bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparities in utilization of autologous stem cell transplantation as consolidative therapy for multiple myeloma: A single-institution retrospective review.
Authors: Lupak Oleksandra , Han Xiaoxia , Patil Neha , Thanikachalam Kannan , Xie Peter , Jabbour Hiba , Al Saheli Zaid , Malapati Sindhu Janarthanam , Farhan Shatha Younis-Mustafa , Emole Josephine
Published: May 2020

e20504

Background: Multiple Myeloma (MM) accounts for about 17% of hematologic malignancies in the United States. It is a disease of older adults, with a median age at diagnosis of 66 years. The incidence in African Americans is 2 to 3 times more that in Whites, and this disparity has been found to be greater among patients less than 50 years. Most guidelines recommend induction therapy with a triplet regimen followed by autologous hematopoietic cell transplantation (HCT). Unfortunately, racial and ethnic minorities have been found to be less likely to receive ASCT. A SEER-Medicare database analysis from 2000 to 2011 noted a lower utilization of ASCT and Bortezomib among black patients. The goal of this study was to evaluate patterns of acceptance of ASCT as consolidative therapy of MM. Because the receipt of upfront ASCT is dependent on response to induction therapy, our study also investigated disparity in transplant outcomes and time to transplant, which are areas that previous studies had not looked at. Methods: In this retrospective review we used Cox PH model to investigate the association between the survival time of the patients (OS) and age of the diagnosis, race, socioeconomic status, disease cytogenetic, and initial induction regimens. 194 patients with a confirmed diagnosis of MM who were referred for autologous hematopoietic stem cell transplantation (ASCT) between January 1st 2009 and June 30st 2019 were included in this study. Patients who received ASCT for relapsed MM were excluded. Results: Using Cox PH model, we found that high risk cytogenetic were significantly associated with shorter overall survival, higher transplant related mortality and relapse related mortality (P < 0.002). Use of aggressive induction choices was associated with poorer transplant outcomes (P 0.02). Time to transplant tended to be shorter in African American compared to other ethnic groups (P 0.07). Income category was not significantly associated with overall survival, time to transplant or transplant / relapse related mortality. Conclusions: Cytogenetic continues to be a significant factor in transplant outcomes affecting overall survival. Time to transplant tended to be shorter in African American comparing to others, potentially reflecting the differences in disease course. Our study provides a more real life data on ASCT outcome patterns. It is hoped that the results of this study will better guide interventions to improve utilization of ASCT as consolidative therapy for MM.
Predictors of response to upfront bortezomib, lenalidomide and dexamethasone (VRd) in multiple myeloma.
Authors: Keruakous Amany , Day Silas , Borogovac Azra , Holter Jennifer L. , Asch Adam Steven , Yuen Carrie
Published: May 2020

e20507

Background: Achievement of response to less than very good partial response (VGPR) after initial induction is an adverse prognostic factor for progression free survival (PFS) in multiple myeloma (MM). Triplet regimen has been demonstrated to be more effective as compared to doublets, with VRd being the preferred induction regimen in newly diagnosed multiple myeloma (NDMM) based on SWOG077 (43.5% VGPR or better). However, recent studies using quadruple combination, daratumumab-VRd, has shown deep response with 63% reached stringent complete remission (sCR) and CR. Balancing efficacy and toxicity in selecting induction regimen in treatment of MM is a challenge due to advanced age and comorbidity. Biomarkers that guided selection based on prediction for efficacy would be clinically useful. In this study we hypothesized that there is a subgroup of patients with MM that would not benefit from upfront VRd could be identified by biologic factors. Methods: For this retrospective study, we selected a cohort of patients with NDMM who were treated with upfront VRd to be evaluated for response after 3-6 cycles of treatment. We identified variables of risk classification that included cytogenetics, ISS stage, immunoglobulin subtype, light chain restriction, pre-treatment albumin level, bone marrow disease burden, end-organ involvement (hypercalcemia, anemia, renal insufficiency and lytic bone lesions), and presence of extra medullary disease. We analyzed the correlation between variables and response to therapy using Chi Square (Fisher’s Exact) test. Results: Among 175 patients treated in our institution starting April 2011 through May 2018, 120 patients received bortezomib-based regimen with 80% (96 subjects) received VRd and 20% (24 subjects) received Vd, with median age of 60.5 (39-74). After 3-6 cycles of VRd, 50% of patients achieved VGPR or better (48/96), 43% achieved partial response (PR) (43/96), 5% did not respond (5/96). Our data showed that immunoglobulin subtype has statistical significant impact on response to VRd; with increased incidence of VGPR or better in IgA myeloma (79%) as compared to IgG myeloma (37%) (P-Value < 0.0006). In IgG myeloma, we showed increased proportion of patients with PR (56%). Additionally, all 5 patients who did not respond to VRd had IgG myeloma. Other variables did not show statistically significant impact to response to upfront VRd. Conclusions: We conclude that IgG subtype MM predicts suboptimal response with VRd. Thus other regimens or four-drug regimen should be considered for upfront therapy in IgG subtype of MM.
Outcomes of daratumumab, pomalidomide, and dexamethasone (DPd) followed by high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) in patients with relapsed/refractory myeloma RRMM.
Authors: Abdallah Al-Ola A. , Dias Ajoy , Kawsar Hameem I , Mohyuddin Ghulam Rehman , Sigle Monia , Mahmoudjafari Zahra , Shune Leyla Osman , McGuirk Joseph , Ganguly Siddhartha
Published: May 2020

