both groups. The median gap between D1 and D2 was 9.3 months in D-Sens pts and 9.0 months in D-Ref pts, however, more D-Sens pts received D1 and D2 LOTs consecutively compared to D-Ref pts (62.0% vs 51.0%). The most common regimen used in D1 was DARA + lenalidomide + dexamethasone (dex; 18.7%) and DARA + bortezomib + dex (18.7%) among D-Sens pts, and DARA + pomalidomide + dex (23.5%) among D-Ref pts. The most common regimen used in D2 was DARA mono (31.3%) in D-Sens pts, and DARA mono (17.6%) and DARA + carfilzomib + dex (17.6%) in D-Ref pts. Overall, 32.0% of D-Sens and 35.3% of D-Ref pts received agents from the same drug class in D1 and D2. The KM median duration of D2 was 7.4 months (95% CI: 5.5-9.5) among D-Sens pts and 6.4 months (95% CI: 3.8-23.5) among D-Ref pts. The proportion of pts that had not received subsequent treatment after D2 was 38.7% and 29.5% at 12 months in the D-Sens and D-Ref groups, respectively. PFS rates at 12 months after D2 initiation were 77.1% in the D-Sens group and 49.4% in the D-Ref group. Conclusion: DARA retreatment is utilized frequently and is effective in the real-world, suggesting the ability to use this approach in subsequent LOTs among pts with RRMM. In the absence of other feasible alternatives, this may be a treatment strategy for patient benefit, regardless of whether they are D-Sens or D-Ref. Future studies are needed to definitively investigate the benefit of DARA retreatment in combination with drugs with novel mechanisms of action.

Background: Immunosuppressive therapy (IST) is considered the standard front-line treatment for acquired severe aplastic anemia (SAA) for pts >40 years. For pts aged <40 years who have a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) is recommended. This recommendation is based on the toxicity associated with alternative donors; haploidentical (HAPLO) and unrelated donor (URD) HSCT for patients who lack a MSD. However, the hematopoietic response after IST is ~ 70-80%, even after augmentation with eltrombopag in the front-line setting, and failure-free survival (FFS, defined as patients alive and in remission without clonal disease more than 10 years after IST) remains < 40%. HSCT is often employed as a second line salvage therapy for those who do not respond to IST or have disease recurrence. However, outcomes after HSCT are often compromised because of IST-related complications such as clonal evolution, development of donor specific antibodies, infectious adverse events and organ dysfunction. In contrast, a successful allogeneic HSCT leads to relatively prompt hematopoietic and immune reconstitution and mitigates the risk of secondary clonal disease. Innovations in recent decades, such as improved graft versus host disease (GVHD) prophylaxis and supportive care, have steadily reduced the morbidity and mortality of adults undergoing HSCT from unrelated or mismatched donors and expanded the donor pool such that almost all pts with SAA have a potential donor available. The use of post-transplant cyclophosphamide (PTCy) is now a well-established approach to facilitate engraftment and mitigate the risk of GVHD. It was successfully used in relapsed/refractory SAA pts using HAPLO donors in the multi-center BMT CTN #1502 trial (NCT02918292). Similar PTCy based approaches have been effective in the upfront setting with HAPLO and URD in small single center studies. Opened in July 2024, the CureAA trial (NCT06517641), seeks to increase donor options for SAA pts who have not yet received IST by using PTCy based GVHD prophylaxis for HSCT using HAPLO or URD. Study Design and Methods: This BMT CTN study (#2207) is a prospective multi-center phase II trial to assess efficacy of HSCT using HAPLO or URD bone marrow with a reduced intensity, thymoglobulin (ATG)-containing preparative regimen and PTCy GVHD prophylaxis in previously untreated SAA pts. This trial has two parallel cohorts for each donor type, HAPLO and URD, with an accrual goal of 30 participants in each cohort. All will receive ATG (0.5mg/kg on day -9 and 2mg/kg on days -8 and -7), cyclophosphamide (14.5mg/kg on days -6 and -5), fludarabine (30mg/m2 on days -6 to -2), 400 cGy total body irradiation (day -1 in a single fraction), a marrow graft (goal >2.5 x 108 nucleated cells per kg of recipient) on day 0 and PTCy (50mg/kg on days +3 and +4). Additionally, participants receive tacrolimus (until day +180) and mycophenolate mofetil days +5-35. The primary objective of the trial is to estimate the GVHD-free failure-free survival (GFFS) rate at 1 year after initiation of conditioning. GFFS is a composite endpoint of survival without grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy within 1 year after initiation of conditioning. Secondary objectives will evaluate patient survival, engraftment, transfusion dependence, cumulative incidence of GVHD and hematologic response. Health related quality of life, healthcare utilization and financial toxicity data will also be collected. These endpoints will allow clinical comparison with current results achieved with upfront IST in other studies. We hypothesize that this HSCT approach will improve survival without significant transplant-associated morbidity by using a low toxicity regimen that reduces rates of GVHD and provides rapid hematologic recovery without graft failure, thereby