tbuckley/cabot-search huggingface dataset:
Characterization of atypical IGH rearrangement patterns in plasma cell neoplasms.
Authors: Nichole Owen, Weimin Bi, Xiaonan Zhao, Janice Smith
Journal: Journal of Clinical Oncology (2024)

e19525 Background: Approximately half of plasma cell neoplasms carry a primary IGH rearrangement, the most common partners being t(4;14) FGFR3/IGH, t(11;14) CCND1/IGH, and t(14;16) IGH/MAF. While the typical IGH breakapart (BAP) patterns are well-described, atypical patterns are scarcely summarized in the literature. Characterizing atypical or variant patterns aid in the interpretation of positive results, the understanding of pathogenesis and clone evolution, and from a lab perspective, ranking probes for reflex when limited sample is available. Methods: Bone marrow samples underwent CD138 separation to enrich for plasma cells. Fluorescent in situ hybridization (FISH) was performed using a panel of probes including the IGH BAP probe (3' red, 5' green). If the IGH BAP probe was positive for any typical or atypical pattern, reflex testing was initiated with dual fusion FISH probes for FGFR3, CCND1 and MAF. For all cases, a typical pattern for the IGH BAP is considered 1Y1R1G and atypical is any deviation from that pattern that includes at least one single red or green signal. For dual fusion probes, the typical pattern is considered 2Y1R1G. Results: Over a two year period at a reference laboratory, 184 bone marrow samples were positive for either a typical or an atypical IGH rearrangement by FISH and reflexed to the dual fusion FISH panel described above. Of these, 19 represented repeat samples from a previously tested patient; however, they were included in this study as clones often evolve leading to different patterns than observed previously. No patient was included more than twice. Of 184 samples, 105 were rearranged with CCND1, 24 with FGFR3, and 15 with MAF. The remaining 38 samples had an unknown partner. These figures approximate the relative frequency of each partner with typical rearrangements described in the literature, with CCND1 as the most common followed by FGFR3 and MAF. For cases with FGFR3 rearrangements, 11/24 had an atypical pattern with the IGH BAP probe. The 1Y1G (n=8) pattern was the most common; this pattern was rarely observed in cases of CCND1 or MAF. For cases with CCND1 rearrangements, 41 had atypical patterns; the most common was 1Y1R (n=22) followed by 1Y2R1G representing a gain of the der(14) (n=10). The 1Y1R pattern is enriched in CCND1 and MAF rearrangements and absent from FGFR3 cases. The 1Y2R1G pattern is unique to CCND1 in this cohort.For MAF, 8/15 cases had an atypical pattern including 5 with the 1Y1R pattern. Other rare atypical patterns were also observed. Conclusions: The most common atypical IGH BAP patterns are characterized and show non-random association with specific rearrangement partners. Utilizing specific atypical patterns as a guide may inform probe choices when limited plasma cells are available, and aid in the interpretation of positive results. [Table: see text]
Assessment of the reversibility of resistance in the absence of antibiotics and its relationship with the resistance gene's fitness cost: a genetic study with mcr-1
Authors: Ziyan Guo, Siyuan Feng, Lujie Liang, Zhuoxing Wu, Lulu Min, Ruizhi Wang, Jiachen Li, Lan-Lan Zhong, Hui Zhao, Xiaoshu Chen, Guo-Bao Tian, Jian-Rong Yang
Journal: The Lancet Microbe (2024)
Novel method for the detection of circulating tumor plasma cells in multiple myeloma.
Authors: Jihyun Lee, Hoin Kang, Soee Kim, Ju Bi Lee, Hyo Yong Kim, Min Hyung Kim, Myeong-Jin Kim, Jungwon Kim
Journal: Journal of Clinical Oncology (2024)

