bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCMA-directed CART therapy in patients with multiple myeloma and CNS involvement.
Authors: Gaballa Mahmoud R. , Castaneda Puglianini Omar Alexis , Cohen Adam D. , Vogl Dan T. , Chung Alfred , Ferreri Christopher J. , Voorhees Peter M. , Hansen Doris K. , Patel Krina K. 
Published: June 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 >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]
Evaluation of a novel method to guide belantamab mafodotin dosing in multiple myeloma based on a patient-reported questionnaire.
Authors: Terpos Evangelos , Gavriatopoulou Maria , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Theodorakakou Foteini , Spiliopoulou Vasiliki , Syrigou Rodanthi , Eleutherakis Papaiakovou Evangelos , Gkolfinopoulos Stavros , Psarros Giorgos , Kastritis Efstathios , Dimopoulos Meletios Athanasios 
Published: June 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 <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]
Second primary B-ALL after exposure to lenalidomide for multiple myeloma: A US multicenter study.
Authors: Lakshman Arjun , Jensen Jeffrey Lee , Chakraborty Rajshekhar , Shaw Gene , Jevremovic Dragan , Shi Min , Cook James R , Monaghan Sara A , Abeykoon Jithma P. , Parrondo Ricardo , Bergsagel Peter Leif , Agha Mounzer E. , Rubinstein Sam , Coombs Catherine Callaghan , Ito Sawa , Shah Mithun Vinod , Advani Anjali S. , Baughn Linda , Kumar Shaji 
Published: June 2024

7533 Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]
Incidence of acute kidney injury in patients with relapsed and refractory multiple myeloma treated with teclistamab vs chimeric antigen receptor T-cell therapy.
Authors: Charkviani Mariam , Vaughan Lisa E , Sandahl Tyler B , Lin Yi , Leung Nelson , Herrmann Sandra M 
Published: June 2024

7542 Background: Teclistamab, a novel bispecific monoclonal antibody targeting CD3 and BCMA, exhibits promising effects for patients with relapsed and refractory multiple myeloma (MM). However, rates of acute kidney injury (AKI) associated with this therapy remains inadequately characterized. Methods: This was a retrospective observational cohort study of patients with relapsed refractory MM who received teclistamab or Chimeric Antigen Receptor T-cell Therapy (CAR-T) therapy at Mayo Clinic between 12/1/2022-5/15/2023 and who were not in kidney failure at the time of treatment. The primary endpoint was incidence of AKI during follow-up; secondary endpoints included treatment and recovery from AKI. AKI was defined based on Kidney Disease Improving Global Outcomes criteria as an increase of serum creatinine levels > 1.5 times their baseline value after starting therapy. Cumulative incidences and Cox proportional hazard regression models were used to evaluate time to event data. Results: A total of 64 patients met inclusion criteria for the study (30 received CAR-T and 34 received teclistamab therapy). There were 14 AKI events occurring during follow-up (10 teclistamab [n = 6 stage 1, n = 3 stage 2 and n = 1 stage 3] and 4 CAR-T [n = 3 stage 1 and n = 1 stage 2]). Cumulative incidence estimates of AKI at 120 days after treatment were 32% (95% CI: 14%-47%) for teclistamab patients and 10% (95% CI: 0%-21%) for CAR-T patients. While patients receiving teclistamab were found to be at increased risk of an incident AKI event compared to patients receiving CAR-T therapy, results were not statistically significant (HR (95% CI): 3.38 (0.93-12.31), p = 0.065). Median time to development of AKI was 30 days (IQR 16, 73) in teclistamab and 59 days (IQR 9, 146) in CAR-T patients. Among the 10 patients in the teclistamab group with an AKI event, 4 (40%) had complete renal recovery and 4 (40%) had partial recovery, while among the 4 patients with CAR-T with an AKI event, 2 (50%) experienced complete renal recovery and 2 (50%) experienced partial recovery. Conclusions: Our study showed that almost one third of patients receiving teclistamab therapy for relapsed and refractory multiple myeloma experienced an incident AKI event during follow-up. This finding underscores the importance of monitoring for kidney function in these patients.
Population attributable fractions for risk factors for the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in the Veteran population.
Authors: Wang Mei , Ji Mengmeng , Schoen Martin W. , Sanfilippo Kristen Marie , Thomas Theodore Seth , Chang Su-Hsin 
Published: June 2024

