bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testing Mayo Clinic’s new 20/20/20 risk stratification model in another cohort of smoldering myeloma patients: A retrospective study.
Authors: Tessier Camille , Allard Thomas , Boudreault Jean-Samuel , Kaedbey Rayan , Fortin Flechere , Ethier Vincent , Pavic Michel 
Published: June 2021

e20005 Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder associated with a high risk of transformation to symptomatic multiple myeloma (MM). SMM risk of progression to MM is highly heterogeneous and several models have been suggested to predict this risk, but none have yet been adopted internationally. Lakshman et al. recently proposed a risk stratification model based on three markers: bone marrow plasma cell (BMPC) percentage > 20%, free light chain ratio (FLCr) > 20 and serum M protein > 20 g/L. In this “20/20/20” model, patients with 0, 1 or ≥ 2 risk factors are respectively considered at low, intermediate and high-risk of progression. The goal of our study was to test this risk model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Methods: We conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Patients were identified by query of the electronic medical records and the 2014 International Myeloma Working Group (IMWG) diagnostic criteria for SMM were used to determine eligibility. The main endpoint was progression to symptomatic multiple myeloma or amyloidosis. Results: All three markers proposed by Lakshman et al. were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95% C.I., 1.90 – 9.61]; p < 0.001), serum M protein ≥ 20g/L (HR: 4.20 [95% C.I., 1.90 – 15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95% C.I., 1.09 – 9.71]; p = 0.035). Immunoparesis (HR: 2.61 [95% C.I., 1.07 – 6.41]; p = 0.036) was also an independent risk factor in our population. The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95% C.I., 3.9 – 54.4) in the high-risk group (p = 0.006). The estimated mean TTP for the low-risk group, the intermediate-risk group and the high-risk group were respectively 78.4 months (95% C.I., 68.3 – 88.5), 48.3 months (95% C.I., 31.9 – 64.8) and 35.2 months (95% C.I., 19.1 – 51.2). Sex, IgA isotype, positive Bence-Jones, abnormal β2-microglobulin and MGUS prior to SMM did not result in an increased risk of progression. The estimated proportion of progression-free patients at 1, 2 and 5 years were 96.8%, 93.4% and 77.5% for the low-risk group, 80.0%, 80.0% and 62.2% for the intermediate risk group and 70.0%, 58.3% and 29.2% for the high-risk group. Conclusions: When Mayo Clinic’s new 20/20/20 risk model was applied to our population, it adequately predicted the risk of progression to symptomatic disease at 2 years. As it relies on readily available biological parameters, this model is easy to use and can be applied in most clinical settings. We believe this model could be used to further study therapeutic approaches in higher risk SMM.
Correlation of Agent Orange exposure, cytogenetics, and clinical outcomes in multiple myeloma and MGUS.
Authors: Kulkarni Pruthali , Copeland Laurel , Hall James Andy , Dodlapati Jyothi 
Published: June 2021

e20008 Background: Multiple myeloma (MM) accounts for 1-2% of cancers worldwide. MM and monoclonal gammopathy of unknown significance (MGUS) are associated with Agent Orange exposure (AO) in Vietnam war veterans. Studies show poor outcomes in AO-exposed patients developing MM. No study has evaluated AO exposure and adverse cytogenetics in patients with MM. Methods: We reviewed patients with MGUS and/or MM in the Central Texas Veterans Health Administration system in 2010-2015 to evaluate AO exposure, adverse cytogenetics, transformation from MM to MGUS, and overall survival (OS). Inclusion criteria were active-duty military when AO was used (1961-1971). Presence of 17p13, t(4;14), t(14;16), t(14;20), or Gain 1q by FISH defined high-risk cytogenetics. Poor prognosis per serum free kappa/lambda ratio was defined as < .03 or > 32 K/L (high-risk). Regulatory review approval was obtained. Cox survival models generated hazard rate ratios and their 95% confidence intervals (HR) for AO status (AO, non-AO, undetermined), age, race/ethnicity, transformation, and FISH data. Results: Among 129 veterans, 30% were Black and 12% Hispanic (mean age 74.0 years, SD 6.9, range 59-97). MGUS was diagnosed in 44%, MM 74%, and transformation 19%. FISH abnormalities were rare thus AO association cannot be definitively stated; see table. A subsample with known AO and K/L (n = 81) showed no association: 69% high-risk had AO vs 76% moderate-risk; chi2 = 0.54; p = .46. In the adjusted model, Hispanic patients (HR = 3.3; 1.2-9.1) and those with high-risk cytogenetics (HR = 6.0; 1.1-34.1) had higher mortality; AO was unrelated. Conclusions: Although preliminary analyses find no associations of AO and transformation with OS, ethnicity and FISH abnormality associations are intriguing. Chart review is 50% complete. The paucity of cytogenetics data begs further examination, and continued study is merited to fully recognize what predisposes MM development following AO exposure.[Table: see text]
Frailty in relapsed/ refractory multiple myeloma registration trials.
Authors: Murugappan Meena N. , King-Kallimanis Bellinda , Kanapuru Bindu , Chen Ting-Yu , Bhatnagar Vishal , Kluetz Paul Gustav 
Published: June 2021

