tbuckley/cabot-search huggingface dataset:
Apixaban versus warfarin for primary thromboprophylaxis in patients with multiple myeloma undergoing immunomodulatory treatment.
Authors: Yu-Cheng Chang, Cho Han Chiang, Zhiting Tang, Xin Ya See, Cho Hung Chiang, Kuan-Yu Chi, Yu Chang, Wenli Gao
Journal: Journal of Clinical Oncology (2024)

7548 Background: Immunomodulatory drugs (IMiDs) have been demonstrated to improve clinical outcomes in patients with multiple myeloma (MM), but are associated with an elevated risk of thromboembolism. Existing guidelines recommend low-dose direct oral anticoagulants as an alternative to warfarin for primary thromboprophylaxis in MM. However, the data comparing these two therapies are limited. We aim to compare the efficacy and safety of apixaban versus warfarin in patients with MM undergoing IMiD treatment. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Analytics Network database, which contains de-identified data from over 120 participating healthcare institutions. We included adult patients with MM who underwent IMiD treatment. Patients treated with apixaban were matched in a 1:1 ratio to those treated with warfarin using clinical variables a priori. The primary safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding, while the primary efficacy outcomes included thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke within a 3-year period following IMiDs initiation. Results: We identified 448 patients on apixaban who were matched to patients on warfarin. In a Cox proportional hazard analysis, apixaban was associated with a 30% lower risk of all-cause mortality compared to warfarin (Hazard ratio (HR), 0.70 [95% CI: 0.56-0.88]).There was a tendency toward a reduced risk of gastrointestinal bleeding in patients treated with apixaban compared to warfarin (HR, 0.58 [95% CI: 0.31-1.08], log-rank p = 0.083). The risk of intracranial hemorrhage was similar between the two groups.The risks of thromboembolic events including pulmonary embolism, deep venous thrombosis, and ischemic stroke were comparable between the apixaban and warfarin cohorts. Conclusions: Apixaban was associated with a lower risk of all-cause mortality and a comparable risk of bleeding and thromboembolism compared with warfarin among MM patients undergoing immunomodulatory treatment. [Table: see text]
Evaluation of a novel method to guide belantamab mafodotin dosing in multiple myeloma based on a patient-reported questionnaire.
Authors: Evangelos Terpos, Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Panagiotis Malandrakis, Despina Fotiou, Magdalini Migkou, Foteini Theodorakakou, Vasiliki Spiliopoulou, Rodanthi Syrigou, Evangelos Eleutherakis Papaiakovou, Stavros Gkolfinopoulos, Giorgos Psarros, Efstathios Kastritis, Meletios Athanasios Dimopoulos
Journal: Journal of Clinical Oncology (2024)

7530 Background: Ocular adverse events (OAEs, best corrected visual acuity [BCVA] change from baseline and keratopathy) are common with belantamab mafodotin (belamaf; GSK2857916) and often necessitate an ophthalmic exam to guide dosing. Herein, we evaluate a novel approach for belamaf dose modifications in transplant ineligible patients (pts) with newly diagnosed MM, treated with an extended schedule of belamaf with lenalidomide and dexamethasone (Rd) in the BelaRd study. Methods: BelaRd (NCT04808037) is an ongoing, phase 1/2 study of 2 Parts. Part 1 established the recommended phase 2 dose (RP2D) of 1.9 mg/kg q8w, extended to q12w to account for OAEs. Part 2 assesses the safety/efficacy of RP2D in Groups A and B, of 15 pts each, and evaluates two sets of guidelines for OAE management. In Group A, dosing is determined by an ophthalmic exam performed by a certified ophthalmologist; in Group B it is determined by the pts’ responses in the Vision Related Anamnestic (VRA) tool and the presence of ≥Grade (Gr) 3 OAEs. VRA is a patient-reported questionnaire capturing ocular symptoms and their impact on activities of daily living (ADL). Herein, we present the OAEs and preliminary efficacy results after 205 ophthalmic and VRA assessments for all Part 2 pts (cut-off date 05/10/2023). Results: By the cut-off date, the median belamaf administrations and number of cycles reached were 3.0/3.0 and 8.0/7.0 for Groups A and B, respectively. The respective rates of Gr2 and ≥Gr3 BCVA change from baseline were 34.6%/24.2% and 6.4%/0.0%, while a meaningful BCVA decline (Snellen score &lt;20/50) and ≥3 lines drop in the better-seeing eye was recorded in 11.0%/7.2% ophthalmological assessments; no ≥Gr3 keratopathy was observed. Among 110/94 VRA assessments, ocular symptoms and ADL impairment, manifesting for ≥50% of the time in the last 24 hours prior to belamaf administration (substantial time), were noted in 6.4%/10.6% and 3.6%/7.4%. Of note, VRA captured a “substantial time” response in 86% of assessments with ≥Gr3 OAEs. Finally, for the response-evaluable pts, at a median follow-up of 7.7 months, ORR was 93.3%/85.7% in Groups A and B (PR/VGPR/CR: 26.7%/53.3%/13.3%; 21.4%/64.3%/0.0%) and the median time to first response was ~ 1 month. Conclusions: The VRA tool was safe and effective in informing belamaf dose modifications. Future analyses will determine if VRA may effectively eliminate the need for an ophthalmic exam prior to belamaf dosing. Clinical trial information: NCT04808037 . [Table: see text]
Expression of alternatively spliced BCMA RNA with skipping of transmembrane domain.