7552 Background: Multiple myeloma (MM) is the most common type of plasma cell cancer in the U.S. MM is consistently proceeded by monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM. However, the contribution of each of these risk factors has not been quantified. We computed the population attributable fractions (PAFs) for selected risk factors in the U.S. Veterans Health Administration (VHA) health system. Methods: Veterans diagnosed with MGUS from 1999-2021 were identified and confirmed via a published natural language processing (NLP) model. We included Black and White patients whose immunoglobulin (Ig) subtype was IgA, IgG, or light chain. Patients who progressed to MM ≤6 months after MGUS diagnosis were excluded. We fit a multivariable time-to-event model controlling for sex, race (Black, White), Ig subtype (IgA, IgG, light chain), agent orange (AO) exposure, as well as M-protein level (≤, >1.5 g/dL), Charlson Comorbidity Index (CCI), obesity status (underweight, normal weight, overweight, obese), and age, all at MGUS diagnosis. The outcome was progression of MGUS to MM, which was also confirmed by a published NLP model. PAF for a risk factor is the fraction of all MM cases in the veteran population that is attributable to this specific risk factor. It accounts for both the prevalence and relative risk of this factor in the population. We calculated PAF for black race, IgA, AO exposure, and overweight/obesity. Results: The analysis included 24,917 patients with MGUS. Among them, 7.8% (n=1,944) progressed to MM (follow-up median 5.6, IQR 3.3-8.8 years). In the veteran population with MGUS, 17.9% of all MM cases was attributable to overweight or obesity (PAF 17.9%, 95% confidence interval [CI] 11.0-24.3%); 7.6% was attributable to black race (PAF 7.6%, 95% CI 4.3-10.9%), 5.7% was attributable to IgA (PAF 5.7%, 95% CI 4.0-7.4%), and 2.4% was attributable to AO exposure (PAF 2.4%, 95% CI 1.0-3.9%). Conclusions: In the veteran population with MGUS, overweight/obesity, the only modifiable factor, is the top contributor to progression to MM cases. In veterans with MGUS, had the overweight or obese MGUS patients to be reversed to normal weight, an estimated 17.9% of the progression cases could have been avoided.Our findings highlight the importance of maintaining a normal weight for reducing the risk of progression of MGUS to MM. [Table: see text]
Real-world outcomes (RWO) with tandem transplantation in patients (pts) with newly diagnosed multiple myeloma (NDMM).
Authors: Parmar Harsh , Barcellos Anna , Biran Noa , Phull Pooja , Vesole David H. , Belli Andrew J. , Fernandes Laura L. , Hansen Eric , Zettler Christina , Wang Ching-Kun , Goran Stefanie , Anderson Courtney , Doucette Kimberley , Gunning Thomas S , Ip Andrew , Siegel David Samuel DiCapua 
Published: June 2024

7564 Background: Stem cell transplant (SCT) followed by maintenance therapy (MT) is the standard of care for transplant eligible NDMM pts. Tandem transplantation has been found to have progression free (PFS) and overall survival (OS) benefit particularly for patients with high-risk cytogenetic abnormalities (HRCA). However, this modality remains under-utilized in clinical practice. We report RWO with tandem transplant (TT) in comparison with single SCT followed by MT (STM). 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 1st SCT (2nd if TT) 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) model was used to compare study cohorts, and hazard ratios (HRs) were estimated using the Cox proportional hazards method. HRCA were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1117 pts met the study criteria. Median age at diagnosis was 60 yrs. 56.9% were male, 68.9% were White, and 32% had HRCA. 937 pts received STM and 180 pts received TT with median follow-up time of 68 months (mos) (95% CI: 65.4, 71.9) and 39 mos (95% CI: 31.9, 50.1), respectively. Median TTNT1 for TT vs STM was 52.7 vs 51 mos, (p=0.85), respectively. Median TTNT2 for TT vs STM was 33.9 vs 11.8 mos, (p<0.001). respectively. Median OS for TT vs STM was not reached (NR) vs 108.1 mos, (p<0.001), respectively. In the PS model, the TT group had significantly lower hazard of TTNT2 and OS events (HRs 0.49 and 0.47, p<0.001 and p=0.01, respectively) as compared to STM. Conclusions: Our study demonstrates significant improvement in unadjusted TTNT2 and OS RWO for TT pts, despite higher incidence of HRCA compared to STM pts. PS analysis demonstrated a similar effect with decreased HRs for TT. OS is an extremely 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]
Automated myeloma cell selection using machine learning and artificial intelligence.
Authors: Louis Sherif , Knecht Hans , Mai Sabine 
Published: June 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 < 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.
1p and 1q: Partners in crime in multiple myeloma.
Authors: Devarakonda Srinivas S. , Vaishnav Arti , Zhao Qiuhong , Bumma Naresh , Cottini Francesca , Sharma Nidhi , Umyarova Elvira , Rosko Ashley Elizabeth , Benson Don M. , Khan Abdullah Mohammad 
Published: June 2024

7571 Background: Cytogenetic abnormalities in multiple myeloma (MM) highly influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) among others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of novel therapies. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients with chromosome 1 abnormalities, mainly del 1p, treated with autologous stem cell transplant (ASCT) consolidation at our institution. Methods: We conducted a retrospective study of all NDMM patients who were treated with ASCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) were defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC CA. Results: Of 511 pts transplanted, 453 had cytogenetic data at the time of diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amplification 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of progression-free survival (PFS) (HR 1.35; 95% CI 1.06-1.73, p=0.016), time to next treatment (TTNT) (HR 1.84; 95% CI 1.40-2.42, p<0.001) and overall survival (OS) (HR 1.47; 95% CI 1.06-2.02, p=0.02) compared to those without, consistent with published literature. The median PFS, TTNT and OS from ASCT in pts with gain/amp 1q were 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from the time of ASCT compared to those without del(1p). Conclusions: In our study of NDMM patients that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite induction therapy involving novel drugs and ASCT consolidation, patients with del(1p) at diagnosis continue to have inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.