bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updates from a phase Ib study of isatuximab (Isa), bortezomib (V) and dexamethasone (D) plus cyclophosphamide (C) or lenalidomide (R) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM).
Authors: Ocio Enrique M. , Rodríguez Otero Paula , Bringhen Sara , Oliva Stefania , Nogai Axel , Attal Michel , Moreau Philippe , Martinez-Lopez Joaquin , Le Roux Nadia , Macé Sandrine , Rouchon Marie-Claude , Wang Qiuyan , Mateos Maria-Victoria 
Published: May 2020

8529 Background: We report updated data from a Phase Ib study of Isa, a CD38 monoclonal antibody, plus VCd or VRd in transplant ineligible patients (pts) with NDMM (NCT02513186). Methods: Isa-VCd: Isa (10 or 20 mg/kg; weekly [QW] cycle 1 [C1], then Q2W), V (1.3 mg/m2; twice weekly C1, then QW), C (300 mg/m2; QW C1, then Days [D] 1, 8, 15 to C12), d (20 mg; twice weekly C1, then D1, 2, 8, 9, 15, 16, 22, 23 to C12). Isa-VRd: Isa (10 mg/kg), V and d as described above; R (25 mg/day; D1–14 and D22–35). Efficacy and safety were evaluated. Conventional (M-protein levels) and minimal residual disease (MRD) IMWG response assessments were compared. MRD negativity was assessed at 10−5 by next-generation sequencing and flow. Mass Spectrometry (MS) negativity (no detectable serum M-protein) was assessed for 13 pts by Immuno-Capture and Liquid Chromatography coupled to High Resolution MS. Results: As of Nov 18, 2019, 17 pts were treated with Isa-VCd (10 mg/kg, n = 13; 20 mg/kg, n = 4), 27 with Isa-VRd; 53% and 63% remained on treatment, respectively. Infusion reactions were seen in 53% of Isa-VCd and 63% of Isa-VRd pts; Grade ≥3 infections in 23% and 37%; serious adverse events in 47% and 52%. See table for efficacy. 3 MRD positive pts were MS positive with persistent detectable M-protein ( > 10 µg/mL). 8/10 MRD negative pts were MS positive (4 at 5-10 µg/mL; 4 at > 10 µg/mL) and 2/10 were MS negative ( < 5 µg/mL). Stable residual M-protein was observed by MS up to 23 months post-MRD negativity. All pts tested by MS are still progression-free. Conclusions: Isa-VCd/VRd shows encouraging efficacy and tolerability in NDMM. MS seems to be more sensitive than MRD; low levels of M-protein were detectable even in MRD negative pts. Clinical trial information: NCT02513186 . [Table: see text]
A phase Ib study of TAK-079, an investigational anti-CD38 monoclonal antibody (mAb) in patients with relapsed/ refractory multiple myeloma (RRMM): Preliminary results.
Authors: Krishnan Amrita Y. , Patel Krina K. , Hari Parameswaran , Jagannath Sundar , Niesvizky Ruben , Silbermann Rebecca Wang , Berg Deborah T. , Li Qing , Allikmets Kristina , Stockerl-Goldstein Keith 
Published: May 2020