making HAPLO and URD HSCT a viable option for initial upfront treatment of SAA. The ability to use mismatched donors will also ensure that a HSCT option is more widely available to all racial/ethnic groups. This collaborative study was funded by grants U10HL069294, U24HL138660 to the BMT CTN from the NHLBI/ NCI, along with funding from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Chronic lymphocytic leukemia (CLL), one of the most common types of leukemia among adults in the US, is characterized by the accumulation of CD5+CD19+ monoclonal B cells. Current clinical treatment approaches for progressive CLL patients focus on novel agents targeting Bruton Tyrosine Kinase (BTK) and Bcl-2. Although clinical trials combining novel agent have shown significant efficacy with high overall response and, in some cases, achievement of high rates of undetectable measurable residual disease (MRD), CLL remains incurable with a majority of patients eventually experiencing relapse of their disease. Therefore, it remains of high interest to expand therapeutic options. Transcriptional chemical inducers of proximity (TCIPs) are small molecules designed and developed by Dr. Gerald R. Crabtree at Stanford University. TCIPs are a new class of anticancer drugs that recruit endogenous cancer drivers or a downstream transcription factor to the promoters of cell death genes and activate their expression, resulting in apoptosis of cancer cells. Current TCIPs are produced by covalently linking small molecules that bind B-cell lymphoma 6 (BCL6) to those that bind to transcriptional activators, such as Bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinases 9 (CDK9). The Stanford team has demonstrated TCIPs generate remarkable killing in diffuse large B cell lymphoma (DLBCL) cell lines, including chemotherapy-resistant, TP53-mutant lines, with a half maximal effective concentration (EC50) of 1-10nM at 72hours (h) and exhibited cell-specific and tissue-specific effects (Gourisankar et al, 2023). We have initiated TCIPs cytotoxicity assessment in primary leukemic cells from untreated CLL patients. Testing two types of TCIPs with a flow cytometry-based apoptosis assay, we found time and dose-dependent drug-associated killing in primary CLL B cells collected from untreated CLL patients over a 24-72h interval. The IC50 for BRD4-BCL6 TCIP JWZ-7-133 at 72h was 560nM while CDK9-BCL6 TCIP BAK-04-232 at 72h was 10nM. After 24, 48, and 72h exposure of CLL B cells to TCIP JWZ-7-133, the IC50 was 1050, 820 and 560nM, respectively. We also found that TCIP JWZ-7-133 exhibited a similar ability to inhibit leukemic cell viability with an IC50 of 1070nM using a cell viability assay, compared to a flow cytometry-based cell death assay (24h IC50 1050nM). CDK9-BCL6 TCIPs are designed and produced by covalently linking BI-3812 (binding to BCL6) and SNS-032 (binding to CDK9) with a rigid linker. BI-3812 is a potent and efficacious BCL6 inhibitor, inhibiting the BTB domain of BCL6, and SNS-032 is a potent and selective inhibitor of CDK9. When CLL B cells were treated with only BI-3812 or SNS-032 or TCIP BAK-04-232 as single agents for 72h, we found that TCIP BAK-04-232 had superior and significant killing effects compared to the single agents, with an IC50 of 10nM. Specifically this killing activity was more than 10-fold compared to SNS-032 alone (IC50 over 100nM), and more than 1,000-fold compared to BI-3812 alone (IC50 over 10,000nM). There remains an urgent to identify new categories of potent drug, inhibitor, or small molecules to expand potential clinical treatment options for patients with CLL. The results presented here indicate that TCIPs targeting BCL6 and BRD4/CDK9 have a strong capacity to induce high levels of cell death in CLL B cells at nanomolar concentrations, and this remarkable killing effect may be due to its unique gain-of-function drug mechanism. TCIPs provide a completely new drug direction and strategy for the design of anticancer drugs: to rewire cancer drivers to activate apoptosis in cancer cells. This study is the first of a kind demonstration of TCIPs in robustly targeting CLL B cells. Further studies to fully validate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the role of TCIPs as a novel therapeutic approach in CLL.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Abstract Objective To study pregnancy outcomes and complications in women with congenital adrenal hyperplasia (CAH). Methods A retrospective multicenter study was conducted at tertiary reference centers in 5 countries (Austria, Germany, Italy, Sweden, USA), including 72 adult women with CAH (nonclassic [NC] n = 34, simple virilizing [SV] n = 21, salt wasting [SW] n = 17). Results A total of 133 pregnancies, 112 live births, and 25 abortions were documented. Prolonged latency to pregnancy was observed (median 11 months in SW, 24 months in SV, 8 months in NC), with a notable use of fertility-enhancing medication (25.6%) and assisted reproductive techniques (30.8%). Over half of the women in each group took more than 12 months to conceive. The average number of live births (1.4-1.6 children per woman) was similar across CAH phenotypes and comparable to the general population. Spontaneous abortion rates (18.0%) were also similar across phenotypes. Primary cesarean section rates (60.9%) were higher than in the general population, though 23.8% of women with SV and 29.4% of women with SW gave birth naturally, despite most having undergone genital surgery. Children categorized as small for gestational age were 20.5%. Pregnancy, delivery, and postpartum complications were rare for mothers and neonates. Conclusion The study indicates a prolonged latency to pregnancy and high use of fertility treatments in CAH patients, regardless of phenotype. Abortion rates were not increased, and overall pregnancy and perinatal outcomes were favorable.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

