bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-year follow-up of treatment-naïve and previously treated patients with Waldenström macroglobulinemia (WM) receiving single-agent zanubrutinib.
Authors: Tam Constantine Si Lun , Opat Stephen , Marlton Paula , Gottlieb David , Simpson David , Cull Gavin , Ritchie David , Verner Emma , Munoz Javier , Tedeschi Alessandra , Huang Jane , Novotny William , Tan Ziwen , Holmgren Eric , Atwal Siminder K. , Seymour John Francis , Roberts Andrew Warwick , Trotman Judith 
Published: May 2020

8051 Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naïve (TN) and relapsed/refractory (R/R) patients with WM. Methods: Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Results: Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusions: Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients was tolerable. Clinical trial information: NCT02343120 . [Table: see text]
Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: Comparison between the standard and IMWG MRD criteria and QIP-MS including FLC (QIP-FLC-MS).
Authors: Puíg Noemí , Contreras Teresa , Paiva Bruno , Cedena M Teresa , Martinez-Lopez Joaquin , Oriol Albert , Gutiérrez Norma , Ríos-Tamayo Rafael , Rosiñol Laura , Calasanz María José , Bargay Joan , de La Rubia Javier , Palomera Luis , Miguel Teodoro Hernández-Garcia , Garcia-Sanz Ramón , Blade Joan , Lahuerta Juan José , San Miguel Jesus , Mateos Maria-Victoria 
Published: May 2020

8512 Background: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of sustained minimal residual disease (MRD) negativity in the bone marrow (BM) by next generation flow (NGF). The value of BM MRD assessment in MM is proven, but alternative, non-invasive methods, accurately reflecting disease burden are needed. Methods: Pts received six 4-week cycles of KRd as induction (K:36mg/m2 twice weekly, R: lenalidomide 25mg po od days 1-21 and d:dexamethasone 40mg po weekly) followed by melphalan 200mg/m2, two further cycles of KRd as consolidation and up to 2 years of Rd (R:10mg/d, d:20mg/week). Efficacy was analyzed in parallel in BM samples by NGF and in serum by SPEP/IFE and QIP-MS/QIP-FLC-MS in 52 out of the 90 pts enrolled in the trial. Standard and MRD responses were carried out as per the IMWG guidelines. For QIP-MS serum immunoglobulins were purified using polyclonal antibodies (anti-IgG, -IgA, -IgM, -total κ and -total λ light chain, -free κ and -free λ light chain). Mass spectra were generated on a MALDI-TOF-MS system. Results: Overall response rate (ORR) was 98% post-induction, 98% post-ASCT, and 100% post-consolidation; 38.4%, 61.5% and 68.6% of pts reached ≥ complete response at each time-point and, among them, 23%, 44% and 55% achieved flow MRD-negativity. Using the combination of QIP-MS/QIP-FLC-MS, the percentage of pts without detectable disease at each timepoint lowered to 12%, 27% and 38% reflecting the higher sensitivity of the method. Against NGF, QIP-MS/QIP-FLC-MS provided negative predictive values of 67%, 92% and 89% (p = 0,0206; p < 0,001; p = 0,003) and identified disease in 95%, 97% and 92% of pts that were positive by NGF-MRD at each respective timepoint. Three pts from this cohort have progressed so far: two were NGF+/MS+ at the three timepoints whilst 1 remained NGF- but QIP-MS/FLC-MS+ throughout. Conclusions: The GEM-CESAR treatment strategy induces a high ORR in HRsMM pts, and the % of cases achieving flow-MRD negativity post-ASCT meets the primary endpoint of the trial. The combined use of QIP-MS and FLC-MS offers higher sensitivity relative to standard methods and may provide relevant information about the right timing for performing a BM aspirate/biopsy. Clinical trial information: NCT02415413 .
Impact of lenalidomide-bortezomib-dexamethasone (RVd) induction on patients with newly diagnosed multiple myeloma and renal impairment: Results from the Connect MM Registry.
Authors: Ailawadhi Sikander , Lee Hans Chulhee , Omel Jim , Toomey Kathleen , Hardin James W. , Gasparetto Cristina , Jagannath Sundar , Rifkin Robert M. , Durie Brian G. , Narang Mohit , Terebelo Howard R. , Wagner Lynne I. , Dhalla Mazaher , He Mia , Srinivasan Shankar , Joshi Prashant Ramesh , Robinson Suzanne , Abonour Rafat 
Published: May 2020