8539 Background: TAK-079 is a subcutaneously (SC) administered mAb with multiple modes of action for killing target cells. Here we report data from an ongoing dose finding study of TAK-079 monotherapy in patients with RRMM (NCT03439280). Methods: Pt were eligible after ≥ 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid; prior anti-CD38 therapy allowed. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. TAK-079 given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity. SC injection was 2 mL administered in ≤ 1 minute. Results: 34 patients were enrolled across 5 fixed dose cohorts (TAK-079 45-135-300-600-1200 mg SC) as of 09 December 2019. Median age was 65 (50–81) years. At study entry, 65% were refractory to both an IMiD and PI; 82% refractory to last line of therapy, 21% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody. Median number of prior therapies was 4 (2,12). No ≥ Grade 1 early or late systemic infusion reactions (IRR) reported. Three ( < 1%) injection site reactions described in > 1200 injections administered; 2 mild pruritis and 1 moderate swelling. Drug related adverse events (AEs), any grade, occurring in at least 10% of patients were: fatigue (21%), anemia (18%), neutropenia (18%), leukopenia (15%). Neutropenia was the only drug related grade 3 AEs in 2 or more patients (n = 2); only drug related SAE was 1 Grade 3 diverticulitis. No drug-related grade 4 AEs, AEs leading to study discontinuation, or on-study deaths reported. Recommended phase 2 dose (RP2) is to be 600 mg based on no reported DLTs, no MTD identified, and preliminary efficacy (PFS and response [ORR]). At the RP2 dose, 9 patients received at least 6 cycles of therapy by the data cutoff; their ORR was 33%, median duration of response was not estimable. The clinical benefit rate (minimal response or better) in all 12 patients enrolled at the RP2 dose was 67%. At a median follow-up of 7.5 months, PFS not estimable at the RP2 dose. Conclusions: TAK-079 monotherapy is safe, generally well tolerated, and active in patients with RRMM through tested doses. Clinical activity occurred early and was durable. With no MTD identified, no IRRs, no significant hematologic toxicity, the RP2 dose is 600 mg. PFS, with a median FU of 7.5 months at the data-cut off, is not estimable at the RP2 dose. Updated safety and efficacy data will be presented. Clinical trial information: NCT03439280 .
DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics.
Authors: Cohen Adam D. , Trudel Suzanne , Lonial Sagar , Libby Edward N. , Lee Hans Chulhee , Besemer Britta , Facon Thierry , Nooka Ajay K. , Callander Natalie Scott , Chari Ajai , Gupta Ira , Paul Sofia , Opalinska Joanna , Richardson Paul G. 
Published: May 2020

8541 Background: Patients with RRMM and HR cytogenetics have a poor prognosis and need effective therapies. In DREAMM-2 (NCT03525678), single-agent belantamab mafodotin (an immunoconjugate targeting B-cell maturation antigen) demonstrated clinically meaningful activity and a manageable safety profile in patients with heavily pretreated RRMM ( Lancet Oncol.2020). We present outcomes in patients with HR-cytogenetics (9-month follow-up). Methods: Patients with RRMM received single-agent belantamab mafodotin (2.5 or 3.4 mg/kg). For this post hoc analysis, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21+ (tested locally). Results: The median number of cycles was 3 (2.5: range: 1–15) and 4 (3.4: range: 1–14). Overall response rate (ORR; ≥partial response [PR] per independent review committee) was 27% in the 2.5 mg/kg group (22% with ≥very good partial response [VGPR]) and 40% in the 3.4 mg/kg group (27% with ≥VGPR). The median duration of response (DoR) was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. The most common adverse events ( > 30% in either group) were consistent with the overall population ( Lancet Oncol.2020): keratopathy (2.5: 59%;3.4: 79%), thrombocytopenia (2.5: 44%; 3.4: 65%), nausea (2.5: 27%; 3.4: 33%), anemia (2.5: 24%; 3.4: 42%), and blurred vision (2.5: 20%; 3.4: 42%). Conclusions: Patients with HR-cytogenetics maintain deep and durable clinical responses with single-agent belantamab mafodotin, comparable to that reported in the overall population. The safety profile remained consistent with previous reports. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]
Prevalence and significance of clonal hematopoiesis of indeterminate prognosis (CHIP) in multiple myeloma.
Authors: Padrnos Leslie Jane , LaPlant Betsy , Kumar Shaji , Henderson Kimbery , Dispenzieri Angela , Lasho Terra L. , Patnaik Mrinal , Stewart A. Keith 
Published: May 2020