Authors: Andrew Ip, Maher Albitar, Hong Zhang, Ahmad Charifa, Sally Agersborg, Arash Mohtashamian, David Samuel DiCapua Siegel, Noa Biran, David H. Vesole, Andrew L Pecora, Andre Goy
Journal: Journal of Clinical Oncology (2024)

7514 Background: The TNFRSF17 gene, which encodes for the B cell maturation antigen (BCMA), is a small gene expressed mainly on the surface of plasma cells and some DLBCL cells. This gene is composed of three exons. Exon 1 is responsible for the extracellular domain, exon 2 for the transmembrane domain, and exon 3 for the TRAF binding domain. The BCMA is currently targeted by various types of immunotherapies as a major therapeutic approach for the treatment of multiple myeloma (MM). This includes CAR-T cells, bi-specific antibodies, and antibody-drug conjugates (ADC). However, emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in BCMA transcripts via sequencing of BCMA RNA in patients with lymphoma or multiple myeloma. Methods: RNA was extracted from 587 fresh bone marrow samples with lymphoid/plasma cell neoplasms or from FFPE samples with lymphoma. In addition, cfRNA was extracted from 260 peripheral blood plasma samples from patients with lymphoma or multiple myeloma. RNA was sequenced using a hybrid capture-targeted RNA panel with analysis focused on TNFRSF17 (BCMA) gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 587 lymphoma/plasma cell samples, 161 (27%) samples showed alternative splicing involving deletion of exon 2 (BCMA∆Ex2). Of the 260 cfRNA samples, 14 (6%) showed BCMA∆Ex2. The median percentage of BCMA∆Ex2 transcripts was 0.7% of total BCMA transcripts in cellular samples as compared with 9% in cfRNA samples. In cellular samples, there was a correlation between levels of BCMA and BCMA∆Ex2 (R=0.63). Cases with higher levels of BCMA had significantly higher levels of BCMA∆Ex2 (P&lt;0.0001, Kruskal-Wallis). In contrast, cfRNA showed no correlation between levels of BCMA and levels of BCMA∆Ex2 (R=021, Spearman) and mildly higher level of BCMA∆Ex2 in cases with higher levels of BCMA (P=0.002, Kruskal-Wallis). Conclusions: BCMA exon 2 skipping is detected in a significant number of patients with multiple myeloma and lymphoma. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 2 skipping deletes the transmembrane domain, this BCMA protein may remain in the cytoplasm or perhaps is secreted as cell-free BCMA protein. The demonstration of relatively higher levels of BCMA∆Ex2 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of BCMA are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal BCMA protein on treatment with the various forms of anti-body-based therapy or CAR-T.
Outcomes of myeloma cast nephropathy in the era of anti-CD38 monoclonal antibody-based frontline therapy: A retrospective cohort study.
