bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-collagen digital proximity signature to indicate prognosis in diffuse large B-cell lymphoma.
Authors: Qaiser Talha , Pugh Matthew , Margielewska Sandra , Hollows Robert , Murray Paul , Rajpoot Nasir 
Published: March 2020

e19073 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous tumor that originates from normal B-cells. Despite the use of combination chemotherapy, around 40% of DLBCL patients die (de Jonge, et al. European Journal of Cancer, 2016). Limited studies have investigated the role of collagen in the acellular tumor microenvironment. In this study, we present a novel digital signature of the proximity of tumor cells and collagen-VI (COL6) that can predict overall survival (OS) in DLBCL patients. To the best of our knowledge, this is the first study of its kind to employ automated image analysis. Methods: The proposed digital proximity signature (DPS) aggregates summary-level statistics from the entire whole slide image (WSI) and serves as a marker of regions, categorizing weak, moderate, significant, and strong tumor-collagen proximity and can be described as a surrogate for signaling. To accomplish this, we developed a novel artificial intelligence (AI) based multi-task model for simultaneous detection and classification of tumor cells and another bespoke method for automatically identifying COL6 fiber. The tumor-collagen proximity analysis was then performed by aggregating tumor cell statistics within the vicinity of COL6 fibres. Finally, the prognostic significance of DPS for OS in DLBCL was investigated with Kaplan-Meier analysis, stratifying patients into two groups based on the median of the DPS values. Results: We took WSIs of DLBCL tissue slides for 32 cases immunohistochemically stained with COL6 and Hematoxylin counterstain. The AI model for tumor cell identification achieved a high F1-score of 0.84, outperforming recent single-task learning models. Our results show that strong proximity of COL6 and tumor cells is linked to better OS in DLBCL patients ( p = 0.03). Conclusions: Our novel digitally computed COL6-tumor proximity signature shows prognostic significance for overall survival on a pilot dataset of 32 DLBCL patients. We are further validating the utility of this novel signature as a prognostic biomarker in larger cohorts of DLBCL patients.
Once-weekly (70 mg/m2) versus twice-weekly (56 mg/m2) dosing of carfilzomib (CFZ) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM).
Authors: Moreau Philippe , Stewart A. Keith , Dimopoulos Meletios A. , Siegel David Samuel DiCapua , Facon Thierry , Berenson James R. , Raje Noopur S. , Berdeja Jesus G. , Orlowski Robert Z. , Yang Hui , Ma Haijun , Klippel Zandra Karina , Zahlten-Kumeli Anita , Mezzi Khalid , Iskander Karim , Mateos Maria-Victoria 
Published: March 2020

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.
Early mortality following diagnosis of multiple myeloma from 2011 to 2016 in Alberta, Canada: Initial results from the population-based Identifying Outcomes in Real-World Multiple Myeloma (INFORMM) study.
Authors: Tay Jason , Chen Guanmin , Cowling Tara , Shaw Eileen , Farris Megan , Liu Fei Fei , Jimenez-Zepeda Victor H. 
Published: March 2020

