bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health related quality of life (HRQoL) in patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE RRMM) treated with idecabtagene vicleucel (ide-cel) versus standard regimens: Patient-reported outcomes (PROs) from KarMMa-3 phase 3 randomized controlled trial (RCT).
Authors: Delforge Michel , Patel Krina K. , Eliason Laurie , Dhanda Devender , Shi Ling , Guo Shien , Marshall Thomas , Arnulf Bertrand , Cavo Michele , Nooka Ajay K. , Manier Salomon , Callander Natalie Scott , Giralt Sergio , Einsele Hermann , Ailawadhi Sikander , Popa McKiver Mihaela , Cook Mark , Rodríguez-Otero Paula 
Published: June 2023

8032 Background: Patients (pts) with TCE RRMM have few treatment (Tx) options and poor HRQoL. Ide-cel, the first in class CAR T cell Tx for pts with TCE RRMM, improved PFS versus standard (std) regimens in the KarMMa-3 trial. We report the PRO results comparing the Tx arms. PROs provide further understanding of Tx benefit of ide-cel from the pts’ perspective. Methods: KarMMa-3 (NCT03651128) is an open-label phase 3 RCT comparing the efficacy and safety of ide-cel with std regimens in pts with TCE RRMM, who had received 2–4 prior regimens. In addition to clinical endpoints, we evaluated the impact of ide-cel compared with std regimens on the changes in HRQoL, measured by the EORTC QLQ-C30, EORTC QLQ-MY20, and the EQ-5D-5L questionnaires. PROs were collected at baseline (screening), day of infusion and monthly from 2–24 months (mo) and thereafter every 3 mo. This interim analysis reports PROs through 20 mo. Comparisons were performed on least squares mean (LSM) changes from baseline over time between arms using constrained longitudinal data analysis (cLDA). Results: In total, 386 pts were randomized (ide-cel, 254; std regimens, 132). PRO compliance was high over time ( > 80%). At baseline, PROs were similar between arms. LSM changes from baseline to 20 mo showed significant differences ( P < 0.05), with effect sizes of 0.3–0.7, in favor of ide-cel for most domains, including global health status/QoL, cognitive functioning, fatigue, and pain (EORTC QLQ-C30); side effects of Tx (EORTC QLQ-MY20); and the EQ-5D-5L VAS. The difference in overall LSM change reached or exceeded the pre-specified between-groups minimal importance difference (MID) for improvement in most domains in favor of ide-cel (Table). Conclusions: Ide-cel showed statistically significant and clinically meaningful improvements in HRQoL, including key MM symptoms and functioning, for pts with TCE RRMM compared with std regimens. The PRO data for ide-cel expands upon the clinical outcomes observed in the KarMMa-3 trial. Clinical trial information: NCT03651128 . [Table: see text]
Evaluation of prophylactic tocilizumab (toci) for the reduction of cytokine release syndrome (CRS) to inform the management of patients (pts) treated with teclistamab in MajesTEC-1.