8542 Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of leukemia-associated somatic mutations in clonally expanded hematopoietic stem cells with a VAF of ≥2%. CHIP has been associated with myeloid malignancies and increased all cause mortality largely from atherovascular disease. The prevalence and impact of CHIP in patients with myeloma (MM) is yet to be defined. Aims: Evaluate the prevalence and significance of CHIP in 101 lenalidomide exposed patients with multiple myeloma. Methods: 101 MM patients, the majority exposed to > 2 years of lenalidomide (Len), with stored mononuclear blood samples were identified for Next Generation Sequencing (NGS) using a panel encompassing 42 gene mutations associated with CHIP. Electronic medical records were reviewed and outcomes of secondary malignancy, macrocytosis, thrombosis and mortality were extracted. Results: Thirty of 101patients were found to have CHIP with the most frequent mutations: DNMT3A (12%), TET2 (5%), and TP53 (4%). One third of patients with CHIP had > 1 mutation (37%). At 68 months median follow up over a quarter of patients experienced thrombosis (31%) and 13% developed subsequent malignancy/premalignant condition including myelodysplastic syndrome (3%). There was no significant difference in age, gender, duration of Len prior to NGS testing, thrombosis complication, or survival in those with versus without a CHIP mutation. At last F/U 30% had died, 25% remained on therapy, 27% were on maintenance therapy and 11% were on observation alone. Conclusions: CHIP mutations are common in plasma cell neoplasms, with 30% of patients in this study retrospectively found to have CHIP mutations by NGS testing. CHIP mutations have been associated with cardiovascular events and malignancy development, however no associations were identified in this small study. Limitations to this study include small sample size, retrospective nature and duration of follow up. Further study of this very common finding in MM patients regarding timing of development and subsequent impact of these mutations could help risk stratify and inform therapy selection. [Table: see text]
The significance of beta-II microglobulin (β2M) and International Staging System (ISS) in multiple myeloma (MM) patients (pts.) with renal impairment (RI).
Authors: Lin Gloria , Hari Parameswaran , Chhabra Saurabh , Hamadani Mehdi , D'Souza Anita , Szabo Aniko , Dhakal Binod 
Published: May 2020

8544 Background: ISS stage which underlies prognostic models used in MM, is derived from albumin and β2M at diagnosis. β2M, a low molecular polypeptide, is present on all nucleated cells and is elevated in pts. with RI. In MM, although the association between β2M and prognosis has been interpreted to reflect a higher tumor burden, RI by itself may explain at least in part the higher levels of β2M seen with this disease. Historically, those presenting with MM and severe RI had a poor prognosis and quite likely the β2M elevation irrespective of kinetics predicted poor prognosis. In this study, we investigated the significance of β2M and ISS staging in MM patients in the setting of RI in the modern era when renal recovery is more common after induction. Methods: MM pts. treated at our institution from 2012-2014 were included and divided into two groups by creatinine (Cr) level at diagnosis: < 2 and ≥2 mg/dl. Demographic and disease characteristics were compared between the two groups using ANOVA and chi-square tests as appropriate. COX regression was used for the multi-variate analysis for survival and the effect of β2M levels, adjusting for albumin levels, on survival was allowed to vary by Cr level to evaluate potential interaction. Results: Of 201 total pts., 163 (81.6%) had Cr < 2 mg/dL and 38 (18.4%) ≥ 2mg/dL at diagnosis with higher β2M and ISS stage in Cr≥2 group. On adjusted analysis, albumin was significantly associated with overall survival (OS) (hazard ratio, HR 0.60; 95% CI 0.36-1; p = 0.04); however, β2M was associated with OS only when Cr < 2 mg/dl (HR 1.13, 95% CI 1.06-1.19; p < 0.0001) but not when Cr≥2 mg/dl (HR 0.98, 95% CI 0.91-1.06; p = 0.65) with significant interaction (p = 0.004). Likewise, the effect of β2M on progression-free survival was significant when Cr < 2 (HR 1.1, 95% CI 1.05-1.19; p = 0.0002), but not Cr≥2 (HR 1.02; 95% CI 0.97-1.08; p = 0.42) with significant interaction (p = 0.03). Conclusions: Our results show that in the era of modern induction therapy and rapid improvement in kidney function, a high β2M may not impact prognosis as adversely, at least in those with RI, since an elevated β2M may be disproportionate to true tumor burden. Thus, ISS staging in these patients should be reevaluated after induction and potential renal recovery. Novel biomarkers may refine MM staging independent of the level of kidney function.
Evaluation of minimal residual disease in relapsed/refractory multiple myeloma patients treated with venetoclax or placebo in combination with bortezomib and dexamethasone: BELLINI study analyses.
Authors: Moreau Philippe , Harrison Simon J. , Cavo Michele , de La Rubia Javier , Popat Rakesh , Hungria Vania , Salwender Hans , Suzuki Kenshi , Kim Inho , Spencer Andrew , O'Dwyer Michael , Hong Wan-Jen , Jalaluddin Muhammad , Yang Xiaoqing , Pauff James Michael , Maciag Paulo Cesar , Ross Jeremy A. , Kumar Shaji 
Published: May 2020