e20508

Background: The number of therapeutic options for patients with RRMM has increased significantly. Our institute treated a series of patients with induction therapy consisting of DPd followed by HDCT/ASCT. We present the early outcomes of these patients. Methods: We treated 16 patients with RRMM at the University of Kansas Health System between May 2016 and October 2019, with DPd as induction therapy followed by HDCT/ASCT. DPd was administered as Daratumumab 16 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks; pomalidomide was dosed at 4 mg orally on days 1-21 of a 28-day cycle; and dexamethasone 20 or 40 mg weekly. Responses were evaluated using the 2016 International Myeloma Working Group (IMWG) criteria. Results: Patients had received a median of two prior regimens. Out of the 16 patients: 81% received ASCT prior to this treatment. In addition, 75%,81% and 68% were refractory to proteasome inhibitors (PI), immunomodulatory agents (IMiDs), and double refractory to IMiDs and PI, respectively. Median time from diagnosis to treatment was 12 months. Median number of DPd cycles received was 4 cycles. A median follow-up of 27 (9-39) months, the overall response rate (ORR) after induction treatment with DPd was 100%. ORR on day 100 post ASCT was 100%, 65% achieved ≥CR, and 81% achieved ≥VGPR. There was no treatment related mortality on day 100. Median progression free survival was 34 months (95%, CI = NA), median overall survival was not reached. The most common grade ≥ 3 adverse events were thrombocytopenia 53%, anemia 40%, neutropenia 53%. Conclusions: DPd as induction therapy followed by HDCT/ASCT demonstrated deep, durable, and clinically meaningful responses with manageable safety profile in patients with RRMM. [Table: see text]
ISS stage and network risk score to predict benefits of multiple myeloma treatment options.
Authors: Liu Yu , Wang Li , Yu Haocheng , Parekh Samir S. , Schadt Eric , Zhu Jun
Published: May 2020

e20511

Background: Multiple myeloma (MM) is molecularly heterogeneous with many treatment regimens developed targeting different aspects of the disease. Multi-omics studies are now widely available, facilitating a precision medicine approach for personalized MM treatments. However, data from these studies vary with respect to treatment regimens, patient age, disease stage, and genomic alterations, thus complicating identification of treatment effects. Methods: From a Multiple Myeloma Molecular Causal Network (M3CN) model we previously described, we identified a prognostic subnetwork (prognNET) associated with survivals of newly diagnosed MM (NDMM) patients. We derived a network risk score (NRS) for each patient by inferring their molecular state with respect to prognNET, and partitioned patients into NRS low, medium, and high groups (referred as NRSL/M/H). We validated NRSL/M/H to be significantly associated with progression free survival (PFS) and overall survival (OS) in single variate and multi-variate Cox regression models including age and ISS stage in TT2,3,4 and HOVON studies. Results: To determine the impact of NRS in an independent contemporary dataset, we examined NDMM patients with RNAseq data in the MMRF-CoMMpass study. Among young patients (age < 65), ones with combined therapies (CoTs) as the first line therapy (n = 363) had better survival than ones on proteasome inhibitors (PIs) (n = 93) (p = 0.027 and 0.002 for PFS and OS). When stratified by ISS stage and NRS, there was no significant difference between CoTs and PIs except that in the stage I-NRSL group, patients on PIs had better PFS than ones on CoTs (p = 0.016). This suggests that NRS may be able to discriminate ISS stage I patients that do not need CoT. Similarly, we studied the ability of NRS to discriminate patients that benefit from autologous stem cell transplant (ASCT). In a model combining age, ISS stage, NSR, and induction treatment, ASCT was associated with better survival. When stratified young patients on CoTs by ISS stage and NRS, only the stage II-NRSM and stage III-NRSM patients benefited from ASCT in term of PFS (p = 0.01 and 0.005) and OS (p = 0.004 and 0.04). Conclusions: Stage and NRS group should be considered in personalizing treatment options for NDMM patients.
Cytogenetic abnormalities in MM: Association with disease characteristics and treatment response.
Authors: Abdallah Nadine , Buadi Francis , Greipp Patricia T. , Gertz Morie A. , Kapoor Prashant , Dispenzieri Angela , Baughn Linda , Lacy Martha , Hayman Suzanne R. , Dingli David , Go Ronald S. , Hobbs Miriam A. , Lin Yi , Kourelis Taxiarchis , Siddiqui Mustaqeem Ahmad , Kyle Robert A. , Ketterling Rhett P. , Rajkumar S. Vincent , Bergsagel Leif P. , Kumar Shaji
Published: May 2020