e20017 Background: Multiple Myeloma (MM) is predominantly a disease of older adults with a median age of onset at 70 years. There is growing interest in using criterion other than chronological age, like frailty, to determine fitness for treatment and ultimately improve clinical outcomes in MM. Frailty is the accumulation of aging-associated diseases and disabilities, making patients more vulnerable to adverse outcomes when exposed to stressors like anti-cancer treatment. MM frailty measures have primarily been developed and tested in newly diagnosed patients. MM patients typically relapse, but there is limited knowledge regarding the prevalence of frailty in the relapsed/refractory (RRMM) setting. The aim of this research was to determine the prevalence of frailty in RRMM commercial clinical trials, at the time of trial enrollment, using the International Myeloma Working Group (IMWG) Frailty Index. Methods: We pooled baseline data from 6 RRMM clinical trials submitted for FDA regulatory review between 2010 and 2020. The IMWG Frailty Index was calculated for each patient based on 4 variables: age (≤75, 75–80, >80 years, score 0, 1, 2, respectively), Charlson Comorbidity Index (CCI; ≤1 or ≥2, score 0 or 1), and (Instrumental) Activities Daily Living (ADL >4 or ≤4, score 0 or 1; IADL >5 or ≤5, score 0 or 1). As ADLs and IADLs are not routinely collected in clinical trials, we substituted this information with corresponding EQ-5D items on self-care and usual activities. Fit, Intermediate-fit, and Frail patients received IMWG scores of 0, 1, and ≥2 respectively. Descriptive statistics for frailty were summarized by age. Results: 2766 RRMM patients were aggregated from six clinical trials. 1502 (54%) patients were Fit, 780 (28%) were Intermediate-fit, and 484 (18%) were Frail. The median age of patients across trials was 65 [range 30-91]. The median CCI was 0 [range 0-7] out of 37. IMWG frailty scores have been presented by age category in Table. Prevalence of frailty at baseline by age in RRMM registration trials. Conclusions: Most patients in RRMM registration trials were classified as Fit at baseline, using the IMWG Frailty Index. This was expected due to stringent trial enrollment criteria which exclude patients with severe comorbidities, as reflected in the low average CCI. The IMWG index heavily weights patient age. As such, there were no Fit patients in the 75 – 80 year old cohort and only Frail patients in the 80+ year old cohort. This is despite the fact that these older patients met stringent trial enrollment criteria and had CCI scores < 7. Chronologic age alone should not be used as an absolute exclusion for treatment, whether in the trial or real-world setting. Future research into frailty indices that do not heavily weight age is warranted.[Table: see text]
Role of adjunct plasma exchange or high cut-off hemodialysis in the management of myeloma cast nephropathy: A systematic review.
Authors: Hanif Nazma , Sana Muhammad Khawar , Abdelazeem Basel , Rafae Abdul , Mushtaq Muhammad Umair , Anwer Faiz 
Published: June 2021