e19520 Background: Multiple Myeloma (MM) is characterized by the proliferation of abnormal plasma cells within the bone marrow. A bone marrow examination is essential for the diagnosis of multiple myeloma. This is a test that causes great pain to patients because it requires collecting and analyzing the bone marrow fluid inside the bone. In addition, there is a disadvantage that it cannot be carried out frequently due to cost issues. Therefore, the development of new diagnostic methods is absolutely necessary. The aim of this study is to access the potential of circulating tumor plasma cells (CTPC) for the diagnosis of MM using CytoGen's Smart Biopsy platform. Methods: Spiking tests using MM cell line (RPMI8226) was conducted with the purpose of making an environment similar to the MM patient's blood. RPMI8226 cells (200 cells) stained with CellTracker were spiked into human blood sample (5mL, healthy donor). Then, spiked cells were isolated by CytoGen’s Smart Biopsy isolator, subsequently recovery rate was accessed by counting of isolated RPMI8226 or immunofluorescence (IF) staining with multiple myeloma-specific marker, CD138. Then, clinical evaluation was performed with bone marrow (3mL) and peripheral blood (5mL) samples of MM patients (n=20). The presence of CTPC in patient samples was tested by IF staining with anti-CD138 antibody. Results: In in vitro experiments to test recovery rate of CTPC using CytoGen's Smart Biopsy isolator, MM cell line’s recovery rate was validated to over 80%. CD138 expression was clearly detected by IF staining of spiking samples of multiple myeloma cell line and was not detected at all in the negative controls. In clinical evaluation study, CTPC was successfully observed after the isolation from bone marrow and peripheral blood using CytoGen's Smart Biopsy isolator by IF staining with CD138. Conclusions: This study shows a novel method for the detection of MM with liquid biopsy. CTPC from liquid biopsy of MM could be isolated using CytoGen's Smart Biopsy isolator with high recovery rate and can clearly be detected with specific marker of MM, CD138 by IF staining. These results suggested that CytoGen's Smart Biopsy platform might be an effective diagnostic tool for the detection of MM. Expanded clinical study will be performed with more MM samples for clinical validation. Clinical trial information: 2013-09-009 .
Survival outcomes in patients with primary plasma cell leukemia treated with novel therapies at University of California San Diego Health: A single institution experience.
Authors: Farid Ghamsari, Aaron Trando, Ah-Reum Jeong, Ila M. Saunders
Journal: Journal of Clinical Oncology (2024)

e19538 Background: Plasma Cell Leukemia (PCL) is a rare, but aggressive and devastating disease for which there is a paucity of data regarding the efficacy and safety of modern therapies to guide management. Data prior to the use of modern therapies showed abysmal overall survival (OS) of approximately 4-12 months. There is generally agreement that novel therapies have improved outcomes, but data supporting this is sparse due to the rarity of the disease. As such, there is currently no standard of care agreed upon by experts, and the specific approach for treatment currently varies by provider. Methods: In this single-center retrospective study, we review the outcomes of patients diagnosed with primary plasma cell leukemia (pPCL) from 2008 to 2023 who received at least one of the novel therapies of immunomodulatory drugs (IMiD), protease inhibitors (PI), and/or anti-CD38 antibodies at University of California San Diego Health. Baseline characteristics and efficacy outcomes were collected. Results: A total of 11 patients were identified who met the inclusion criteria. The median age at time of diagnosis was 50. The median circulating plasma cells at diagnosis was 34%. All but 2 patients had &gt; 20% circulating plasma cells. The remaining two had circulating plasma cells of 10% and 14% meeting the newly re-worked definition of plasma cell leukemia. One patient had a single extramedullary plasmacytoma at the time of diagnosis. High risk cytogenetics, defined as having t(4;14), t(14;16), t(14;20), Del17p, Gain1q, were characterized for all patients. 4 had one high risk mutation, 3 had two mutations. Only one patient’s first line did not include any of the novel therapies. 81% of patients’ first line of therapy included a form of cytotoxic chemotherapy (of which 55% of those were cisplatin, doxorubicin, cyclophosphamide, etoposide (PACE)). The most common first line of therapy was bortezomib (V), dexamethasone (D), PACE, +/- thalidomide (T) or lenalidomide (R), and +/- stem cell transplant (SCT). The other 19% of first line therapies contained exclusively novel therapies; namely VTD and daratumamab-RVD. Seven patients underwent SCT. One patient who underwent allogeneic transplant as part of their first line therapy has not yet relapsed 5 years post-transplant. Median OS was 28.8 months (95% CI 17.3 –not reached (NR)). First progression free survival (PFS) was 5.7 months (95% CI 2.3 – NR). For patients with available data, overall response rate (ORR) to 1st line of therapy was 60%. Conclusions: Our results demonstrate that the outcomes of patients with PCL have greatly improved with the use of novel therapies. The small sample size and heterogeneity of the treatments prohibited correlative statistical analysis. Prospective studies are needed to determine the best treatment option for this high-risk population which is excluded from most myeloma trials.
Effect of maintenance therapy (MT) on real-world outcomes (RWO) of patients (pts) with newly diagnosed multiple myeloma (NDMM) post stem cell transplant (SCT).
Authors: Harsh Parmar, Anna Barcellos, Noa Biran, Pooja Phull, David H. Vesole, Andrew J. Belli, Laura L. Fernandes, Eric Hansen, Christina Zettler, Ching-Kun Wang, Stefanie Goran, Courtney Anderson, Kimberley Doucette, Thomas S Gunning, Andrew Ip, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2024)