Authors: Michael Sang Hughes, Metodi Balev, Jai Radhakrishnan, Divaya Bhutani, Markus Y. Mapara, Andrew Eisenberger, Suzanne Lentzsch, Rajshekhar Chakraborty
Journal: Journal of Clinical Oncology (2024)

7555 Background: Myeloma cast nephropathy (MCN) has been a well-known negative predictive marker in newly diagnosed multiple myeloma (NDMM). Anti-CD38 + monoclonal antibodies (mAb) have improved outcomes, but little is known about their impact in patients with MCN. We performed a retrospective cohort study to investigate the outcomes of patients with MCN in the era of anti-CD38 + mAb-based frontline therapy. Methods: 115 NDDM patients received frontline anti-CD38 + mAb from 11/15/18 to 1/24/23. MCN was defined as evidence of light chain casts on biopsy, serum creatinine of &gt;2mg/dL, or 2021 CKD-EPI eGFR of &lt;40mL/min/1.73m 2 ; ≥1g/d proteinuria; and involved FLC ≥50mg/dL. 23 had MCN; 92 were contemporary controls. We obtained data regarding clinical course. Results: 6 MCN patients needed hemodialysis (HD) at diagnosis. MCN patients had similar R2-ISS to controls. Median proteinuria in MCN patients was 5.7g/d more than in controls; serum creatinine (Cr) was 3.2mg/dL higher; and median hemoglobin was 1.5g/dL less. More MCN patients received quadruplet regimens (86.9% vs 62.0%, p = 0.010); similar proportions were transplanted. At 1, 3, and 6 months, serum Cr was higher in MCN patients (p &lt; 0.001, p = 0.002, p = 0.002). Urine protein:creatinine ratios trended toward difference at 1 month (2.04 vs 0.15g/g MCN vs controls, p = 0.061) but were similar at 3 and 6 months. Response rates at 6 months did not differ. 4 MCN patients still required HD after 6 months. Median follow-up was 23.0-23.5 months. 4 MCN patients died, 1 due to progressive disease. No significant difference in disease-free survival (DFS; HR = 0.58, 95% CI 0.20-1.64, p = 0.295), time to next treatment (TTNT; HR = 0.53, 95% CI 0.20-1.39, p = 0.191), or overall survival (OS; HR 0.610, 95% CI 0.19-1.98, p = 0.406) was seen at any point between MCN and control cohorts. 1 year DFS, TTNT, and OS were: 87.0% MCN, 94.5% control; 77.2% MCN, 91.7% control; 87.9% MCN, 96.1% control. By statistical equivalence testing, MCN DFS and TTNT were within 6 months of control DFS and TTNT (p = 0.038, p = 0.032); MCN OS was within 5 months of control OS (p = 0.034). Conclusions: Patients with NDMM and MCN who receive upfront anti-CD38 + mAb therapy experience prolonged survival compared to prior findings. Anti-CD38 + mAb may substantially reduce, though not fully eliminate, the negative survival impact of MCN. Multiple mechanisms, including time to proteinuria resolution, may be involved. Further study is warranted. [Table: see text]
Impact of hyponatremia on multiple myeloma hospitalizations: A nationwide analysis.
Authors: Jayalekshmi Jayakumar, Manasa Ginjupalli, Mrunanjali Gaddam, Bhavyakumar Vachhani, Rabia Iqbal, Daniel Stein, Priya Hotwani, Ankushi Sanghvi, Dhairya Nanavaty, Vikash Kumar, Rishav Sinha, Surbhi Singh, Jincy Clement
Journal: Journal of Clinical Oncology (2024)

e19529 Background: Pseudohyponatremia has been studied to be a common laboratory artifact associated with Multiple Myeloma[MM] due to the paraproteinemia and the fluid shift. But recent studies are emerging with evidence of true hyponatremia in patients with MM usually associated with reduced anion gap. Hyponatremia is also one of the adverse effects with chemotherapy and major comorbidity associated with MM. In this study, we tried to study the effect of hyponatremia on the outcomes of MM. Methods: A retrospective analysis was formulated using the National Inpatient Sample database from 2016-2020. ICD 10 codes were used to find correlation between MM and Hyponatremia. The effects on morbidity, mortality, and secondary outcomes were compared in MM patients with Hyponatremia and without Hyponatremia. Categorical variables were compared using chi-square test, and continuous variables were compared using t-test. Multivariable regression analyses were performed adjusting for demographics, hospital-level characteristics, and relevant comorbidities. These included: Age, gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, adrenal insufficiency, polydipsia, hypothyroidism, alcohol use disorder, and various patient and hospital characteristics. Results: A total of 576,869 adults with MM were identified, of which 13.3% were diagnosed with hyponatremia. Mean age was 69 years, and 44 % were females. Patients with hyponatremia had 7.2% in-hospital mortality compared to 4.6% for patients without hyponatremia with an OR 1.61 [p-value 0.00]. Multivariate regression analysis showed that among those with MM, presence of hyponatremia increased the chance of mortality with OR 1.54 [1.43 - 1.65, p- value 0.00]. Hyponatremia also had significant impact on secondary outcomes including cerebral edema with OR 2.28 [1.76 - 2.95, p - value 0.00], AKI with OR 2.02 [1.94 - 2.09, p-value 0.00], Need for ventilator 2.28 [1.76 - 2.95, p-value 0.00] and sepsis 1.74 [1.66-1.81, p-value 0.00]. However there was no statistically significant differences found in venous thromboembolism and altered mental status. Hyponatremia also had an increased length of stay and Total hospital source utilization (Table). Conclusions: Hyponatremia is associated with multiple complications in MM hospitalizations. They even tend to portend worse prognosis as per our results. Further prospective studies are required to prove this association and management strategies should be established to improve outcomes and prevent complications. [Table: see text]
Indirect comparison of linvoseltamab versus teclistamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).