e20032 Background: Renal impairment by cast nephropathy is a common complication in multiple myeloma. Tubulointerstitial injury results from precipitation of filtered free light chains (FLC) with Uromodulin in the distal convoluted tubules. Rapid reduction in serum FLC levels has shown to improve renal function in modeling studies. Extracorporeal light chain removal techniques such as plasma exchange (PEX) and high cut-off hemodialysis (HCO-HD) have been explored as potential adjunct treatment options for cast nephropathy in various clinical trials. Methods: PubMed, Cochrane library, and Clinicaltrials.gov were searched systematically for the use of plasma exchange and/or hemodialysis with chemotherapy in the treatment of myeloma cast nephropathy using their MeSH words and keywords. PRISMA guidelines were followed for screening and 5 out of 866 studies were finalized (N = 342). Results: Zucchelli et al. 1988 (n = 29) reported a dramatic reduction in Bence Jones protein (BJP) levels of 0.81 ± 0.46 g/day (P value < 0.01) and 1-year survival rate of 66% in the PEX group and decrease in BJP of 3.25 +/- 0.21 g/day (P-value < 0.05) with a survival rate of 28% in the control group. Clark et al. 2005 (n = 104) reported a primary composite response (patient alive at 6 months + dialysis independence + serum creatinine improvement of 50% at 6 months) in 57.9% of patients in the PEX group and 69.2% in the control group [95% CI, -8.3% to 29.1%]; P = 0.36. Johnson et al. 1990 (n = 21) reported a mean change of 880 μmol /L ± 260(SD) in serum creatinine in the PEX group and 570 μmol /L +/-240 in the control group. HD independence at 3 months was reported as 41.3% (n = 19) in the HCO-HD group and 33.3% (n = 16) in the conventional HD group (95% CI -12%–27.9%; P = 0.42) in the MYRE trial 2017 (n = 98). The EuLITE trial 2019 (n = 90) compared the efficacy of the high cut-off vs high flux hemodialysis (HF-HD) technique and concluded that there was no clinical benefit of one over the other. Independence from HD was achieved in 56% (n = 24) in the HCO-HD cohort vs 51% (n = 24) in HF-HD cohort (relative risk [RR] 1.09, 95% CI 0.74–1.61; P = 0.81). Conclusions: The use of high cut-off hemodialysis and plasma exchange as adjunct therapy did not show any significant survival benefit or improvement in clinical outcome. The role of routine use of PEX/HCO-HD in the management of cast nephropathy is still unclear and the decision to use these modalities should be made on an individual basis.
Continuous genomic monitoring of multiple myeloma patients to identify patients of high risk for poor prognosis.
Authors: Liu Yu , Yu Haocheng , Lagana Alessandro , Parekh Samir , Schadt Eric , Wang Li , Zhu Jun 
Published: June 2021

e20035 Background: Multiple myeloma (MM) is heterogeneous from symptoms, mechanisms of tumorigenesis and progression, to the treatment outcome. Besides age and tumor stage, prognostic models based on the genomic or transcriptomic profiles were developed to stratify patients into risk groups at diagnosis. Even though mutation burden at diagnosis is not associated with overall survival (OS), its change during the course of treatment, which might reflect the emergence of treatment resistant subclones, could provide insights about the MM evolution and hence associate with patient outcome. Methods: In this study, we developed a new parameter referred to as “tumor evolution rate” and investigated its association withclinical outcomes. The tumor evolution rate was measured as the rate of acquiring new somatic mutations among the sequential samples from the same patients. We utilized genomic data generated on 140 MM patients with two sequential samples from the MMRF CoMMpass database. The prognostic power of evolution rate was compared with other clinical parameters as well as gene expression-based markers. Results: There was significant heterogeneity in the evolution rate among MM patients (median, 0.114; 0.011 – 2.34 new mutations per day). The evolution rate was significantly associated with OS in a univariate Cox regression model (Wald test p = 5.0×10-7). When stratified into high, intermediate and low-rate groups, they had a median OS of 316, 743 and 998 days after the collection date of 2nd samples, respectively (logrank test p = 1.0×10-6). With age and ISS stage as covariates in the multivariate Cox regression model, the evolution rate remained significantly associated with OS (p = 6.3×10-6). The mutation burden itself at either sampling time was not associated with OS. For patients with two sequential samples collected less than 2 years apart (N =82), the evolution rate was significantly associated with OS (Wald test p = 2.0×10-6). However, for patients with two sequential samples collected more than 2 years apart, the evolution rate was not significantly associated with OS anymore, likely due to the inaccurate evolution rate estimates over long intervals. In addition, the patient stratified by the evolution rate shared some similarity with those stratified via a gene expression-based prognostic model (previously developed by us). The majority of patients in the low or intermediate risk group based on gene expression were in the low or intermediate evolution rate group. For patients with a high-risk prognosis (n = 21), 57% (12 out of 21) had tumors with a high evolution rate during treatment, suggesting alternative treatment options may be needed for this group of patients. Conclusions: Our study demonstrated that the tumor evolution rate as derived from continuous monitoring of tumor genomic changes provided extra prognostic information for identifying MM patients of poor prognosis after drug treatment.
Clinical presentation and outcome of patients with AL amyloidosis requiring salvage therapy.
Authors: Wang Chen , Zhang Yumeng , Duncanson Lauren , Brayer Jason B. , Hansen Doris K. , Alsina Melissa , Nishihori Taiga , Liu Hien , Ochoa-Bayona Jose L. , Shain Kenneth H. , Reu Frederic J. , Baz Rachid C. , Blue Brandon Jamaal 
Published: June 2021

e20043 Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]
Deep learning survival model on transcriptomes level in patients with non-small cell lung cancer.
Authors: Yu Hao , Yang Li , Lam Ka-On , Jin Jian-Yue , Hu Chen , Kong Feng-Ming Spring 
Published: June 2021