Authors: van de Donk Niels W.C.J. , Garfall Alfred L. , Benboubker Lotfi , Uttervall Katarina , Groen Kaz , Rosiñol Laura , Hodin Caroline , Stephenson Tara , Trancucci Danielle , Perales-Puchalt Alfredo , Kobos Rachel , Banerjee Arnob , Mateos Maria-Victoria 
Published: June 2023

8033 Background: Teclistamab is the first BCMA × CD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM). In MajesTEC-1, CRS occurred in 72.1% of pts treated at the recommended phase 2 dose (RP2D) of weekly teclistamab 1.5 mg/kg (50.3% grade [gr] 1; 21.2% gr 2; 0.6% gr 3), and was successfully managed using toci in 36.4% of pts (± other interventions) without affecting response to teclistamab. Emerging data show that prophylactic administration of toci prior to first dose of bispecific antibodies reduces CRS incidence and severity, which may facilitate outpatient initiation of therapy. The current analysis includes the first prospective study of effects of prophylactic toci on incidence and severity of CRS with teclistamab. Methods: Eligible pts were aged ≥18 y with RRMM and had previously received a PI, IMiD, and anti-CD38 antibody. Pts received subcutaneous teclistamab (following 2 step-up doses) in a prospective exploratory cohort at the RP2D or in a fixed-dose cohort. Toci (single 8 mg/kg IV dose) was given ≤4 hours before the first teclistamab step-up dose. CRS was graded per Lee et al 2014 and managed per institutional guidelines. Results: 14 pts were included: median age 64 y (range 50–82); all pts had ECOG score ≤1 and ISS I/II; 91% had standard cytogenetic risk; 21% had extramedullary plasmacytomas; 31% had ≥30% BMPCs; median 4 prior lines of therapy (range 2–7); 64% triple-class refractory. Median follow-up was 1.2 mo (range 0.2–4.6). CRS occurred in 4 pts (29%; no gr ≥3 CRS); 1 had a subsequent CRS event (table). Median time to onset was 2 d (range 1–3); median duration was 2 d (range 2–4); all events were managed with toci and resolved without teclistamab discontinuation. 7 of 14 pts had gr 3/4 neutropenia (consistent with the overall MajesTEC-1 population). 2/14 had a gr 3/4 infection. 2/14 had a neurotoxicity AE. Of the response evaluable patients, 4/7 responded. Cytokine and PK data in additional pts with longer follow-up will be presented to further inform pt management. Conclusions: A single dose of toci before teclistamab treatment appeared to reduce the incidence of CRS relative to the overall MajesTEC-1 study population with no new safety signals and no evidence of impact on response to teclistamab considering the short follow-up. Prophylactic toci has the potential to reduce CRS risk in pts with disease profiles suitable for outpatient dosing, reducing the burden of hospitalization during teclistamab step-up dosing. Clinical trial information: NCT03145181 , NCT04557098 . [Table: see text]
Clinical characteristics, markers of adverse prognosis, and predictors of development of extramedullary multiple myeloma.
Authors: Zanwar Saurabh , Ho Matthew , Kapoor Prashant , Binder Moritz , Buadi Francis , Dispenzieri Angela , Dingli David , Fonder Amie L. , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hwa Yi Lisa , Hobbs Miriam A. , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Muchtar Eli , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji 
Published: June 2023

8043 Background: Extramedullary Multiple Myeloma (EMM) has an aggressive clinical course and can present at diagnosis [primary EMM, (pEMM)] or relapse [secondary EMM, (sEMM)]. Here, we report clinical characteristics and outcomes of EMM, and predictive factors for the development of sEMM. Methods: We identified 299 patients with biopsy-proven EMM between 01/01/2000 and 12/31/2021. Patients with solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia were excluded. A 1:1 matched pair analysis (matched for year of diagnosis of MM for comparable follow-up and treatment eras) was performed to compare clinical characteristics and outcomes for patients with and without sEMM. Results: The median follow-up from the diagnosis of MM was 11.5 years (95%CI: 9.3-14.8). Of 299 patients, 204 (68%) patients had sEMM and 95 (32%) had pEMM, with largely comparable baseline characteristics (Table). The median overall survival (OS) from the diagnosis of sEMM was 0.7 (95% CI: 0.6-0.9) years compared to 3.6 (95%CI: 