7562 Background: SCT followed by MT is the standard of care for pts with transplant-eligible (TE) NDMM. Five randomized clinical trials (RCTs) comparing lenalidomide MT versus no MT showed improved progression free survival (PFS), but no overall survival (OS) benefit except for one by McCarthy et al. that allowed pt crossover between treatment arms. Use of MT has also been associated with an increased risk of second primary malignancies and an inferior quality of life. We report RWO post SCT with and without MT in TE NDMM. Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from SCT to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) matched analysis was used to compare study cohorts and report hazard ratios (HRs) using the Cox proportional hazards method. High risk cytogenetic abnormalities (HRCA) were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1928 ptsmet the study criteria: 957 pts received SCT with MT (M) and 971 pts received no MT (NM). Median age at Dx was 61 y, 57% were male, 70% were White, and 31.2% had HRCA with a median follow-up of 64 months (mos) (95% CI: 61.6, 66.7). In the M vs NM arms, 29.6% and 32.7% pts had HRCA, respectively. Median TTNT1 for M vs NM was 51 vs 36 months (mos), (p&lt;0.001), respectively. Median TTNT2 for M vs NM was 11.7 vs 21.6 mos, (p&lt;0.001), respectively. Median OS for M vs NM was 108.8 mos vs 126.3 mos, (p=0.08), respectively. In the PS model, the NM group had significantly lower hazard of TTNT2 and OS events (HRs 0.65 and 0.85, p&lt;0.001 and p=0.08, respectively). Conclusions: Our study demonstrates improved TTNT2 outcomes with the NM approach. M therapy did not have an impact on OS in this cohort. Both results indicate an absence of long-term benefit with the use of M therapy. OS is a difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]
An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.
Authors: Yuqin Song, Xiaoqiong Tang, Qingqing Cai, Lihong Liu, Hongmei Jing, Ming Jiang, Xiuhua Sun, Jianqiu Wu, Yu Yang, Huijing Wu, Zhigang Peng, Kaiyang Ding, Shuhua Yi, Xiaojing Yan, Guowu Wu, Yudan Wu, Jie Cui, Pengju Ou, Fenlai Tan, Jun Zhu
Journal: Journal of Clinical Oncology (2024)

TPS7098 Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .
Analyzing the impact of type 1 and type 2 diabetes on patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM): A retrospective study at a tertiary care center.
Authors: Ram Prakash Thirugnanasambandam
Journal: Journal of Clinical Oncology (2024)

e19512 Background: Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM) are hematologic conditions characterized by demographic and clinical feature variations. Examining the prevalence and outcomes of MGUS and MM in individuals with different types of diabetes is crucial for personalized healthcare. The primary aim of this study was to explore potential differences in prevalence and outcomes between type 1 and type 2 diabetes populations. Methods: A cohort of 193 patients(pts),obtained from a large endocrine clinic in Brooklyn,New York, between 2015 and 2024, comprising 56 pts with MGUS and 137 pts with MM, was analyzed for demographic characteristics, comorbidities (hypertension, hyperlipidemia, chronic kidney disease), Hemoglobin A1C levels, and diabetes type. Fisher’s exact test and chi-square test were employed to assess the statistical significance of associations. Results: The cohort predominantly consisted of Black individuals (93%), with a statistically significant association between race and the conditions (p = 0.036). While gender distribution showed no significant association, a borderline significance was observed in the relationship between the type of diabetes and the conditions (p = 0.061). Age, co-morbidities, and Hemoglobin A1C levels did not exhibit significant associations with MGUS or MM. Conclusions: In conclusion, our preliminary analysis reveals significant associations between race and the potential links between types of diabetes and occurrences of MGUS and MM. Ongoing research aims to expand the cohort, addressing data limitations for a more comprehensive exploration. This study establishes a foundation for understanding and offers insights into personalized healthcare strategies for individuals with MGUS or MM who have diabetes. [Table: see text]
BCMA-directed CART therapy in patients with multiple myeloma and CNS involvement.
Authors: Mahmoud R. Gaballa, Omar Alexis Castaneda Puglianini, Adam D. Cohen, Dan T. Vogl, Alfred Chung, Christopher J. Ferreri, Peter M. Voorhees, Doris K. Hansen, Krina K. Patel
Journal: Journal of Clinical Oncology (2024)