8518 Background: Patients (pts) with newly diagnosed multiple myeloma (NDMM) and renal impairment (RI) are often excluded from clinical trials. Data are limited on the effects of induction treatment in these pts, who may also be ineligible for autologous stem cell transplant (SCT) due to severity of RI. This analysis investigated the impact of RVd induction on renal function in transplant eligible (TE) and noneligible (TNE) pts from the Connect MM Registry, a US, multicenter, prospective, observational study. Methods: Eligible pts were ≥ 18 y and had symptomatic MM diagnosed ≤ 2 mos prior to enrollment, as defined by the International Myeloma Working Group criteria. For this analysis, pts that received front-line RVd for ≥ 3 cycles were grouped per transplant eligibility and renal function at baseline (BL; creatinine clearance [CrCl] < 30, 30-50, > 50-80, and > 80). Pts with progressive disease at BL were excluded. Renal function at 3 mos was measured. Median unadjusted progression-free survival (PFS) was calculated from start of regimen in TE and TNE populations, with pts grouped by CrCl (≤ 60 or > 60) at BL. Results: As of 7/23/19, 421 TE and 212 TNE pts received RVd for ≥ 3 cycles. TE and TNE pts were grouped by BL CrCl of < 30 (20 and 16 pts), 30-50 (36 and 50 pts), > 50-80 (117 and 63 pts), and > 80 (248 and 83 pts). Renal function improvement was observed in all pts receiving RVd, including those with moderate (30-50 CrCl) and severe (< 30 CrCl) RI at BL (Table). In pts with > 60 CrCl and ≤ 60 CrCl at BL, median PFS in TE pts was 48.6 mos and 43.2 mos, respectively. In TNE pts, median PFS was 36.4 mos and 30.6 mos, respectively. Conclusions: The results from the Connect MM Registry indicate that pts with NDMM and RI (including moderate and severe) who receive front-line RVd for ≥ 3 cycles may see improvement in renal function at 3 mos, regardless of transplant eligibility. RVd therefore can potentially be used in pts with RI. This analysis provides real-world data that support further investigation of RVd treatment in pts with moderate or severe RI. Clinical trial information: NCT01081028 . [Table: see text]
DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment.
Authors: Lee Hans Chulhee , Cohen Adam D. , Chari Ajai , Hultcrantz Malin , Nooka Ajay K. , Callander Natalie Scott , Suvannasankha Attaya , Badros Ashraf , Libby Edward N. , Trudel Suzanne , Richardson Paul G. , Sborov Douglas Weston , Rodríguez Otero Paula , Lonial Sagar , Zhi Eric , Lewis Eric , Gupta Ira , Opalinska Joanna 
Published: May 2020

8519 Background: Renal impairment, a frequent complication and poor prognostic factor in RRMM, often leads to poor tolerability of standard regimens. We report outcomes in patients with renal impairment receiving single-agent belantamab mafodotin (2.5 or 3.4 mg/kg; B-cell maturation antigen targeting immunoconjugate not renally metabolized) from the DREAMM-2 post-hoc analysis (NCT03525678). Methods: Eligible patients with RRMM had no active renal conditions and adequate renal function (based on albumin/creatinine ratio [<500 mg/g] and eGFR [mL/min/1.73 m2]: normal [≥90], mild impairment [mild, ≥60≤90], moderate impairment [mod, ≥30≤60]). Results: Overall response rates (95% CI) in patients with mild/mod impairment (2.5 mg/kg: 32% [21.4–44.0]; 3.4 mg/kg: 36% [25.6–48.5]) were similar to those in the overall population ( Lancet Oncol.2020). The median duration of response (DoR) was not reached (NR) in 2.5 mg/kg mild/mod subgroup (95% CI estimate: 4.2 months–NR); median DoR was 7.5 months (4.9–NR) in 3.4 mg/kg mild/mod subgroup. Rates of keratopathy and albuminuria were similar regardless of renal function; rates of anemia, pyrexia, and thrombocytopenia were more frequent in patients with impaired renal function (Table). eGFR did not change or changed to normal in most patients. Conclusions: Following treatment with single-agent belantamab mafodotin, patients with mild/mod renal impairment achieved a similar efficacy and safety profile as patients with normal renal function. 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]
A phase II, single-arm study of denosumab in multiple myeloma patients with renal insufficiency.
Authors: O'Donnell Elizabeth , Yee Andrew Jenho , Nadeem Omar , Lipe Brea , Laubach Jacob , Malek Ehsan , Branagan Andrew , Friedman Robb S. , Richardson Paul G. , Nooka Ajay K. , Raje Noopur S. 
Published: May 2020