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( < 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p < 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [Table: see text]
Castleman disease spectrum.
Authors: Khor Johnson , Pierson Sheila K. , Powers Victoria , Tamakloe Mark-Avery , Gorzewski Alexander , Floess Katherine , Ziglar Jasira , Haljasmaa Eric , Ren Yue , Casper Corey , Lechowicz Mary Jo , Uldrick Thomas S. , Chadburn Amy , Srkalovic Gordan , Lim Megan S. , Li Hongzhe , Jaffe Elaine S. , Van Rhee Frits , Fajgenbaum David C. 
Published: May 2020

8548 Background: Castleman disease (CD) describes a group of lymphoproliferative disorders that share characteristic histopathology. Unicentric CD (UCD) and idiopathic multicentric CD (iMCD) are differentiated by the number of enlarged lymph node (LN) regions: UCD involves 1 region and iMCD involves > 1 region. UCD typically has mild or no symptoms whereas iMCD requires abnormal labs and symptoms for diagnosis and can progress to life-threatening multi-organ failure. Review of an international natural history registry of CD revealed patients across a broad spectrum with regards to number of enlarged LN regions and disease severity. We hypothesize that there is a positive correlation between disease activity and the number of enlarged LNs and that the spectrum of CD is more complex than a binary UCD-iMCD dichotomy. Methods: Herein, enrolled UCD and iMCD patients whose diagnosis was confirmed by an expert-panel were selected for analysis (N = 81). A standardized disease activity score (scale 0-1) was computed for each patient using available diagnostic values of C-reactive protein, hemoglobin, and albumin (CHA score). Results: We looked at the association between number of enlarged LNs and CHA and found a significant positive correlation (R = 0.65, p < 0.0001). Given this, we divided the cohort into groups of mild, moderate, and extensive lymphadenopathy according to the number of regions of enlarged LNs at the time of diagnosis: group 1 (1 enlarged LN region); group 2 (2-4 enlarged LN regions); and group 3 (≥5 enlarged LN regions). We identified 20 patients in group 1, 19 in group 2, and 42 in group 3 with no statistical differences in sex, race, or age at diagnosis. Histopathological subtype differed significantly among groups. Group 1 was 89% hyaline vascular (HV)/ hypervascular (HpV) and 11% mixed (Mx); group 2 was 74% HV/HpV, 21% Mx, and 5% plasmacytic (Pl); and group 3 was 64% HV/HpV, 32% Mx, and 5% Pl. We then looked at CHA score in these groups and found that group 3 patients have a significantly greater CHA score (median [IQR]: 0.46 [0.49]) than both group 2 (0.08 [0.14]) and group 1 (0.0 [0.10]) (adjusted p < 0.001 for both) while there was no difference between groups 1 and 2. Conclusions: These results suggest that disease severity is positively associated with the number of enlarged LNs. The different proportions of histopathological subtypes between the three groups could indicate different pathologic mechanisms are involved. Further work is needed to determine if patients with a few enlarged LNs exhibit disease more closely to UCD or iMCD and to understand long-term outcomes for these patients.
Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161.
Authors: Leal Ticiana , Wang Yating , Dowlati Afshin , Lewis DeQuincy Andrew , Chen Yuanbin , Mohindra Amit Ramesh , Razaq Mohammad , Ahuja Harish G. , Liu Jijun , King David M. , Sumey Christopher Joseph , Ramalingam Suresh S. 
Published: May 2020