7519 Background: CART therapy represents a breakthrough in therapy for patients (ptns) with relapsed or refractory (R/R) multiple myeloma (MM). Pts with MM who have CNS involvement are commonly excluded from clinical trials and have limited therapeutic options. We evaluated the safety and efficacy of BCMA-directed CART therapies in ptns with MM and CNS involvement. Methods: 5 US academic medical centers contributed data to this retrospective analysis. 11 ptns with MM with CNS involvement received BCMA-directed CART (7 and 4 pts received ide-cel and cilta-cel, respectively). Results: Eight (72%) ptns were male, 3 (27%) had high-risk (HR) cytogenetics, and 10 (91%) had extramedullary disease (dz). Four (36%) ptns had brain/cranial nerve dz, 1 (9%) had spine dz, and 6 (55%) had both. CNS dz was evident on MRI in 100% of ptns and on CSF in 4 ptns (36%). Five ptns (45%) had ≤60 days between CNS diagnosis and CART therapy, 3 (27%) had &gt;300 days from CNS dz with 2 requiring CNS-directed therapy (CNS-Tx) close to CART during bridging, and 3 (27%) were diagnosed soon after CART infusion. Six (55%) ptns received CNS-Tx as part of bridging; radiotherapy (RT, 2 ptns), RT + intrathecal (IT) chemotherapy (chemo) (2 ptns), IT chemo (1 ptn), and surgery + RT (1 ptn). Five (45%) ptns didn’t receive CNS-Tx as part of bridging for the following reasons; 3 were diagnosed soon post CART and received RT post-infusion, 1 had recent chemo, and 1 was treated for CNS dz 587 days prior to CART and didn’t require CNS-Tx during bridging. Seven ptns (64%) had treated CNS dz at the time of lymphodepleting chemo. Nine (82%) ptns had grade (G) 1/2 CRS and none had G ≥3CRS. Two ptns (18%) had G1 ICANS, 1 (9%) had G3 ICANS, and none had G4 ICANS. Two ptns experienced delayed neurotoxicity post ide-cel, 1 with delayed lethargy that was treated with steroids, and the other with progressive multifocal leukoencephalopathy that was treated with steroids plus pembrolizumab. None had delayed parkinsonian side effects. With a median follow-up of 104 days post-infusion, the best responses achieved were 45% CR/sCR, 18% VGPR, 9% PR, with an overall response (ORR) of 73%. Seven ptns were evaluable for CNS responses by day 90 with a 100% CNS response rate defined by improved imaging findings or clearance of CSF involvement. CNS recurrence occurred in 1 ptn (9%) by day 172 while 5 (45%) had continued systemic response at last assessment. Conclusions: This study suggests that BCMA directed CART therapy in ptns with MM and CNS involvement is safe and feasible. Of the evaluable ptns for CNS response, 100% showed CNS response by day 90. Larger studies with longer follow up are needed to confirm these findings. [Table: see text]
Automated myeloma cell selection using machine learning and artificial intelligence.
Authors: Sherif Louis, Hans Knecht, Sabine Mai
Journal: Journal of Clinical Oncology (2024)

7565 Background: Precision of sampling is critical to achieve accurate results relevant to diagnostics and prognostics. Sampling errors may compromise the sensitivity and specificity of otherwise credible diagnostics technologies. Our 3- dimensional (3D) telomeres profiling methodology is conducted on individual target cells selected from the patient sample processed using 3D immuno-FISH. In our traditional workflow target cells are manually selected by highly trained personnel based on morphological characteristics and/ or immunophenotypic characteristics, namely cells positive for CD138 and CD56. However, the variability among trained operators required rounds of verification by a second and third operator and an approval by a Hematopathologist or the Lab Director to confirm the selected cells in some cases. Therefore, automated detection of myeloma cells is of paramount importance. Methods: In this study we employed machine learning and artificial intelligence (AI) tools to develop an automated algorithm capable of streamlining target cell (i.e. myeloma) selection and minimize or eliminate operator introduced variability. Training libraries were built using positive and negative cells. Over 5000 cells were used in the algorithm training process. We employed iterative rounds of validation and refinement to achieve a high precision automated tool. AI then identified myeloma cells in an automated fashion and the results of AI identification were confirmed by a Hematopathologist. Results: We report the results of a comparative analysis done on 20 myeloma patients at different stages of the disease including MGUS, smouldering myeloma and active myeloma. Also, the sample type included bone marrow smears, purified mono-nucleated plasma cells and bone marrow biopsies. 50 verified manually selected target cells and 50 target cells selected by the automated cell selection tool, approved by a skilled operator, from the same sample of each patient were analyzed using the TeloView platform. The TeloView platform quantifies 6 telomeric molecular and structural parameters. We conducted statistical analysis to calculate Coefficient of Variation (CV) between the results of each patient. We set the acceptable variability to &lt; 15%. We achieved CVs of less than 10% among all patients included in the analysis. Conclusions: The automated cell selection tool streamlined this critical sampling process in our workflow minimizing operator-introduced variability, reducing the processing time to a fraction of the time required for manual cell selection and verification which enables high throughput for the 3D telomeres profiling while maintaining precision.