e20518 Background: Non-small cell lung cancer (NSCLC) is associated with poor prognosis. Global gene expression profiling with overall survival (OS) may help improving individualize survival. In this study, we identify biological important gene clusters and studied their prognostic abilities for OS by deep learning method. Methods: Using GEO genomics data repository, we identified 196 NSCLC patients (trainset: GSE37745) and 181 NSCLC patients (testset: GSE50081) with clinical information and long-term follow-up. In both cohorts, expression profiling was performed on RNA from tumor tissues using Affymetrix microarrays HG-U133-Plus2; and normalized using the Robust Multiarray Averaging (RMA). We established deep learning survival models through neural network extension of the Cox regression model for predicting OS, which were developed by 5-folds cross-validation in GSE37745 and independently validated in GSE50081. Significant RNA-seq and clinical variables were multiple inputs. Concordance index (CI) was evaluated and compared with multivariable Cox regression. Then we conducted Uniform Manifold Approximation and Projection (UMAP) using weights in hidden layer of the model for clustering the important RNA-seq and then performed enrichment analysis though GO/KEGG for revealing biological progresses. Results: Total 1039 RNA-seq levels were found significant with OS ( P < 0.05) by Cox proportional hazard model adjusted by clinical variables (age, gender, cancer stage, histology) in trainset. The deep learning survival model with 20 most significant RNA-seq and clinical variables had best average performances as CI = 0.74±0.04 in trainset (GSE37745) and CI = 0.68±0.06 in testset (GSE50081) in 10 iterations, better than multivariable Cox regression ( P < 0.05). The deep learning survival model with all significant RNA-seq were also established and the weights in the hidden layer were clustered by UMAP into 5 positive and 5 negative clusters. The clusters were enriched, such as in positive clusters, negative regulation of RNA metabolic process, negative regulation of RNA biosynthetic process and positive regulation of protein modification process were top three significant biological processes for shorten survival; while in negative clusters, DNA metabolic process, positive regulation of phosphate metabolic process and positive regulation of RNA metabolic process were the top three for prolonged survival. Conclusions: In this study, the deep learning survival algorithm was established for survival prediction based on a transcriptome level in patients with NSCLC. Given the models’ robustness and better performances, our study would be useful at predicting and applying more biological information for survival.
Surgery versus radiation therapy outcomes in patients with clinical stage 0 non-small cell lung cancer.
Authors: Narayana Swapna , Kovacs Attila J. , Borgert Andrew J. , McGee Matthew , Frankki Susan M. , Marinier David E. 
Published: June 2021

e20537 Background: There are currently no clear national guidelines for management of in-situ (stage 0) non-small cell lung cancer (NSCLC). With no prospective clinical trial data, treatment strategies include both surgical resection and definitive radiation therapy (RT). We aimed to investigate survival outcomes in patients with stage 0 NSCLC who underwent surgery or RT. We also aimed to identify any differences in the treatments that the two groups received with respect to rural versus urban setting and racial variation. Methods: The 2016 National Cancer Data Base was reviewed from 2006-2015 for patients registered with a pathological diagnosis of Stage 0 NSCLC, based on the AJCC 7th edition classification for lung cancer. Patients with a prior history of malignancy, secondary malignancy other than lung, and contraindications to surgery were excluded. Univariate comparison and multivariate logistic regression modeling were utilized to identify factors associated with receipt of surgery. Patients were stratified into two groups, surgical resection and RT. Kaplan-Meier estimators and Cox proportional-hazards regression were used to compare overall survival(OS). Propensity score matching was performed using relevant demographic and clinical factors associated with receipt of surgery. All analysis was completed in SAS version 9.4 and p-values less than 0.05 were considered significant. Results: A total of 156 patients were identified with Stage 0 NSCLC who received surgery (n = 104) or RT (n = 52). Surgery was defined as lobectomy or less. Histologic subtypes were squamous cell carcinoma (54%), adenocarcinoma (45%), and bronchioloalveolar carcinoma (1%). Median age was 65 years for the surgical resection cohort and 70 years for the RT cohort. From diagnosis, median time to surgery was 21 days for the surgical resection cohort and 47 days to start of radiation for RT cohort. We did not identify any major differences with respect to rural versus urban setting or racial differences within the surgery and RT cohorts. Patients who underwent surgical resection had a superior 5 year overall survival 65% (CI, 43.49-80.56) when compared to patients who underwent RT 37% (CI, 10.63-65.05), hazard rate 0.403, p = 0.0009, 95% CI. 0.236 – 0.689). Conclusions: Our findings show a significant improved survival with surgical resection compared to RT in patients diagnosed with Stage 0 NSCLC.