2.4-5.6) years for pEMM (p<0.0001). For sEMM, mutlvariable analysis (MVA) for OS identified visceral organ involvement (eg. liver, lung/pleura, brain, pancreas, etc.) to be associated with inferior OS [HR 1.6 (95% CI: 1.1-2.4), p=0.01]; high-risk cytogenetics (HR-CTG), ISS-3 stage, and age did not impact OS from sEMM. For pEMM, HR-CTG [HR 2.3 (95% CI 1.1 -4.8), p=0.03] and ISS-3 stage [HR 3.1 (95% CI 1.5-6.7), p=0.003] were associated with inferior OS on MVA whereas visceral EMM or age did not impact OS from pEMM. On univariate analysis, patients with sEMM were younger (median age 58.7 vs 61 years, p=0.006), had a higher proportion of 1q duplication (32% vs 17%, p=0.001), t(4;14) [16% vs 9%, p=0.047] and elevated LDH (30% vs 19%, p=0.04), compared to the matched cohort of patients without sEMM. On MVA, younger age at diagnosis, t(4;14) and 1q duplication at diagnosis of MM were independent predictors of development of sEMM. The median OS from diagnosis of MM was 5.4 years (95%CI: 4.1-6.2) for patients with sEMM versus 7.5 years (95% CI: 6.4-10.1; p <0.001) for the matched cohort. Secondary EMM was an independent poor prognostic marker for OS from the diagnosis of MM [HR 1.6 (95%CI: 1.2-2.1); p=0.004] in addition to age, ISS3 disease and HR-CTG. Conclusions: Outcomes of patients with EMM, especially sEMM, remain dismal. Patients with sEMM have higher rates of 1q duplication and t(4;14) at diagnosis of MM and carried an independent adverse prognosis in a matched cohort. [Table: see text]
Lenalidomide-based monotherapy versus augmented therapy for maintenance in standard risk multiple myeloma patients with no complete response post autologous hematopoietic cell transplantation.
Authors: Awada Hussein , Hajj Ali Adel , Tabaja Chadi , Khouri Jack , Anwer Faiz 
Published: June 2023

8055 Background: Standard risk (SR) multiple myeloma (MM) is typically characterized by the absence of poor prognostic cytogenetic aberrations, and better outcomes. However, outcomes in SR MM remain far from homogeneous, especially in patients undergoing autologous hematopoietic cell transplant (AHCT). While many patients do well initially, relapse is inevitable. Here, we studied the role of lenalidomide (R) maintenance therapy in determining outcomes in SR MM with no complete response (non-CR) post-AHCT. Methods: We retrospectively reviewed all MM patients who underwent AHCT at the Cleveland Clinic between January 1, 2011 and January 15, 2021. Electronic medical charts were accessed to retrieve data on demographic characteristics, comorbidities, International Scoring System (ISS) staging, cytogenetic risk categorization, serum and bone marrow studies, as well as maintenance therapy. SR MM was considered in patients who did not have t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Remission status was determined by serum studies at 3 months post-AHCT. The primary endpoint was median time to either progression or death, reported as time to event (TTE) determined by Kaplan Meier analysis. Results: A total of 517 patients were reviewed, of whom 279 were determined as SR MM. Further stratification yielded 100 non-CR SR patients on lenalidomide-based maintenance, of whom 87 were on R monotherapy and 13 on R combination. Comparison between the R-monotherapy and combination groups showed similar age at AHCT (60.5 vs 56 years, P=0.07), time to transplant (23.5 vs 30.8%, P=0.7), albumin levels (<3.5 g/dL 25 vs 25%, P=1), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (≥3 43.5 vs 30.8%, P=0.5), Male preponderance (58.8 vs 69.2%, P=0.6), ethnicity (White 82.4 vs 76.9%, P=0.7), ISS stages (I 41 vs 45.5%, II 41 vs 36.4%, III 17.9 vs 18.2%, P=0.9), pre-AHCT lines of therapy (≥2 31.8 vs 38.5%, P=0.8), and pre-AHCT bone marrow plasma cells (≥10%:9.5 vs 7.7%, P=1), respectively. The only significant difference between the two groups was in the MM immunoglobulin subtype (IgG 80 vs 50%, P=0.02). Kaplan-Meier analysis for median TTE revealed that the R monotherapy group had a significantly shorter median TTE at 38.1 months versus 68.6 months (P=0.03) for the R combination group. Conclusions: SR MM patients who do not achieve a CR post-AHCT have better outcomes with R-combination rather than monotherapy.
Presence of hyperdiploidy and history of tobacco use in African American patients with SMM.