8520 Background: Bone destruction is a devastating consequence of multiple myeloma (MM). An unmet medical need exists for the management of skeletal complications in MM patients with renal insufficiency. Despite the effectiveness of intravenous bisphosphonates, their use is limited in situations where renal dysfunction is present. Denosumab is a fully human monoclonal IgG2 antibody to RANKL that has been shown to be non-inferior to zoledronic acid for SRE rates in MM (Raje, et al. Lancet Oncol). More importantly, it does not have the same renal toxicity as the bisphosphonates. We hypothesize that denosumab can be safely and effectively administered in MM patients with renal insufficiency to improve bone health. This may fill a gap in clinical care for bone-directed therapy in this patient population. Methods: This multi-center study will include forty adult patients with newly diagnosed or relapsed MM with a creatinine clearance of less than 30 mL/min (NCT02833610). All patients will receive a subcutaneous injection of denosumab 120 mg Q4W for a total of 12 cycles. In addition, it is required that all subjects receive daily vitamin D and calcium supplementation at standard doses (at least 2000 mg calcium citrate and1000 IU of vitamin D), unless documented hypercalcemia develops on study. The primary objective is to assess the effect of denosumab 120 mg Q4W on serum c-terminal telopeptide (sCTX). Secondary objectives include evaluation of safety and tolerability of denosumab in patients with renal insufficiency, incidence of hypocalcemia, effect on bone mineral density, effect on urinary n-terminal telopeptide, and proportion of patients who have a documented skeletal-related event. Results: At the time of this analysis, a total of 20 out of a planned 40 patients have been enrolled, including 9 women, 11 men. Of those treated, 8 patients have completed the planned 12 cycles of therapy. Hypocalcemia was observed in 7 (35%) patients. Four patients (20%) experienced grade 3 hypocalcemia, 3 (15%) grade 2 or less. Two patients developed osteonecrosis of the jaw, one (5%) grade 1 and one (5%) grade 4 event. Data for the analysis of the primary endpoint of sCTX levels will be presented. Conclusions: Investigation of denosumab in MM patients with renal insufficiency defined as a creatinine clearance less than 30 mL/min is ongoing. Early data support that denosumab can be safely administered in this population. However, incidence of hypocalcemia despite aggressive prophylactic calcium dosing underscores the importance of the trial to inform safe practice in this more fragile population. Clinical trial information: NCT02833610 .
Genetic polymorphisms associated with clostridium difficile infection in multiple myeloma patients undergoing autologous stem cell transplantation.
Authors: Hamadeh Issam , Shahid Zainab , Bhutani Manisha , Patel Jai Narendra , Steuerwald Nury , Hamilton Alicia , Atrash Shebli , Friend Reed N. , Paul Barry , Voorhees Peter Michael , Usmani Saad Zafar , He Jiaxian 
Published: May 2020