e20520

Background: Cytogenetic abnormalities detected by FISH are found in the majority of multiple myeloma (MM) patients. Although their prognostic value has been studied extensively, less is known about their association with disease characteristics and treatment response. Methods: To address these questions, we designed a retrospective study including 2031 Mayo Clinic patients diagnosed with MM from 2004 to 2018. We compared baseline characteristics and treatment outcomes between primary cytogenetic groups: t(11;14), t(4;14), t(14;16), (14;20), t(6;14), unknown IgH translocation/del and trisomy (without IgH translocation). These included 373, 177, 78, 20, 18, 228 and 791 patients respectively. Kruskal-Wallis and Fisher’s exact tests were used for categorical and continuous variables respectively. Time to next treatment (TTNT) was estimated using Kaplan-Meier method and compared using Log-Rank test. Results: t(4;14), t(14;16), t(6;14) and t(14;20) groups were associated with hemoglobin < 10 g/dL, beta2microglobulin > 5.5 µg/ml, ISS stage 3 and ≥50% bone marrow plasma cells. The latter 3 groups were also associated with renal dysfunction (Cr ≥2 mg/dL) and higher urinary monoclonal protein. t(4;14) was associated with IgA isotype, serum monoclonal protein ≥1g/dL and plasma cell labeling index ≥1%. Light chain myeloma was more prevalent in patients with t(11;14). Overall response rate (ORR) to proteasome inhibitor (PI) induction was higher for those with IgH translocations (any) compared to trisomies (85% vs 77% P = 0.02), while ORR was higher for those with trisomies with immunomodulatory drug (IMiD) induction (90% vs 78% P < 0.01). The rate of ≥ very good partial response was higher for patients with high risk IgH translocations [t(4;14), t(14;16) or t(14;20)] compared to standard risk with PI-IMiD combination treatment (88% vs 65% P < 0.01). Otherwise, response rates did not differ between these 2 groups. TTNT was longer in patients with trisomies compared to those with IgH translocation with IMiD or PI-IMiD treatments (32.2 vs 19 and 44 vs 27.4 months, respectively P < 0.01). For all cytogenetic groups, better treatment responses and longer TTNT were seen with PI-IMiD combinations compared to other treatments. Conclusions: t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high risk disease characteristics. Patients with IgH translocations may have better response to PI induction compared to those with trisomies, while those with trisomies may have better response to IMiD treatment, with best outcomes for both seen with PI-IMiD combinations.
Assessing the relationship in relapsed-refractory multiple myeloma between response, progression, and survival between pooled clinical trial subjects and a real-world electronic medical record data source.
Authors: Watson Mark Layton , Hurmiz Charlie , Smith Jordan , Marada Suresh , Galaznik Aaron , Diamond Sheila , Fields Bryant , Davi Ruthanna
Published: May 2020

e20525

Background: Despite new treatments, Relapsed-Refractory Multiple Myeloma (RRMM) remains an incurable disease1. In a recent study by Moreau et al, there was a demonstrated survival benefit to treatment with pomalidomide in RRMM patients2. To better understand how the relationships between initial depth of response and long-term prognosis can inform clinical decision making and guide new compound development, we performed an analysis of standardized clinical trial patient pool data compared with Real-World Data (RWD), across multiple studies. Methods: Pooled clinical trial data was obtained from a Study Data Tabulation Model (SDTM) dataset (n=1,815) from the Medidata Enterprise Data Store. De-identified Oncology EMR data was sourced from the Guardian Research Network™ (GRN)5 of integrated delivery systems from 2010-2018, with robust clinical endpoint extraction and curation to enable outcomes comparisons (n=962). Subject selection was refined based on the inclusion/exclusion criteria from the NIMBUS trial2. Response, Progression-free survival (PFS), and Overall Survival (OS) were extracted. Patients were stratified by age, gender, and prior regimens. Log-rank tests were conducted to compare PFS and OS in patient sub-populations at 90, 180, and 240 days from most recent treatment start. Cox proportional hazard models assessed predictors of survival. Rates were estimated for common adverse events, including leukopenia, neutropenia, and thrombocytopenia. Factors associated with neutropenia were assessed using logistic regression. Results: Within pooled trial and RWD patients, the majority were on regimens with proteasome inhibitors, followed by immunomodulators, and approximately one third on monoclonal antibodies. Within the pooled trial analysis, survival rates were consistent with published literature rates, at ~4 months and ~12 months, respectively. EMR data analysis showed overall longer times to progression with an increased depth of response, with similar associations. Frequency-Factored Time-to-Progression also decreased. Conclusions: The use of SDTM for pooled clinical trial analyses, together with real-world data, can overcome individual trial sample size limitations and biases. Together this approach can expand the range of populations, relative treatment comparisons, and clinical events that can be studied to more comprehensively understand the complexity of the oncology treatment landscape.
Daratumumab (Dara) and hyperfractionated cyclophosphamide (HyperCy)/dexamethasone (Dex) with and without carfilzomib (Car) for the treatment of relapsed/refractory multiple myeloma (RRMM).
Authors: Shank Brandon R. , Primeaux Brian , Horowitz Sandra B. , Yeung Erin K. , Lee Irene Y. , Kaufman Gregory Peter , Lee Hans Chulhee , Manasanch Elisabet Esteve , Patel Krina K. , Orlowski Robert Z. , Weber Donna M. , Thomas Sheeba K.
Published: May 2020

e20528

Background: RRMM can be associated with high disease burden and/or end organ damage requiring rapid disease control. Our group has previously published data with hyperCy-bortezomib (bor)-doxorubicin-dex (Tabchi et al. 2019) for such patients (pts). Dara, a monoclonal antibody targeting CD38, has limited overlapping toxicities with cytotoxic chemotherapy, making it an attractive partner for hyperCy-dex. We report our retrospective experience of pts treated with dara-hyperCy-dex ± car. Methods: Between 5/2016-8/2019, 53 pts were treated with dara (16 mg/kg IV d1,8,15,22)-hyperCy (300-350 mg/m2 IV q12h x 6-8 doses d1-3/4)-dex (20-40 mg IV/PO d1-4, 8-11, 15-18, 22-23) alone (27 records), or with car (20 mg/m2 IV d1-2, 27-36 mg/m2 IV d8-9, 15-16) (32 records) on 28 day cycles. Pts received growth factor, anti-fungal, anti-bacterial, anti-viral, and peptic ulcer prophylaxis. High-risk MM (HRMM) was defined by t(4;14), t(14;16), and/or del 17p. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Each instance of treatment (tx) started > 60 days from the previous cycle start date was counted as a separate record. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were assessed per pt, based on earliest administration date. Results: Median age of pts was 61 (26-77) years. Median number of prior therapies was 4 (1-18). Previous exposure to both lenalidomide and pomalidomide (93%), both bor and car (83%), and dara (64%) was frequent. HRMM was present in 20/42 evaluable pts. After a median of 1 cycle (1-5), ORR was 63%, with ≥ very good partial response in 24%. DCR was 86%. Median PFS was 4.3 months. Median OS was 9.7 months. Grade 3-4 hematologic toxicities included 66% neutropenia, 66% anemia, and 68% thrombocytopenia. Grade 3-4 non-hematologic toxicities included 42% febrile neutropenia, 19% bacteremia, and 15% pneumonia. Within 60 days of tx, 7 pts underwent autologous stem cell transplant (ASCT), and 7 pts died. Conclusions: Dara-hyperCy-dex ± car demonstrates a high ORR and DCR in heavily treated and HRMM, allowing bridging of some pts to ASCT. High rates of hematologic toxicity and risk of infection are manageable with twice weekly monitoring for transfusion support, as well as early detection and intervention for infections. Rates of end organ damage reversal will be presented.
Intestinal microbiome diversity and clinical outcomes with multiple myeloma: A systematic review.
Authors: Ashraf Aqsa , Nabeel Shaha , Ahmed Zahoor , Farooqui Arafat Ali , Rehman Saif ur , Batool syeda Sabeeka , Shah Zunairah , Faisal Muhammad Salman , Farooqi Muhammad Saad , Akhtar Aisha , Anwer Faiz
Published: May 2020