Authors: Sundar Jagannath, Hans C. Lee, Joshua Ryan Richter, Jeffrey A. Zonder, James E. Hoffman, Zheng-Yi Zhou, Viviana Garcia Horton, Mirko Fillbrunn, Hongjue Wang, Matthew Mattera, Qiufei Ma, Timothy J Inocencio, Yingxin Xu, Evelien Bergrath, James Harnett, Tito Roccia, Glenn Scott Kroog, Karen Rodriguez-Lorenc, Yariv Houvras, Naresh Bumma
Journal: Journal of Clinical Oncology (2024)

7560 Background: No head-to-head clinical trials have compared effectiveness of anti-BCMA×CD3 bispecific antibodies for TCE RRMM. This analysis compared efficacy of linvoseltamab vs teclistamab via an unanchored matching-adjusted indirect comparison (MAIC). Methods: A MAIC was deemed feasible after excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 (linvoseltamab) to match MajesTEC-1 (teclistamab) criteria. Pt-level data from LINKER-MM1 (107 pts receiving 200 mg in Phase 1/2, data cut-off [DCO] 9/2023, median follow-up 11.1 months [mos]) and published data from MajesTEC-1’s efficacy population (150 pts, DCO 11/2021, median follow-up 9.8 mos) were analyzed. LINKER-MM1 pts were weighted to match key baseline characteristics in MajesTEC-1 (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status) selected via a prespecified algorithm (Kumar et al., 2023). Objective response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), and minimal residual disease (MRD) negativity (- [at 10-5 threshold]) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported before and after matching; a sensitivity analysis included all LINKER-MM1 200 mg pts (n=117). Results: Effective sample size for linvoseltamab was 82 after matching and baseline characteristics were balanced with MajesTEC-1. Before and after matching, linvoseltamab exhibited higher ORR, ≥VGPR, ≥CR, and MRD(-) rates, with significant differences in ≥CR. Linvoseltamab had significantly longer PFS and a trend toward longer OS and DOR (Table). Sensitivity analysis results were similar. Conclusions: The results suggest potentially greater efficacy for linvoseltamab vs teclistamab for all outcomes, highlighting its potential as a highly effective treatment option for TCE RRMM. [Table: see text]
Class comparison of BCMA-directed therapies in relapsed multiple myeloma.
Authors: Matthew J. Rees, Aytaj Mammadzadeh, Abiola Bolarinwa, Mohammed E Elhaj, Arwa Bohra, Sikander Ailawadhi, Ricardo Parrondo, Saurabh Chhabra, Yi Lin, Moritz Binder, Suzanne R. Hayman, Angela Dispenzieri, Francis Buadi, David Dingli, Rahma M. Warsame, Radhika Bansal, Prashant Kapoor, Morie A. Gertz, Eli Muchtar, Shaji Kumar
Journal: Journal of Clinical Oncology (2024)

7515 Background: BCMA directed CAR T cells, antibody drug conjugates (ADCs), and T cell engagers (TCEs) each have distinct strengths and weaknesses. While these agents have shown unprecedented response rates and survival outcomes, no head-head comparisons exist. We assessed the relative efficacy of different BCMA-therapies in relapsed myeloma, with a focus on high-risk subgroups. Methods: Retrospective study of MM patients treated at Mayo Clinic with commercial or investigational BCMA targeted therapies between April 2018-June 2023. Results: 385 patients (ADC=59, TCE=134, CAR T=192) with a median follow up of 20-months. The median time from diagnosis was 6.1 years. The table shows disease, and treatment characteristics. Amongst ADCs and TCEs recipients, the median treatment duration was 1.9 and 3.5 months respectively, disease progression (64% and 79%) and intolerance (22% and 10%) were the most common reasons for discontinuation. The overall response rates were 27, 50, and 86% for ADCs, TCEs and CAR T, respectively. Compared to ADCs, CAR T was associated with improved PFS (adjusted HR PFS =0.29, 95%CI=0.20-0.43) and OS (aHR OS =0.28, 95%CI=0.18-0.44) when adjusting for age, R-ISS, double hit high risk cytogenetic abnormalities (HRCAs), extramedullary disease (EMD, excluding paraskeletal plasmacytomas), triple class refractoriness, and the number of lines of therapy (LOTs) received in the preceding 1 year. Likewise