e19509 Background: The clinical outcomes of patients with newly diagnosed multiple myeloma (NDMM) have improved. However, early mortality (EM) post-diagnosis remains a concern, with incidence ranging from 13% at 2 months to 29% at 1 year after diagnosis. EM can be influenced by patient age, comorbidities, performance status, therapy, and disease biology. Our aim is to examine EM incidence in patients with NDMM and to describe variables that may influence EM in the era of novel chemotherapeutic agents using the INFORMM Study, an ongoing, province-wide real-world evidence study in Alberta, Canada. Methods: Using administrative health data in Alberta (population 4.32 million in 2018), we identified our study population from a validated algorithm of International Classification of Diseases-9 and -10 diagnostic codes. Additionally, the NDMM cohort was confirmed using bone marrow biopsy records, and patients who received therapy for myeloma were derived from the province-wide Pharmaceutical Information Network database. EM was defined as death by any cause within 90 days of diagnosis. Further analyses will be performed to explore potential risk factors associated with EM using regression modeling. Results: We identified 1,729 patients diagnosed with NDMM between 2011 and 2016. EM occurred in 185 patients (10.7%). Of the 185 patients who experienced EM, 156 (84.3%) were aged ≥ 65 years, 174 (94.1%) had a Charlson Comorbidity Index score ≥ 3, and 48 (25.9%) had infectious complications within 90 days of diagnosis. In addition, 99 (53.5%) patients received ≥ 1 anti-myeloma therapy regimen (lenalidomide-based = 5, bortezomib-based = 22, other = 72), whereas 86 (46.5%) did not receive any anti-myeloma therapy. Conclusions: Despite advances in chemotherapeutics and supportive care, patients with NDMM still have a high risk of EM. The higher EM incidence observed in older patients could be attributable to treatment toxicity, comorbidities, or issues surrounding delivery of suitable treatments. Clinicians should consider potential factors associated with EM in their care plan, including in serious illness conversations.
The impact of newly approved drugs on clinical and operational strategies for multiple myeloma clinical trials.
Authors: Krishnan Bhavani , Collins Bernadette , Cho Michael Jeffrey , Partridge Tanya , Vighnay Durga , Given Marie , Enschede Sari Heitner , Bochenska Katarzyna , Hodge Jeff Paul 
Published: March 2020

e19511 Background: The global burden of multiple myeloma (MM) has increased steadily in last 3 decades. The IARC reports there were ~160,000 new cases worldwide in 2018. There has been an increase in the development and approval of more effective targeted therapy options (new immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies); this, coupled with high adoption of these therapies presents a major challenge in enrollment of current ongoing clinical trials. We assessed the impact of near-term regulatory approvals on clinical trial enrollment. Methods: Public domain clinical trial enrollment data from MM studies (Phase I, I/II, II) closed/completed between 2011-2018 were used to determine enrollment trends pre and post 2014. We leveraged real-world medical claims data to project/model adoption of recently approved drugs in the U.S.; additionally, drug sales volume data was used to evaluate ex-US national adoption trends. The utilization rates of 5 recently approved drugs by regimen and line of treatment was determined. Results: In the U.S., there is a 13% increase in median enrollment duration with a corresponding 25% decrease in median p/s/m enrollment in MM studies, irrespective of phase, where enrollment was completed between 2015 -2018 compared to 2011-2014. We hypothesize that one of the factors for this increase in enrollment timeline is the approval and adoption of newly approved therapies post 2014. Two of the five recently approved drugs show a steady increase in the number of patients treated over 2016, 2017 and 2018, while one of the drugs plateaus over the same period. Outside of the U.S., our analysis confirms the existence of gaps in time to approval /adoption of recently approved drugs; for example, we observe a two-year delay in approval/adoption for one of the drugs in France compared to the other countries in Western Europe. Conclusions: There are over 10 investigational MM drugs currently in development which are anticipated to be granted approval between 2019-2021. Factoring the real-world adoption of near-term drug approval into global clinical and operational strategies offers insights into mitigating potential future enrollment challenges.
Treatment sequencing patterns for relapsed refractory multiple myeloma (RRMM) in the era of new therapies in a single center institution.
Authors: Tungesvik Alexandre , Sudalagunta Praneeth Reddy , Huang Jessica , Dimaggio Elizabeth , De Avila Gabe , Tandon Ankita , Nelson Rebecca , Olson Laura , Tobon Katherine , Shain Kenneth H. , Brayer Jason B. 
Published: March 2020