e20542

Background: Human gastrointestinal microbiome (GM) plays a role in food digestion, drug metabolism and protection against infections. We systematically reviewed the outcomes for multiple myeloma (MM) patients (pts) and its changes in GM diversity (GMD) with regimen-related toxicities. Methods: After a systematic search of PubMed, Embase, Web of Science, Cochrane, and Clinicaltrials.gov (until 01/12/2020), 9 out of 135 studies met our inclusion criteria. Results: GM changes were studied in 1343 pts. 1070 pts received Autologous (Auto) and 119 pts received Allogeneic (Allo) hematopoietic cell transplantation (HCT). 1. Impact of Induction without HCT: Higher levels of Eubacterium hallii and Faecalibacterium prausnitzii in 16 (MM) minimal residual disease (MRD) –ive pts and lower levels in 18 (MM) MRD +ive pts were noted (Pianko 2019). 2. Impact of HCT and microbiome: 1142 pts (MM = 1011) were studied; day+15 samples showed reduction of Bacteroidetes in Auto-HCT compared with Allo-HCT pts. Pts with graft versus host disease (GVHD) harbored more Firmicutes, Proteobacteria and less Bacteroidetes than pts without GVHD (Chiusolo 2015). Day+30 fecal samples (FS) revealed increase in Proteobacteria, Clostridium difficile and decrease in Firmicutes, Fusarium in FS while oral samples (OrS) showed increase in Firmicutes and decrease in Proteobacteria and Glomerella. Increased gastrointestinal adverse effects (AEs) (40%) correlated with decreased GMD especially in pts with ulcerative oral mucositis (OM) (Alexa 2019, El-Jurdi 2019, Apewokin 2015). At 3 years, Allo-HCT pts with highest GMD manifested least treatment-related mortality (TRM) (9%) and vice versa (Taur 2014). 3. Impact of Post-HCT Lactobacillus Probiotics (LBP) or Antibiotics: Improvement in AEs with LBP was statistically insignificant (Gorshein 2017, Giammarco 2016). Pts showed better clinical outcomes with ciprofloxacin and metronidazole (Cp-M) (n = 68) than Ciprofloxacin (n = 66) alone; i.e. overall survival (49% vs 42%), increased number of FS without anaerobic bacteria (53% vs 23%), GVHD (25% vs 50%), OM (82% vs 92%) (Beelen 1999). Conclusions: Treatment for MM alters microbiome diversity. Increased diversity was associated with fewer gastrointestinal AEs. Improvement in AEs with LBP was statistically insignificant. Post-HCT use of Cp-M showed better overall survival.
Exploring multiple myeloma survivor interest in lifestyle interventions.
Authors: Hodge Allen , Williams Alexis , D'Souza Anita , Sheean Patricia M. , Hari Parameswaran , Dhakal Binod , Flynn Kathryn E , Stolley Melinda
Published: May 2020

e20558

Background: Multiple Myeloma (MM) is the second most common hematological malignancy in the U.S., with higher rates observed in older adults and African Americans (AA). Given treatment advances, most individuals survive at least 5-10 years, making symptom management important. Many survivors struggle with pain, fatigue and limited physical function, all of which may be improved through lifestyle changes. Due to concerns about safety and patient interest, few efforts have considered such interventions. We report the results of an exploratory study to inform a lifestyle program tailored to the needs of the diverse MM survivor community. Methods: MM survivors at least 100 days post-auto transplant with ECOG status of 0-1 completed validated questionnaires and a qualitative interview assessing quality of life, physical activity patterns, social support and interests for a lifestyle program. Results: We recruited 20 survivors, mean age 70 (7.0) years, 70% women, 40% African American, 75% married, 60% college educated. Eighty-three percent were overweight or obese, mean Godin score was 17.56 (18.1) representing insufficient physical activity and 78% did not engage in resistance training at least twice weekly. PROMIS-29 scores indicated that MM survivors had worse physical function, fatigue and pain interference than the general population. However, they reported less social isolation and more social support (informational, instrumental, emotional, companionship). Qualitative data highlighted barriers to healthy lifestyles including “not knowing what dietary changes to make,” fatigue, and safety concerns related to physical activity. Although 67% reported that their oncology team had discussed lifestyle changes with them, most related minimal guidance was given, leaving them confused and wanting more information. All participants acknowledged the potential benefits of healthy eating and exercise on function, fatigue, pain and mood. Particular interests for a lifestyle program included: 1) focused dietary counseling with recipes and cooking guidance; 2) health coach to motivate, and to model and monitor safe exercise; 3) healthcare provider engagement to address health concerns; and 4) preference for in-person with opportunity for web-based program if unable to attend. Many were interested in joining an advisory group to inform intervention development and survivor engagement. Conclusions: MM survivors emphasized their strong interest in having a program where they could meet other MM survivors, discuss their concerns, but also focus on positive behavior changes.
Health related quality of life (HRQoL) outcomes from the phase III CANDOR study comparing carfilzomib, dexamethasone, and daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in patients (Pts) with relapsed or refractory multiple myeloma.
Authors: Siegel David Samuel DiCapua , Weisel Katja , Zahlten-Kumeli Anita , Medhekar Rohan , Sapra Sandhya , Ding Bifeng , Leleu Xavier
Published: May 2020