9000 Background: Immune checkpoint inhibition is now given in combination with chemotherapy for first line (1L) therapy of extensive stage small cell lung cancer (ES-SCLC). We conducted a randomized phase II study of nivolumab (anti-PD1) in combination with platinum-etoposide (CE) as 1L treatment for patients with ES-SCLC (EA5161, NCT03382561). Methods: Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. Patients were randomized 1:1 to nivolumab 360 mg + CE every 21 days for 4 cycles followed by maintenance nivolumab 240 mg every 2 weeks until progression or up to 2 years (arm A) or CE every 21 days for 4 cycles followed by observation (arm B). Prophylactic cranial irradiation (PCI) was permitted at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across both arms. The primary endpoint was PFS in eligible and treated patients. Secondary endpoints included OS, ORR, and safety. Adverse events (AEs) were graded per NCI-CTCAE v4.0. Results: This study was activated in May 2018 and completed accrual in December 2018. 160 patients were enrolled. Baseline characteristics were well balanced between arms. In the ITT population (n = 160), nivolumab + CE significantly improved the PFS compared to CE with HR 0.65 (95% CI, 0.46, 0.91; p = 0.012); mPFS 5.5 versus 4.6 months, respectively. Secondary endpoint of OS was also improved with nivolumab + CE versus CE with HR 0.67 (95% CI, 0.46, 0.98; p = 0.038); mOS 11.3 versus 8.5 months. Among patients who initiated study therapy, nivolumab + CE significantly improved the PFS compared to CE with HR 0.68 (95% CI, 0.48, 1.00; p = 0.047); mPFS 5.5 versus 4.7 months, respectively; in this population, OS was also improved with nivolumab + CE versus CE with HR 0.73 (95% CI, 0.49, 1.11; p = 0.14); mOS 11.3 versus 9.3 months. The ORR was 52.29% versus 47.71%. The incidence of treatment-related grade 3/4 AEs was 77% versus 62% and AEs leading to discontinuation 6.21% versus 2.07%. Ten patients remain on maintenance nivolumab. Lethal adverse events independent of treatment were similar between the two arms (9 in arm A; 7 in arm B). Conclusions: The addition of nivolumab to CE as 1L treatment for ES-SCLC significantly improved PFS and OS. No new safety signals were observed. Clinical trial information: NCT03382561.
Role of adjuvant chemotherapy in patients with pathological stage I NSCLC with high-risk features.
Authors: Arjyal Lubina , Uprety Dipesh , Frankki Susan M , Borgert Andrew J , Marinier David E. 
Published: May 2020

9022 Background: Lobectomy is the current standard of care for patients with stage I non-small cell lung cancer (NSCLC). There is a lack of prospective data on the benefit of adjuvant chemotherapy (CT) in patients with negative margins but with high-risk features: lympho-vascular invasion (LVI) or visceral pleural invasion (VPI). We aimed to investigate the benefit of adjuvant CT in patients with pathological stage I NSCLC with high-risk features. Methods: The 2016 National Cancer Database was queried to identify patients with pathological stage I NSCLC (8th edition AJCC staging) diagnosed from 2010-2015 who received lobectomy/pneumonectomy with clear surgical margins. Patients were stratified into high risk (tumor size ≥2 cm with LVI and/or VPI) or low risk group. Multivariate Cox proportional hazards regression and propensity score matched Kaplan-Meier survival analysis were used to compare overall survival between those who received adjuvant CT and those who did not. Results: 34,556 patients were identified with 1114 (3.2%) receiving adjuvant CT. On multivariate Cox regression analysis, high risk tumors (hazard ratio [95% confidence interval] = 1.31 [1.25-1.38]) and lack of adjuvant chemotherapy (1.25 [1.09-1.44]) were associated with worse overall survival (OS). Additionally, male sex, age ≥ 60 years, higher comorbidity burden, lack of insurance, low facility volume, low median income, non-squamous histology were associated with worse OS. After propensity score matching, Kaplan-Meier survival analysis of the high risk subgroup (n = 2923) showed a significant difference in overall survival (OS) between those who received adjuvant CT (n = 1032, 5 year OS, 74.7%; 95% CI, 70.9%-78.0%) and those who did not (n = 1891, 5 year OS, 66.9%; CI, 63.9%-69.6%; p = 0.0002). In patients with no high risk factors for recurrence (n = 384), OS was not significantly different between the patients who received adjuvant CT (n = 78, 5 year OS, 75.8%; CI, 61.3%-85.5%) and those who did not receive adjuvant CT (n = 306, 5 year OS, 77.1%; CI, 70.0%-82.7%; p = 0.3). Conclusions: Our study showed better survival with adjuvant CT in patients with pathological stage I NSCLC who have tumor size greater than 2 cm, LVI and/or VPI.