8522 Background: CDI is the primary cause of infectious diarrhea in immunocompromised patients including those undergoing autologous stem cell transplant (SCT). Given the key role of gut microbiome and its interaction with host immune system, we investigated whether polymorphisms in innate immunity genes (identified through Ingenuity Pathway Analysis) were associated with CDI. Methods: We queried our database to identify MM patients who underwent an autologous SCT between April 2015-June 2019. Patients who had their buccal swabs collected through an IRB approved specimen collection protocol were included herein. Data were collected on age, conditioning regimen, CDI diagnosis, time from admission until CDI diagnosis, absolute neutrophil count (ANC) at time of CDI diagnosis, and antibiotic prophylaxis. Genomic DNA was extracted from buccal swabs and genotyped for 62 single nucleotide polymorphisms (SNPs) in ASPH , RLBP1L1, ATP7B, IL-8, FAK, TNFRSF14, CTH, TLR and IL-4. Univariate and multivariate logistic regression analyses were performed to assess association between CDI and presence of SNPs in these genes. Results: A total of 83 patients were identified (25 cases and 58 controls). Baseline characteristics were comparable between two groups. Median age was 67 years (range: 50-79). All patients received high dose melphalan as conditioning, and the same antibiotic prophylaxis during peri-transplant period. Median time from hospitalization until CDI diagnosis was 10 days (IQR:9 days), and median ANC was 0.7/mL (IQR:1.6/mL). Two SNPs (rs2227307 T > G in IL-8 and rs2234167 G > A in TNFRSF14) were significantly associated with CDI risk in both univariate and multivariate logistic regression analyses (Table). Conclusions: Our findings suggest that rs227307G (in IL-8) and rs2234167A (in TNFRSF14) alleles are potential risk factors for CDI after autologous SCT. Our findings, if validated in a larger cohort, would support genetic testing as a screening tool to identify patients who might benefit from prophylaxis against CDI. [Table: see text]
Efficacy and safety of carfilzomib, dexamethasone, daratumumab (KdD) twice-weekly at 56 mg/m2 and once-weekly at 70 mg/m2 in relapsed or refractory multiple myeloma (RRMM): Cross-study comparison of candor and MMY1001.
Authors: Leleu Xavier , Beksac Meral , Chou Takaaki , Dimopoulos Meletios A. , Yoon Sung-Soo , Prince H. Miles , Pour Ludek , Shelekhova Tatiana , Chari Ajai , Khurana Monica , Obreja Mihaela , Qi Ming , Oriol Albert , Siegel David Samuel DiCapua 
Published: May 2020

8526 Background: CANDOR, a randomized phase 3 study, showed significantly improved progression-free survival (PFS) and overall response rate (ORR) for twice-weekly KdD 56 mg/m2(TW KdD56) vs Kd in RRMM, with a 37% risk reduction in disease progression or death (Usmani, 2019). The benefit of once-weekly carfilzomib (K) at 70mg/m2 for the same triplet, KdD (OW KdD70), in RRMM was shown in the nonrandomized MMY1001 study. We performed robust cross-study comparisons to investigate how TW KdD56 compares to OW KdD70. Methods: For alignment of inclusion criteria, the primary analysis set for this cross-study comparison included individual data from CANDOR pts with prior exposure to bortezomib and immunomodulatory drug, and all pts in MMY1001. Propensity score method (Rambaldi, 2019; Kumar, 2019) allowed reliable cross-study comparison, controlling for baseline prespecified covariates such as age, creatinine clearance, performance status, prior treatment exposure/refractoriness, and time from initial diagnosis and relapse. Propensity score adjustment based on inverse probability of treatment weighting (IPTW) was implemented on efficacy endpoints, while safety was evaluated side-by-side. Results: The unadjusted and adjusted propensity score comparison of CANDOR and MMY1001 showed similar efficacy in terms of ORR and PFS in the TW KdD56 and OW KdD70 groups (Table). As propensity score comparisons were for efficacy only, safety comparisons between CANDOR and MMY1001 included differing sample sizes and treatment duration (Table). The safety of KdD56 and KdD70 was consistent with the known safety profiles of individual study treatments. Conclusions: OW KdD70 is an efficacious dosing option with favorable benefit-risk, comparable to TW KdD56. The OW KdD70 dosing option represents a more convenient regimen that might encourage adherence and potentially lead to better outcomes for RRMM pts. Clinical trial information: NCT03158688 . [Table: see text]
Correlation between 24-hour proteinuria and spot urine albumin to creatinine ratio in systemic light chain amyloidosis.
Authors: Visram Alissa , Al Saleh Abdullah S. , Muchtar Eli , McDonald Jennifer , Parmar Harsh V , Vaxman Iuliana , Dispenzieri Angela , Buadi Francis , Gertz Morie A. , Leung Nelson 
Published: May 2020