e20563

Background: In the CANDOR study (N = 466) of pts with relapsed or refractory multiple myeloma (RRMM), a statistically significant improvement in progression-free survival (HR = 0.63; 95% CI, 0.46-0.85; p = 0.0014) was observed in the KdD vs Kd arms. Here, we report a secondary endpoint of CANDOR evaluating HRQoL. Methods: HRQoL was assessed using the Global Health status (GHS)/Quality of Life (QoL) domain of the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30), which was completed on Day 1 of Cycle 1 and every 28±7 days through the first follow-up visit. The GHS/QoL was scored from 0–100, with higher scores indicating better QoL. The scores were compared between the KdD and Kd arms using a restricted maximum likelihood-based mixed effects model for repeated measures under the assumption of missing data at random. A minimally important difference of 5 points between arms was prespecified. An exploratory time-by-time sensitivity analysis by ANCOVA was used to evaluate the treatment effect on the GHS/QoL score among pts who remained on treatment until the specified visit (cycle 3 and every 3 cycles thereafter). Results: GHS/QoL completion rates from baseline through up to cycle 26 (study ongoing) for randomized pts who remained on treatment were > 81% for both the KdD and Kd arms; the median extent of missing GHS/QoL data was 5.3% for the KdD arm and 12.1% for the Kd arm. KdD was associated with higher GHS/QoL scores relative to Kd starting at Cycle 7 and this was maintained until Cycle 26 (by mixed effect model, overall LSME difference [95% CI], 0.06 [–2.39, 2.50]; p = 0.96). At Cycle 18, the mean difference between arms approached the prespecified clinically meaningful difference of 5 points (by ANCOVA, [difference: KdD–Kd (SE), 4.06 (2.45)]). In an exploratory analysis of pts who remained on treatment at each cycle, a higher rate of pts reported an improvement of ≥10 points in GHS/QoL score from baseline in the KdD vs Kd arms, with the greatest differences observed at Cycle 7 (Odds Ratio [OR] for KdD/Kd [95% CI], 2.37 [1.29, 4.34]), Cycle 9 (OR [95% CI], 2.96 [1.46–6.03]), Cycle 13 (OR [95% CI], 2.44 (1.15-5.17), and Cycle 16 (OR [95% CI], 2.77 [1.27–6.07]). Conclusions: In addition to the superior clinical benefit observed with KdD vs Kd, HRQoL was maintained with the KdD triplet. A higher rate of pts treated with KdD reported an improvement of ≥10 points from baseline. Clinical trial information: NCT03158688.
HealthTree Patient Portal mediated myeloma patient-reported vaccination and antibiotic use.
Authors: Thompson Michael A. , Ahlstrom Jenny , Sweeney Nathan W.
Published: May 2020

e20567

Background: Multiple myeloma (MM) is a cancer of the immune system. Infection is a major cause of morbidity and mortality in MM. Vaccines are the first line of prevention for infectious diseases. Anti-microbial prophylaxis may improve patient (pt) outcomes, but real-world use has not been well characterized. In order to engage the pt community regarding vaccination we utilized HealthTree (www.healthtree.org). Methods: An investigator-submitted online survey asking about infection prophylaxis and vaccinations was fielded to 4,944 pts from May 10, 2019, to January 9, 2020. The HealthTree platform queries pts about sharing data for research purposes. De-identified responses were aggregated and reviewed. The study was determined to be exempt by the Western Institutional Review Board. Results: 458 MM pts participated in the surveys and were able to select more than one option with the total response indicated below. Abbreviated questions and simplified responses are noted in Table including: 1. Have you ever been vaccinated in the last 5 years with a pneumococcal vaccine (PV)? 2. In the last 3 flu seasons, have you received the influenza vaccine (FV)? 3. After you began myeloma treatment, did you ever receive the anti-Varicella Zoster Virus (VZV, shingles) vaccine? 4. Were you (or are you currently) treated with anti-viral prophylaxis? 5. Were you (or are you currently) treated with antibiotic bactrim? 6. Were you (or are you currently) treated with levofloxacin prior to stem cell transplant or at the beginning of your MM therapy? Conclusions: Both FV and PV were fairly high in this self-selected cohort of volunteers compared with a large health system ( http://ow.ly/O8Dx30b9Wuc ) and a global registry ( http://ow.ly/Uofg30h6Qen ). Most did not receive an anti-VZV vaccine, but a few received a live vaccine. Anti-viral prophylaxis was common, but not universal. Anti-PJP and levofloxacin use were reported by a minority of participants. Pt reported interventions via an online portal can help investigators survey the pt community and result in hypothesis generating research questions including investigating vaccine: types, dosing, sequencing, and use of anti-infective interventions. [Table: see text]
Impact of doxycycline on outcomes in AL amyloidosis.
Authors: Blue Brandon Jamaal , Duncanson Lauren , Hansen Doris K. , Zhang Yumeng , Liu Hien D , Nishihori Taiga , Ochoa-Bayona Jose L. , Baz Rachid C.
Published: May 2020