Abstract Objectives Protein-truncating variants in the TTN gene are a well-established cause of dilated cardiomyopathy (DCM). We report a novel case of DCM caused by a mobile element insertion (MEI) in TTN, through which we highlight the key features of MEIs in next-generation sequencing data. Because of the rarity of MEIs, the next-generation sequencing data features associated with these events may be mistaken as noise, potentially leading to missed diagnoses. Methods Next-generation sequencing gene panel testing for DCM was performed on a 17-year-old male patient presenting with severe left ventricular dilatation and systolic dysfunction. Manta was used for structural variant detection, followed by manual review of NGS data for potential structural variants. Results Manta detected a potential insertion in TTN. Manual review identified hallmark features consistent with a LINE-1 MEI. This finding was orthogonally confirmed by long-range polymerase chain reaction and gel electrophoresis, which indicated an insertion of approximately 4 to 5 kilobase pairs. The insertion disrupted the reading frame of TTN within an A-band exon, resulting in protein truncation that was classified as likely pathogenic. Conclusions This case expands the mutational spectrum of TTN protein-truncating variants. It also underscores the importance of recognizing rarer types of pathogenic variants (eg, MEIs) to produce accurate genetic diagnostics.

Summary: Sacral reconstruction post tumor resection has historically been executed with the placement of hardware or free tissue transfer. Reconstruction using a vascularized bone graft is an alternative that avoids the complications associated with hardware placement or free tissue transfer. This article describes the first documented case of spinoplastic reconstruction using an iliac crest vascularized bone graft (IC-VBG) after the resection of a sacral ependymoma. This is a case of a 17-year-old boy with a history of a sacral myxopapillary ependymoma. He presented to a local emergency department complaining of 6 months of urinary incontinence and progressive paresthesias affecting the left lower extremity. Magnetic resonance imaging was significant for a lesion located in the extradural spinal canal. Biopsy confirmed a myxopapillary ependymoma, World Health Organization grade II. The initial intervention involved tumor resection with titanium hardware placement. He subsequently required replacement of the titanium hardware with carbon fiber, secondary to the need for surveillance imaging. He underwent harvesting and inset of the IC-VBG at the time of hardware replacement. IC-VBG is a safe and effective modality for spinoplastic reconstruction. It enhances the potential for solid bony union and offers a practical alternative to free bone transfer. This approach provides an asset to add to a reconstructive surgeon’s armamentarium, making it an essential tool for reconstructive surgeons working in conjunction with spinal surgery colleagues.

Preoperative anemia is common and associated with worse outcomes in cardiac surgery including acute kidney injury, red blood cell transfusion, cardiovascular complications, stroke, infection, and death. Patient blood management programs, which include dedicated clinical programs to diagnose and treat anemia in advance of surgery (ie, preoperative anemia programs), have been highlighted as a means to optimize the blood health of each patient, thereby decreasing risk for allogeneic transfusion and improving clinical outcomes. However, there remain implementation challenges for preoperative anemia programs, including difficulties with education of patients and staff, short lead times to address anemia, infrastructure and staffing limitations, lack of clear leadership or ownership of preoperative anemia, the need to develop treatment algorithms and ensure appropriate infusion therapy support, lack of capital support, and insurance/reimbursement concerns, amongst others. The purpose of this advisory from the Society of Cardiovascular Anesthesiologists (SCA) Clinical Practice Improvement Committee and the Subcommittee on Patient Blood Management with endorsement from the Society for the Advancement of Patient Blood Management (SABM) is to provide guidance on the development and implementation of a preoperative anemia clinic or service line, including identification and navigation through potential logistical barriers. A detailed analysis of financial incentives is highlighted in our companion article in this edition focuses on the return on investment of anemia management. Although originating with a focus on anemia before cardiac surgery, this advisory is broadly applicable to all perioperative patients.