8549 Background: Proteinuria evaluation is essential for diagnosing and monitoring of renal involvement in light chain (AL) amyloidosis. A 24 hour protein collection (24h UP) is the gold standard for proteinuria assessment however it is cumbersome and can be inaccurate. A spot urine albumin to creatinine ratio (uACR) has been proposed as a convenient method to estimate 24hUP. We aimed to validate the correlation between uACR and 24hUP in a large cohort of patients. Methods: We retrospectively studied systemic AL amyloidosis patients evaluated between 2010 and 2019 at Mayo Clinic, with a uACR and 24hUP collected less than 7 days apart. Linear regression analysis was used to construct a prediction model for 24hUP with uACR as the primary predictor. Possible confounders (age, gender, body mass index, morning versus afternoon spot urine collection, estimated glomerular filtration rate) for the primary relationship between uACR and 24h UP were evaluated in the model. We used receiver operating characteristic (ROC) analysis to identify the best uACR cutoff to predict significant proteinuria (defined as a 24hUP > 500mg). Results: We included 665 patients, with a median age of 66 years (IQR 59-72). The spot urine was collected in the morning (before 1200 hours) in 382 (57%) patients, and in the afternoon in 283 (43%) patients. The median 24hUP was 321 (IQR 129-2512.5) mg, median uACR was 107 (IQR 13.5-1845) mg/g, and median serum creatinine was 1.2 (IQR 1-1.8) mg/dL. The uACR correlated well with 24h UP (Pearson’s r= 0.83, 95% CI 0.80-0.85). Linear regression showed that E (24h UPi) = 362 + 1.05(uACRi), and this model was statistically and clinically significant (p < 0.001 and R2 of 0.68, respectively). Age, gender, body mass index, eGFR, and time of day of spot urine collection did not confound the primary relationship between uACR and 24hUP, and no collinearity was observed. A uACR cutoff of > 280 mg/g was the best predictor of a 24hUP > 500 mg (area under the ROC curve 0.98, sensitivity 92%, specificity 97%). For simplicity, we assessed the predictive value of uACR > 300 mg/g for 24h UP > 500 mg. Among patients with 24huACR > 300 mg/g 264 (96%) had a 24hUP > 500 mg, and 31 (7%) of patients with uACR < 300 mg/g had a 24h UP > 500 mg (p < 0.001). Conclusions: In systemic AL amyloid patients, we showed that uACR on a random urine sample correlated well with 24h UP, and can be used to estimate proteinuria with a linear regression model. Based on these findings, and the convenience of uACR testing for patients, we propose that uACR should be used to monitor renal response to AL amyloidosis therapy.
PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—A PrECOG LLC study.
Authors: Forde Patrick M. , Sun Zhuoxin , Anagnostou Valsamo , Kindler Hedy L. , Purcell William T. , Goulart Bernardo H. L. , Dudek Arkadiusz Z. , Borghaei Hossein , Brahmer Julie R. , Ramalingam Suresh S. 
Published: May 2020

9003 Background: First-line CP was FDA-approved in 2004 for unresectable MPM. Given the role of inflammation in MPM and promising responses to PD-1 pathway blockade in pretreated MPM, we conducted a phase 2 single arm study of the anti-PD-L1 antibody, durvalumab (durva), combined with CP for patients (pts) with untreated MPM of any subtype. Methods: Eligible pts were treatment-naïve with surgically unresectable MPM. Primary endpoint was overall survival (OS); pts received up to 6 cycles of durva-CP, followed by maintenance durva up to 1 year. Carboplatin was permitted for pts with baseline hearing or renal impairment. The first 15 pts were monitored for dose-limiting toxicities (DLTs). Secondary endpoints included toxicity, objective response by modified RECIST, progression-free survival (PFS), and correlative analyses. With a sample size of 55 patients and 32 events, the study had 90% power to detect a 58% improvement in median OS from 12 months (m) (historical control) to 19 m with durva-CP. Results: PrE0505 enrolled 55 patients at 15 US-based sites between 06/2017 and 06/2018. Histologic subtypes were epithelioid (75%), biphasic (11%), sarcomatoid (13%), and desmoplastic (2%). There were no DLTs during the run-in period. As of January 2020 the median follow up is 20.6 m and 29 deaths have occurred. The median OS at the time of report is 21.1 m. The 12 m OS rate was 70% with a 2 sided 95% confidence interval (56%, 81%) and two-sided 80% CI (62%, 78%). Analyses for the secondary endpoints were ongoing at abstract submission. Exome sequencing, TCR sequencing and dual PD-L1/CD8 staining have been completed on baseline tumors from at least 45 of the 55 patients enrolled as well as RNA sequencing for those with adequate tissue. Initial results show that tumors harbored an average tumor mutation burden of 22 somatic sequence alterations and varying levels of aneuploidy were detected. Conclusions: The combination of chemotherapy with durvalumab delivered a promising median OS for previously untreated pts with unresectable MPM. Full results from the study along with the extensive correlative analyses performed will be reported. The phase 3 PrE0506/DREAM3R trial evaluating CP-durvalumab versus CP alone will commence enrollment in the United States and Australia in 2020. Clinical trial information: NCT02899195.