compared to ADCs, TCEs were associated with superior PFS (aHR PFS =0.59, 95%CI=0.40-0.86) and OS (aHR OS =0.60, 95%CI=0.39-0.93). Amongst patients with plasma cell leukemia (PCL) or EMD at the time of BCMA therapy (n=123), median PFS was poor irrespective of the therapeutic class at 1.3, 1.7 and 6.1 months for ADCs, TCEs and CAR T, respectively. Equally, for patients previously treated with BCMA therapy (n=58), median PFS was poor regardless of class at 1.9, 2.4 and 3 months for ADCs, TCEs and CAR T, respectively. Of 229 relapses the mode of relapse was known in 192 cases (84%), with 101 (52%) having EMD at relapse. Conclusions: While contingent on myriad other factors, patients able to receive BCMA-directed CAR T therapy experience superior survival compared to ADC and TCEs. EMD, PCL and BCMA-exposed populations are recalcitrant to BCMA-directed immunotherapy, and EMD is a common means of relapse. [Table: see text]
Genome-wide 5-hydroxymethylation mapping and epigenetic pathways in multiple myeloma.
Authors: Zhou Zhang, Bei Wang, Krissana Kowitwanich, Xiaolong Cui, Parveen Bhatti, Chuan He, Brian Chiu, Wei Zhang
Journal: Journal of Clinical Oncology (2024)

7566 Background: Multiple myeloma (MM), a B-cell neoplasm characterized by bone marrow infiltration of malignant plasma cells, is the second most common blood malignancy, with an estimated number of ~35,000 new patients annually in the United States. The molecular pathogenesis of MM is complex and involves various genetic and epigenetic alterations. Key molecular mechanisms, including chromosomal abnormalities such as translocations involving the immunoglobulin heavy chain locus and various oncogenes (e.g., MMSET, FGFR3, CCND1, MAF), alterations in epigenetic regulators (e.g., EZH2, DNMT3A), dysregulation of cell cycle control, and aberrant activation of signaling pathways (e.g., NF-kB, PI3K/AKT, and JAK/STAT), play critical roles in MM pathogenesis. However, epigenetic pathways implicated in MM has not been comprehensively investigated, partly due to technical limitations that cannot distinguish major cytosine modification types. Methods: Using the 5hmC-Seal, a highly sensitive chemical labeling technique, we profiled genome-wide 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA) from a population-based case-control study of MM (cases, n = 313; controls, n = 317) conducted in Canada. Results: The 5hmC modification levels were summarized for various genomic features, showing an enrichment in gene bodies and enhancer markers, consistent with the putative role of gene regulation for 5hmC modification. A genome-wide scan of gene bodies identified 771 differential features between cases and controls, adjusting for age, sex, smoking status, education, and first two principal components, at a permutation-based empirical p-value cutoff of 10 -4 . For instance, IL1RAP, a component of the interleukin-1 signaling cascade, may impact tumor progression and immune system evasion. Furthermore, functional analysis indicated canonical pathways associated with MM pathology and treatment, such as calcium signaling, and synthesis and secretion of cortisol/aldosterone, were enriched in the differential 5hmC features between cases and controls. Notably, the calcium signaling pathway, integral to Ca 2+ transport and involved in various physiological and pathological processes, plays a critical role in MM pathogenesis. Within this pathway, the CAMK1D gene, which has been identified as a crucial regulator of tumor-intrinsic immune resistance, showed differential 5hmC level between cases and controls, highlighting a vital connection between epigenetic modifications and immune evasion mechanisms in MM. Conclusions: Leveraging a state-of-the-art technique, we identified novel epigenetic modifications and pathways in the risk of MM. This approach establishes a solid foundation for further investigating etiology of MM, deepening our understanding of the disease, and advancing the discovery of biomarkers, which could potentially guide preventive strategies.