Authors: Parikh Rujul H , Goyal Subir , Liu Yuan , Hofmeister Craig C. , Kaufman Jonathan L. , Heffner Leonard T. , Boise Lawrence H , Gupta Vikas Anand , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Joseph Nisha S 
Published: June 2023

8062 Background: Smoldering multiple myeloma (SMM) has a clinically variable course in progression to active myeloma (MM). Accurate risk stratification is essential in identifying which patients may benefit from early therapeutic intervention. Current models do not account for the potential impact of race on risk of progression to SMM. Here, we seek to identify independent risk factors for progression in African American (AA) versus white patients in a real-world single institutional database of SMM patients. Methods: We retrospectively identified 224 patients (pts) with untreated SMM from 2007 to 2021 treated at our institution. Patient demographics and disease characteristics were obtained from our IRB-approved myeloma database. TTP was defined as the time from diagnosis of SMM to diagnosis of active MM, estimated by Kaplan-Meier and compared by log-rank test. Univariate analyses were performed using Cox proportional hazard models for TTP. Results: A total of 224 pts (AA 35%, white 47%, other/unknown 17%) were identified with median age 62y (range 32-82). Median follow-up was 4.3y in Whites and 5y in AA pts. Notable characteristics include M/F 45%/54%, IgG/IgA/FLC 76%/17%/6%, 30% current/past smoker (median 15 pack-years), 12% alcohol use (≥10 drinks/wk), 45% with BMI > 30. Multiple cytogenetic abnormalities were defined as presence of ≥2 of the following: t(4;14), t(14;16), gain(1q21), del(1p), del(13), or del(17p). The median TTP (mTTP) was 6.8 [95% CI (3.7, 8.2)] years in whites and 5.6 [95% CI (4.6, 11.8)] years in AA. On univariate analysis, M-spike > 1.5, involved K/L ratio > 12, and bone marrow PC > 20% were associated with increased risk of progression for both AA and whites (all p < 0.05). As expected, gain of 1q21 was associated with increased risk of progression for both groups, though more pronounced in AA (HR 2.94, p = 0.025) versus whites (HR 2.33, p = 0.013). Hyperdiploidy was associated with shorter mTTP in AA (HR 3.03, p = 0.004) compared to whites (HR 1.39, p = 0.3). Multiple cytogenetic abnormalities was associated with shorter mTTP in whites (HR 2.63, p = 0.004) but was not statistically significant in AA (HR 2.63, p = 0.104). Interestingly, tobacco use was associated with shorter mTTP in Blacks (HR 2.94, p = 0.005) but not in whites (HR 0.96, p = 0.85). Conclusions: Understanding the potential impact of racial background on progression from SMM to MM is critical in the appropriate management of all patients with SMM. In this database, with a large proportion of AA patients, hyperdiploidy and +1q portend high risk of progression in AA patients. Further study is needed to better classify these potential differences to ensure risk stratification models are applicable to all patients.
Surgical outcomes of patients with resectable non-small-cell lung cancer receiving neoadjuvant immunotherapy with nivolumab plus relatlimab or nivolumab: Findings from the prospective, randomized, multicentric phase II study NEOpredict-Lung.