e20568

Background: It has been shown in mouse models doxycycline(Doxy) interferes with amyloid fibril formation. Retrospective data suggests the addition of Doxy to standard chemotherapy(chemo) reduces mortality in cardiac amyloidosis. We examined the relationship between Doxy use, treatment, and OS in a cohort of AL Amyloidosis(AL) within an academic center. Methods: AL pts between 2008 and 2020 at Moffitt Cancer Center. For this study we included patients with AL, with all types of organ involvement. We excluded pts with non-AL Amyloidosis and pts with localized amyloidosis were excluded. Data on organ involved, organ response, date of death, treatment were obtained for each pt. OS was defined as time from AL diagnosis to date of death. Univariate comparisons were performed to identify differences in treatment and other prognostic variables between Doxy groups, where appropriate (Table). Results: 209 pts that met inclusion criteria, 13 pts(6%) had cardiac involvement with AL. Of those 13 pts, only 3 pts(23%) received Doxy in addition to standard of care chemo. For this study, we included all types of AL for total 209 pts. Of the 209 pts, 9.5% received Doxy in addition to standard of care chemo and 90.5% pts did not receive Doxy and had chemo alone. Pts who received Doxy had more proteinuria (suggesting more significant renal involvement) but other characteristics were not statistically different including cardiac biomarkers (table). A numerically higher rate of organ response (67% versus 43%) was noted in patients who received Doxy but this didn’t reach statistical significance. Further the OS was numerically higher for Doxy treated pts however again this didn’t meet statistical significance. Conclusions: We noted higher organ responses and overall survival in Doxy treated pts, we could not identify statistical differences in outcomes possibly because of the sample size. Nevertheless, further follow up is warranted and Doxy may be associated with improved outcomes in AL. [Table: see text]
Comprehensive analysis of T-cell receptor sequencing in resectable squamous cell lung cancer patients with neoadjuvant therapy of PD-1 inhibitor and chemotherapy.
Authors: Feng Yuan , Xiao Shanshan , Sun Wei , Ma Yuanyuan , Hong Yang , Pu Yue , Lin Rui , Wang Tao , Lin Dongmei , Yang Yue
Published: May 2020

e21012

Background: Cancer therapies alter the tumor microenvironment such as the infiltration of T cells. Neoadjuvant therapy to squamous cell lung cancer patients using PD-1 inhibitor expands specific T cell clones. However, the T cell clones and diversity in tumors and lymph nodes according to different neoadjuvant settings remain largely unknown. In this study, we used T-cell receptor (TCR) sequencing technology to investigate the TCR clonotypes and diversities in squamous cell NSCLC patients who received neoadjuvant chemotherapy and PD-1 inhibitor plus chemotherapy. Methods: Tumor tissues, non-metastatic lymph nodes (NMLN)s, and available metastatic lymph nodes (MLNs) were collected from two patient groups. Each group enrolled three patients who received either neoadjuvant chemotherapy or PD-1 inhibitor plus chemotherapy. DNA samples were harvested and processed for multiplex PCR for the third complementary determining region (CDR3) of TCR-β chain followed by the next generation sequencing analysis. Differences of the CDR3 clonotypes and clonal diversities were analyzed by bioinformatics tools including the Mixcr software. Results: For all the six patients, TCR clonotypes in the tumor tissues were found to be fewer than those from the lymph nodes in the same patient, consistent with a hypothesis that most of the tumor infiltrated T cells after therapy derive from the lymph nodes. Some clonotypes among the top 10 highest frequencies were found in different samples from the same patient, further supporting the lymph node origin of the tumor infiltrating T cells after therapies. Interestingly, TCR clonal diversity was higher in the NMLNs compared with the MLNs, but clonotype overlap with tumor tissues was higher in the MLNs than NMLNs; these results could imply that TCR clonotypes in the primary lymph node were more stimulated. Additionally, there were very few clonotypes shared between different patients, indicating the heterogeneity of immune response for different individuals. Due to the limited sample size, we could not find the systemic difference between the two patient groups. Conclusions: TCR sequencing technology can detect the CDR3 clonotypes in tumor tissues and lymph nodes of cancer patients, providing new opportunities for revealing patients' response to chemotherapy and immunotherapy. Further analysis will be performed to investigate TCR clonotype differences caused by immunotherapy.
The mutation profile of genes related to primary resistance to EGFR-TKI in early NSCLC.
Authors: Ye Jiangang , Zhang Qi , Zhang Xing , Qin Huijuan , Tian Minqi
Published: May 2020