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.
Incidence of serious adverse events in bortezomib, lenalidomide and bortezomib plus lenalidomide maintenance for multiple myeloma: Interim analysis of MMRF-CoMMpass study.
Authors: Vosuri Venkata , Fiala Mark A , Ballard Wenners , Wildes Tanya Marya , Schroeder Mark A. , Vij Ravi , Stockerl-Goldstein Keith 
Published: March 2020

e19516 Background: Autologous stem cell transplantation (ASCT) followed by maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. Maintenance typically consists of lenalidomide (LEN), however, bortezomib (BOR) and bortezomib-lenalidomide combination are other options. The respective toxicity of these regimens has not been well studied. We performed secondary data analysis to compare incidence of serious adverse events associated with each maintenance therapy group during post-ASCT maintenance treatment period. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis from the CoMMpass study. We extracted data of first-time autologous stem cell transplant patients who completed maintenance therapy post-ASCT. We categorized patients into three sub groups bortezomib, lenalidomide or combination (bortezomib and lenalidomide) maintenance therapy. Incidence rate for serious adverse events (grade 3 or higher) was calculated by number of events per 100 person-months for each maintenance therapy. Results: 231 patients were eligible for our analysis. 169 patients received lenalidomide, 27 bortezomib and 35 combination. The most common adverse event was neutropenia and second most common is pneumonia. Neutropenia incidence was 1.1,0.7 and 0.9 per 100 person-months in lenalidomide, bortezomib and combination regimens respectively. Incidence of deep vein thrombosis, GI intolerance and peripheral neuropathy 0.1 per 100 person-months respectively was observed in lenalidomide group only. Combination maintenance had the highest total adverse event incidence rate of 5.4 per 100 person-months. Incidence of 1.7 and 3.8 per 100 person-months is observed in bortezomib and lenalidomide cohorts respectively. Conclusions: Lenalidomide and bortezomib maintenance had similar incidence of serious adverse events. A higher incidence of serious adverse events was noted in the combination lenalidomide/bortezomib regimens. Interestingly, we observed lower incidence of adverse events in all groups in CoMMpass study compared to respective clinical trials involving maintenance regimens. This may be due to under reporting of adverse events in CoMMpass study. The incidence of adverse events mentioned above should be interpreted in the context of drugs and other factors involved in the disease.
Factors associated with over and underuse of response evaluation in elderly myeloma patients.
Authors: Leng Siyang , Lentzsch Suzanne , Chen Yizhen , Bhutani Divaya , Wright Jason Dennis , Accordino Melissa Kate , Hershman Dawn L. , Neugut Alfred I. 
Published: March 2020

e19518 Background: Most patients with multiple myeloma (MM) have detectable monoclonal protein. While guidelines do not specify the frequency of lab testing for response evaluation, most MM clinical trials perform monthly assessment. We examined the use of 4 serologic tests – protein electrophoresis (SPEP), immunofixation (IFE), quantitative immunoglobulins (QIG), and free light chain (FLC) in newly-diagnosed MM patients. Methods: We identified patients age ≥65 with MM (ICD-O 34000) in the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2000-2013. Patients were required to have bone marrow biopsy within 6 months of diagnosis, and taken chemotherapy approved for MM. Use of a test was defined as having ≥1 instance of its CPT code within 12 months of diagnosis. Patients with > 12 instances were defined as overusers. Multiple instances of a test on the same date were counted once. Multivariable logistic regression models using covariates including: age and year at MM diagnosis, race, marital status, Charlson comorbidity, chemotherapy use, number of hospitalizations and oncology office visits within 12 months of diagnosis, were developed to examine associations with overuse. Results: Among 6,214 identified patients, users were: SPEP 5,532 (89%), IFE 4,745 (76%), QIG 5,524 (89%), and FLC 3,864 (62%). The median (interquartile range) times each test was used in the first year following diagnosis were: SPEP 6 (3-10), IFE 3 (2-7), QIG 6 (3-10), FLC 5 (2-9). The numbers of overusers were: SPEP 721 (13%), IFE 265 (6%), QIG 498 (9%), FLC 350 (9%). 231 (4%) patients were overusers of 2 tests. Factors associated with overuse common to all 4 tests were: younger age at diagnosis (eg, SPEP: odds ratio (OR) 2.0 for aged 65-74 vs ≥85; P < .001), more oncology office visits (eg, QIG: OR 2.2 for > 15 vs 0-6; P < .001), and use of combination chemotherapy (eg, SPEP: OR 2.2 for proteasome inhibitor + immunomodulatory drug (IMID) vs those on IMID ; P < .001). Conclusions: In our Medicare population, patients on average underwent response evaluation much less often than monthly, but we also found overuse. Further investigation of the use of these tests is warranted given their central importance to MM care and their cumulative financial cost.
3-weekly daratumumab-IMiD-dexamethasone is highly efficacious and cost-effective in relapsed/refractory multiple myeloma.
Authors: Chim James , Wong Vincent , AU Elaine , Kwong Yok-Lam 
Published: March 2020