Authors: Aigner Clemens , Du Pont Bert , Hartemink Koen , Wiesweg Marcel , Vanbockrijck Michel , Darwiche Kaid , Hegedus Balazs , Schramm Alexander , Hautzel Hubertus , Maes Brigitte , Theegarten Dirk , Schildhaus Hans-Ulrich , Baas Paul , Cuppens Kristof , Schuler Martin H. , Plönes Till 
Published: June 2023

8500 Background: Feasibility of surgical resection for non-small-cell lung cancer (NSCLC) after preoperative immune checkpoint inhibitor therapy (PICIT) with PD-1/PD-L1 and CTLA-4 inhibitors has been established. This study reports the first data on surgery after preoperative LAG-3 inhibition in NSCLC patients. Methods: Patients with histologically confirmed NSCLC stage IB, II or IIIA (UICC 8th edition) were randomized to receive two preoperative doses (q14d) of nivolumab (240 mg, arm A), or nivolumab (240 mg) plus relatlimab (80 mg, arm B). Primary study endpoint was the number of patients undergoing curatively intended surgery within 43 days of initiation of PICIT. Surgery was performed following the institutional standards. Outcomes and perioperative events were prospectively recorded. Results: 60 patients (29 female) were randomized 1:1 from 4/2020 to 7/2022. All patients were operated within 43 days after initiation of PICIT. Median age in arm A was 65 (43-78) years and 67 (44-81) years in arm B. Clinical UICC stages were similar between both arms. Central tumor location was present in 50% in arm A and 45% in arm B. R0 resection was achieved in 57 patients (95% ITT population, 98,3% curatively resected population). Two patients had pleural carcinosis only detected at surgery, and 1 patient had R1 resection. Resection was performed by lobectomy (n=23 and 24), bilobectomy (2 and 1), sleeve lobectomy (5 and 4) and combined lobectomy+segmentectomy (0 and 1). Surgical approach was either by videothoracoscopy (n=60% and 63,3%) or thoracotomy (n=40% and 36,6%). Conversion was required in 3 vs. 2 patients. Median operation time was 149 (77-234) and 165 (61-205) minutes. Median number of resected lymph nodes was 15 (3-52) and 10 (3-50). Intraoperative bleeding from the pulmonary artery was observed in 1 patient in each arm and was managed without sequelae. Postoperative complications occurred in 33,3% and 26,6%. Median hospital stay was 7 (2-22) and 5,5 (2-24) days. Complete or major histopathological response was observed in 27% and 30%. Overall perioperative 30-day mortality was 0%. No negative impact on adjuvant therapy was observed. The 12 months OS rate across both arms was 96% (95% Cl: 83-99%), the DFS rate was 91 % (78-97%). Conclusions: Curative surgical resection following neoadjuvant combined PD-1/LAG-3 inhibition was equally safe and feasible as after PD-1 inhibition alone. Perioperative course, complications rate and outcome are comparable to other neoadjuvant regimens. Standard adjuvant therapies can be safely administered in this setting. Clinical trial information: NCT04205552 .
Association of somatic mutations and histologic subtype/grade on prognosis and PD-L1 expression in mesothelioma.
Authors: Zhu Allen , Husain Aliya N. , Hermina Andrew , Mitchell Owen , Mueller Jeffrey S. , Drazer Michael William , Kindler Hedy L. , Kwon Jung Woo 
Published: June 2023

8507 Background: Mesothelioma includes epithelioid, sarcomatoid, and biphasic histologic subtypes, and the epithelioid subtype is histologically graded based on mitotic count and nuclear atypia. Correlation between the most common somatic mutations ( BAP1, NF2, TP53, CDKN2A), and overall survival is poorly understood. High PD-L1 expression is a poor prognostic factor for survival and may be a predictor of response to immunotherapy. Few studies have evaluated the relationships between these factors. Methods: We performed a retrospective study in 217 patients with pleural, peritoneal and bicavitary mesothelioma as part of an IRB-approved biobanking protocol. Histologic subtype, grade of epithelioid mesothelioma, tumor stage, and overall survival time were determined. Next-generation DNA sequencing (NGS) was used to identify the prevalence of somatic mutations. PD-L1 immunohistochemistry was obtained on 184 samples and quantified as percentage of tumor cells. Histologic subtype, nuclear grade, clinical stage, PD-L1 expression, survival time, and the prevalence of each mutation were compared using chi-squared, Kruskal-Wallis, or Cox proportional hazard tests. All p-values were determined in R version 4.2.0 using a two-sided alpha error of 0.05 to mark statistical significance. Results: The most frequent somatic mutations were found in BAP1 (99/217, 45.6%), CDKN2A (47/217, 21.7%), TP53 (37/217, 17.1%), and NF2 (31/217, 14.3%). Patients with CDKN2A-mutated mesothelioma experienced shorter survival (p=0.032). TP53 mutations were associated with higher nuclear grade (p=0.015), higher mitotic count (p=0.013), and greater nuclear atypia (p=0.015). TP53 mutations were more prevalent in pleural than peritoneal mesothelioma (p=0.016) and in tumors without lymph node metastasis (p=0.05). As expected, patients with epithelioid mesothelioma had superior overall survival (p=0.02) and their tumors had lower PD-L1 expression (p=0.007) than either sarcomatoid or biphasic mesotheliomas. Neither PD-L1 expression nor mutations in BAP1, NF2, CDKN2A, or TERT were associated with nuclear grade, atypia, or mitotic count. No association was found between BAP1 or NF2 mutations and tumor stage, lymph node metastasis, or PD-L1 expression. Conclusions: To our knowledge, this is the first study of this scale to correlate PD-L1 expression, somatic mutation data, histologic features, and survival in mesothelioma patients. The most significant findings were that patients with CDKN2A mutations had shorter survival and TP53 mutations, which were more prevalent in pleural mesotheliomas, were associated with higher nuclear grade, higher mitotic count, and greater nuclear atypia. An ongoing analysis evaluates the contribution of germline mutations, which occurred in a significant proportion (15.7%) of this mesothelioma patient cohort.