e21014

Background: In targeted therapy for patients with advanced non-small cell lung cancer (NSCLC), approximately 30% of NSCLC patients with EGFR mutations develop primary resistance at the beginning of treatment with TKIs. However, the knowledge of primary resistance in early-stage NSCLC patients with EGFR positve remains poorly understood. Methods: Mutations of nine genes that may be related to primary resistance EGFR TKIs in advanced non-small cell lung cancer were chosen through pubmed and other databases including EGFR T790M, EGFR 20ins, PIK3CA, KRAS, BRAF, ERBB2 amplification, MET amplification, PTEN deletion and BCL2L11 deletion. Gene mutations related to primary resistance in patients with early-stage lung cancer (I-IIIA) from the TCGA database were analyzed. Results: According to TCGA database, there were 1089 patients with NSCLC of which 585 were lung adenocarcinoma and 504 lung were squamous cell carcinoma. A number of 46 EGFR-sensitive (19del / L858R) mutations were observed in adenocarcinoma, of which the clinical information of which 44 cases harbored competed clinical information including 39 patients with early stage could be identified as follows,1 patient in stage I, 11 patients in stage IA, 8 patients in stage IB, 7 patients in stage IIA, 4 patients in stage IIB, 8 patients in stage IIIA, 1 patient in stage IIIB and 4 patients in stage IV, respectively. Among the 39 cases of early non-small cell lung cancer with EGFR-sensitive mutations, 2 case of EGFR T790M mutations (5.12%), 2 case of PIK3CA (5.12%), 2 case of BRAF (5.12%), 11 case of MET (DUP) (28.2 %), 8 case of ERBB2 (DUP) (20.5%) and 5 case of PTEN (Del) (12.8%) mutations were observed respectively. Meanwhile, none of primary resistance gene mutations could be found in non-small cell lung squamous cell cancer(0/1). Conclusions: The presence of different mutation frequency in the primary resistance genes associated with EGFR TKIs in patients with early NSCLC was proved. Our study suggested it was necessary for patients to test mutations in primary resistance genes before accepted the adjuvant and neoadjuvant therapy using TKIs. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Phase I/II study of vorolanib plus nivolumab in patients with thoracic malignancies: immunotherapy (IO) correlatives to differentiate responders from nonresponders.
Authors: Beckermann Katy , Bestvina Christine M. , Whisenant Jennifer G. , Borghaei Hossein , Owonikoko Taofeek Kunle , Berry Lynne D , Shyr Yu , Liang Chris , Selvaggi Giovanni , Wakelee Heather A. , Horn Leora
Published: May 2020

e21019

Background: VEGF inhibition is suggested to enhance innate T cell function, activate dendritic cells, block recruitment of regulatory T cells, and decrease myeloid-derived suppressor cells. Vorolanib is a tyrosine kinase inhibitor that is structurally similar to sunitinib but designed to improve safety without compromising efficacy. Response to checkpoint inhibitors in patients with thoracic tumors is limited, thus we designed this multi-institutional, phase I/II study (NCT03583086) to explore safety and efficacy of combining vorolanib and nivolumab. Here we present updated results in the NSCLC, thymic, and SCLC cohorts, including patients previously treated with single agent IO. Methods: The Phase I maximum tolerated dose was 200 mg vorolanib and 240 mg nivolumab q2w. Phase II is ongoing and uses a two-stage MinMax design to assess the objective response rate (RR) in SCLC, thymic carcinoma, and three NSCLC cohorts: 1) IO naïve; 2) primary refractory, defined as radiographic progression < 12 weeks of starting IO; and 3) acquired resistance, defined as achieving at least stable disease ≥12 weeks to IO followed by progression. Results: As of December 2019, 37 patients had enrolled, 38% female, 11% never smokers, median age 66. The disease control rate (DCR) across all cohorts is 65% (20/31 evaluable patients) and the RR is 13% (4/31). In the NSCLC cohort, the overall RR is 14% (3/21); the RR is 33% (2/6) in IO naïve patients, including 2 on therapy > 17 months. RR in the NSCLC patients with acquired resistance is 14% (1/7) with an 86% (6/7) DCR. No responses in the primary refractory cohort but the DCR is 50% (4/8). DCR in the SCLC and thymic cohorts is 40% (2/5) and 50% (2/4), respectively; 1 thymic patient had a partial response with a complete response in target lesions. Exploratory correlatives, including mass cytometry analysis and single cell gene expression, are being performed in order to understand changes in macrophages and T cell activation markers to differentiate the underlying biology of the tumor and the microenvironment between responders and nonresponders. Conclusions: The addition of vorolanib nearly doubled the RR in the IO naïve NSCLC patients compared to historical data with single agent nivolumab. Additionally, 67% of NSCLC patients with prior IO achieved at least stable disease, 1 patient with acquired resistance had a response. Correlatives that may help define biomarkers of response to therapy will be presented among different cohorts of patients. Clinical trial information: NCT03583086 .
Clinical and patho-genomic characteristics of concomitant mutated status of TP53, EGFR, KRAS genes in Chinese patients with resected lung adenocarcinoma.
Authors: Yuan Qiu , Yang Haihong , Chen Hanzhang , Deng Qiuhua , Liu Liping , Xiao Dakai , Lin Yongping , He Jianxing , Zhu Changbin , Li Weiwei , Shao Di , Jiang Wenxi
Published: May 2020