e19521 Background: Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2-weekly for 8 doses, and then every 4-weekly thereafter. Given the high cost and the long half-life as an antibody, a 3-weekly dosing of dara was used together with IMiD/dexamethasone. Methods: Dara at 16mg/kg was used every 3-weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression. Results: Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50-84 years) were studied. The median number of previous therapies was 2 (range: 1-5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara-lenalidomide-dex in six (46.2%), and dara-pomalidomide-dex in seven (53.8%). Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3-10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade ¾: 76.9%), infusion reaction (38.5%, all grade ½), neuropathy (38.5%, all grade ½), gastrointestinal (all grades: 38.5%, grade ¾: 7.7%), and sepsis (all grades: 30.8%; grade ¾: 23.1%). Neutropenia was effectively prevented with prophylactic G-CSF. Conclusions: In conclusion , a 3-weekly dara-IMiD-dex regimen is highly efficacious, inducing deep and rapid responses, hence cost-effective for less affluent countries. In view of prevalent grade 3/4 neutropenia despite less frequent dara, 3-weekly dara might be more suitable for Asian patients.
Safety and efficacy of four drug regimens in newly diagnosed multiple myeloma: Systematic review.
Authors: Grewal Udhayvir Singh , Chakraborty Rajshekhar , Raziq Fazal I , Ashraf Afia , Majeed Ammara , Kapoor Vikas , Hubben Anne , Parikh Rujul , Lakhani Midhat , Latif Azka , Russ Atlantis Dawn , Anwer Faiz 
Published: March 2020

e19537 Background: To improve outcomes, multiple agents with varied mechanisms of action targeting different multiple myeloma (MM) clones are needed. Methods: Systematic review of ongoing phase I-III clinical trials in newly diagnosed multiple myeloma (NDMM) was performed, (PRISMA guidelines) using 5 databases. Results: 8 trials n = 1,990 patients included (Table 1). We evaluated the efficacy of following four drug combinations Isatuximab (Isa), bortezomib (V), lenalidomide (R)dexamethasone (d) (Isa-VRd) Daratumumab (Dara) plus V, Melphalan (M) and Prednisone (P) (Dara-VMP) vs VMP Dara-VRd vs VRd Carfilzomib (K), Cyclophosphamide (C), R, Dexamethasone (KCRD) vs an immunomodulatory agent containing triplet (CTD/CRD) Dara with Ixazomib (I), R,d (Dara- IRd) Dara, Cyclophosphamide (Cy), V,d (Dara-CyBord) Elotuzumab (Elo) VRd Dara with K,R,d (Dara- KRd) For transplant-eligible patients, Dara-VRd demonstrated the best treatment response (VGPR = 100%, CR rate = 63% and 15 months PFS = 94%). Dara-VMP (ORR = 90.9%,VGPR+ = 72.9%, mPFS at 27. 8 m = NR) and Isa+VRd (ORR = 93%, VGPR = 71.43%, 7.5 m PFS = 100%) were associated with improvement in OR in transplant ineligible patients. Dara-KRd showed excellent efficacy (ORR = 100%, ≥VGPR = 86%) with 100% 6 m PFS. Conclusions: Four-drug regimens have improved efficacy (higher ORR, deeper response, higher proportion of MRD negativity and higher ≥VGPR responses) compared to three-drug regimens in NDMM, with a comparable incidence of toxicities. Longer follow-up is needed. [Table: see text]