Bemcentinib and pembrolizumab in patients with relapsed mesothelioma: MIST3, a phase IIa trial with cellular and molecular correlates of efficacy.
Authors: Krebs Matthew G , Branson Amy , Barber Shaun , Poile Charlotte , King Amy , Greystoke Alastair , Moody Sam , Nolan Luke , Scotland Molly , Darlison Liz , Bajaj Amrita , Morgan Bruno , Brookes Cassandra , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne L. , Fennell Dean Anthony 
Published: June 2023

8511 Background: AXL receptor tyrosine kinase is a key facilitator of immune escape and drug resistance, conferring a more aggressive phenotype. Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM), however, responses are only observed in a fraction of patients. Preclinical studies suggest that dual PD1 and AXL inhibition is synergistic. We developed a multi-centre, molecularly stratified phase IIa trial to evaluate the efficacy of AXL/PD-1 inhibition with bemcentinib (Bem)/pembrolizumab (Pem) and to uncover cellular and molecular determinants of efficacy as arm 3 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST3). Methods: Patients with pleural mesothelioma were enrolled. Key inclusion factors were ECOG performance status (PS) 0-1, prior platinum-based chemotherapy (maximum of 2 prior lines allowed), evidence of disease progression with measurable disease by CT (Modified RECIST 1.1), and adequate haematological/organ function. All patients received 200mg Pem IV q3W in combination with Bem, loading dose 400mg PO for the first 3 days and then 200mg od q3w. Primary endpoint was disease control rate at 12 weeks (DCR12w). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate (ORR) and toxicity (NCI CTCAE 4.03). Pre-treatment fresh biopsy was required to enable multiplex immunofluorescence, whole exome and RNA transcriptome sequencing. Gut microbiome 16s RNA sequencing also was undertaken at baseline (n=21). Results: Between September 2020 and March 2022, 26 patients with MM started treatment and received at least one dose of Pem Bem. Median age was 72.5 (range, 55-85) years, 88% were male 12% were female, Histology: 88% epithelioid, 8% Biphasic, 4% Sarcomatoid, ECOG PS1 77%, > 1 prior systemic therapy 35%. The median cycles of Pem Bem was 4 (IQR, 2-11). The DCR12w was 46.2% (12/26) (90% confidence limit (CI), 29.2% –63.4 %;), ORR was 15.4% (95%CI, 4.4- 34.9%; all PR)) with stable disease in 57.7% (36.9 – 76.6%); DCR24w was 38.5% (10/26) (95%CI, 20.2% – 59.4%). Adverse events (any cause): ≥ grade 3 toxicities affected 38% of pts and there were no treatment-related deaths. The most frequent adverse events recorded were fatigue in 12/26 (46%) patients and nausea in 11/26 (42%) patients. Conclusions: MiST3 met its primary endpoint and warrants further evaluation. Analysis of the cellular and molecular correlates of response are ongoing and will be presented. Clinical trial information: NCT03654833 .