e21024

Background: Alterations of TP53, EGFR, KRAS genes are of importance in LUAD etiology, vital prognostic markers as well as therapeutic targets as recently reported. In addition, in advanced or metastatic NSCLC, concomitant mutations of TP53 with EGFR or KRAS closely associated with prognosis and TKIs’ efficacy. While, distribution of concomitant mutations of TP53, EGFR and KRAS in early stage or resectable LUAD remained to be elucidated. Methods: 434 patients with defined pathological diagnosis of LUAD were recruited from 1st.Jan.2019-31st.Dec.2019, which made 468 FFPE blocks for the study. Histology and composition were given by authorized by pathologist. Genomic DNA from FFPE samples and peripheral blood was extracted. 636 cancer-related genes were specifically captured and sequenced by MGI-seq 2000. Association of concomitant status with clinical and genomic characteristics was further analyzed. Results: Generally, TP53, EGFR and KRAS mutation rate is 26.7%, 60.9% and 10% respectively. Among these samples, Subtypes of EGFR mutations significantly differed in between tumors rising in left and right lung (P = 0.048). Tumors with KRAS mutations occurred more easily in right lung than those with TP53 or EGFR mutations (P = 0.012, P = 0.043 respectively). In addition, histology subtype and clinical stage were closely associated with TP53, EGFR and KRAS mutation status (P < 0.001). 90 samples (19.2%) carried concomitant TP53 and EGFR mutation, 14 samples (3%) were TP53/KRAS co-mutated. LUAD samples with EGFR amplification had higher rate of concomitant TP53/EGFR mutations (RR:1.1,95%CI: 1.032 to 1.159,P = 0.0009). Moreover, KRAS G13 mutated samples more easily co-mutated with TP53 mutations compared with those with mutations in G12 loci (RR:1.33,95%CI: 1.24 to 1.37,P = 0.024). Further, samples with non-concomitant TP53 mutations had highest level of tumor mutation burden (muts/Mb) (median TMB = 9.74 vs 2.05 for TP53/EGFR/KRAS wild type, P < 0.0001). Samples with concomitant TP53/EGFR mutations and TP53/KRAS mutations displayed higher TMB level than their non-concomitant compartment (P < 0.001 and P = 0.05 respectively). Conclusions: TP53,EGFR and KRAS mutations and their concomitant mutation status displayed diverse correlation with spatial, clinical and genomic characteristics in resectable LUAD patients. This correlation may indicate complex biological heterogeneity of LUAD which may need further exploration.
The validity of 5-aminorevrinic acid as a biomarker for risk screening and supportive diagnostic parameters in lung cancer patients.
Authors: Yamauchi Yoshikane , Saito Yuichi , Murakami Koji , Kanamoto Yasuyuki , Asami Momoko , Yokote Fumi , Sakai Takashi , Sakao Yukinori , Tanaka Toru , Kawamura Masafumi
Published: May 2020

e21027

Background: Early detection and treatment of cancer is an important issue that affect the prognosis of cancer patients. Photodynamic screening with 5-aminorevrinic acid (ALA-PDS) is simple and non-invasive procedure for risk screening of cancer, and it is gradually recognized as the predictable biomarkers for cancer in Japan. In this study, we examined the predictability of lung cancer by ALA-PDS and its usefulness as a supportive parameter for preoperative diagnosis. Methods: Eighty-five lung cancer patients (48 males and 37 females) just before lung resection were enrolled. 5-aminolevulinic acid phosphate 150mg was taken at night and urine samples were collected in the next morning. The porphyrin metabolites in the urine samples were detected by solid phase extraction method, previously reported from our group. Afterwards, the data was adjusted depending renal function. The data was compared with that from healthy volunteer without any abnormal symptom and physical disorder. Results: The average age of 85 patients was 70 years (46-85). The number of patients in each pathological stage was 2 in Stage 0, 58 in Stage IA and IB, 15 in Stage IIA and IIB, 8 in Stage IIIA and IIIB, and 2 in Stage IV, respectively. The diagnosis was 61 cases of adenocarcinoma and 22 cases of squamous cell carcinoma. Urinary porphyrin metabolites in lung cancer patients increased significantly as compared to those of healthy volunteers (2,847nM/gCRE vs 1,668nM/gCRE, p < 0.001). Increase of urinary porphyrin metabolites was observed even in stage 0 or I patients, but the correlation with stage progression was not clear (Stage 0 and I vs Stage II vs Stage III and IV: 2,757nM/gCRE vs 3,099nM/gCRE vs 3,010nM/gCRE). Furthermore, urinary porphyrin metabolites were confirmed to be significantly increased even in PET-negative cancer patients, compared to healthy volunteers (p < 0.001). Conclusions: ALA-PDS was able to predict lung cancer in our cohort. Moreover, it was also suggested that it may be useful as a supportive parameter for diagnosis of early stage lung cancer or PET negative lung cancer.
A rare family case study of multiple siblings with multiple synchronous primary lung cancers.
Authors: Lin Rui , Wang Tao , Xiao Shanshan , Mao Ruifang , Pu Yue , Liu Hong
Published: May 2020

e21028

Background: Familial lung cancer is rare, let alone inherited lung cancer with multiple synchronous primary lung cancer lesions. Study of inherited lung cancer may facilitate the understanding of the molecular mechanism of the tumorigenesis. Methods: We identified an extremely rare family of five siblings, four with multiple primary lung adenocarcinomas by pathological examination. DNA samples were extracted from the patient tumor tissues and libraries were prepared for next-generation sequencing (NGS) analysis using a custom 500-gene cancer panel. Results: EGFR L858R or 19DEL mutations were identified in at least one lesion in all of the four lung cancer patients. Interestingly, lung cancer patient L1 had EGFR 19DEL in one lesion and L858R in the other, lung cancer patient L2 had EGFR L858R and KRAS G12C mutation in lesion 1 and lesion 2, respectively. The mutation statuses of EGFR and KRAS were confirmed by ARMS-PCR. The mutational spectrum of the two lesions from the same patient distinguished significantly based on the 500-gene NGS panel analysis, further demonstrating the heterogeneity of cancer mutations. Taken together, these results indicate that patients L1 and L2 both had synchronous primary lung cancers. Due to the small lesions, the two lesions for patient L3 were mixed together; the concurrent EGFR L858R and 19DEL mutations in the tissue sample implicated different drivers in the two different lesions since co-occurring of these two mutations was very rare. For patient L4, EGFR L858R was identified in one lesion and uncommon mutations with low frequencies were observed in the other lesion, consistent with different driving mechanisms for the two lesions. Conclusions: To our knowledge, this is the first study identifying a family of multiple siblings with multiple synchronous primary lung cancers and using NGS to reveal the genetics. Together with germline mutation analysis, this study may shed light on the tumorigenesis of familial lung cancer.