bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line CyborD treatment for graft ineligible multiple myeloma patients: Real-life efficacy and tolerability.
Authors: Duquette Dominic , Germain Marie-Michelle 
Published: May 2020

e20516 Background: CyborD is a regimen that was widely adopted in Canada around 2010 despite very little data supporting it’s use. The aim of the study is to describe the efficacy and tolerability of First line CyborD regimen for graft ineligible myeloma patients. Methods: This is a retrospective study at two centres in the CHU de Québec for patients with graft ineligible multiple myeloma patients treated with first line CyborD regimen between 2013 and 2018. The objectives are to describe the efficacy and tolerability of CyborD and to document PFS and OS. Results: 51 patients were included in this study with a median follow-up of 31 months. Partial response or better (≥ PR) was obtain in 84% of patients and 63% of patients achieved a very good response or better (≥ VGPR). A high rate of 26% of complete response (CR) was also obtained. A median PFS of 30 months was obtained while 75% of patients were still alive at that time. Estimated survival at 48 months was 63%. Severe toxicities (grade 3 or 4) were seen as anemia (20%), neutropenia (10%), bacterial infection (16%), diarrhea (12%) and renal toxicity (4%). Side effects related to dexamethasone in this fragile patient population reached 69% of patients but only 28% needed a dose reduction. Conclusions: First-line CyborD treatment was highly effective for graft ineligible multiple myeloma patients and this is a very well tolerated regimen. It compares favorably to RD regimen making it still an excellent first-line treatment for this elderly population. [Table: see text]
Bendamustine-bortezomib-dexamethasone (BVD) in heavily pretreated multiple myeloma: Old/new in novel agents' era.
Authors: Cerchione Claudio , Catalano Lucio , Nappi Davide , Pareto Anna Emanuele , Pane Fabrizio , Martinelli Giovanni 
Published: May 2020

e20517 Background: Bendamustine is a bifunctional alkylating agent, with low toxicity, proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). In this retrospective study, It has been evaluated efficacy and tolerance of Bendamustine, in combination with bortezomib-dexamethasone (BVD) in patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. A retrospective real-life analysis of patients with rrMM who had been treated with BVD as salvage therapy has been performed. Methods: 56 patients (31 M/25 F), with rrMM, median age at diagnosis 57.3 years (r. 36-82), median age at start of treatment 61.8 years (r.37-83) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. All patients had previously been treated with schedule containing bortezomib and IMIDs, and 30% had also received radiotherapy. 67%of them had undergone at least to a single auSCT. All patients were relapsed and refractory to last therapies received before BVD. Results: Bendamustine was well tolerated, with grade 3 transfusion-dependent anemia in 41% of patients, and 37% grade 3 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. According to IMWG, after a median follow-up of 14 months (r.2-36), ORR was 64% (36/56: 4 CR, 7 VGPR, 16 PR, 9 MR) with 8 PD and 12 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Three patients have shown a notable PR after failure of novel agents (i.e. Carfilzomib and Pomalidomide). Median time to response was 1.2 months (r.1-3), median OS from diagnosis was 62.7 months (r.6-151), median OS from start of Bendamustine was 9.8 months (r.2-36). Conclusions: The triplet Bendamustine-Bortezomib-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT.
Exploring the validity of a synthetic control arm (SCA) for augmentation or replacement of a randomized control in difficult-to-study indications: A case study in relapsed or refractory multiple myeloma (R/R MM).
Authors: Davi Ruthie , Yin Xiang , Stewart Mark 
Published: May 2020

e20521 Background: The randomized clinical trial (RCT) is the gold standard in drug development. However, for indications where patients have a strong preference for the investigational product, such as many oncology and rare diseases, the use of a SCA may improve drug development and reduce patient burden. SCA is an external control constructed from patient-level data from previous clinical trials to match the baseline characteristics of the patients in an investigational group and can augment a single-arm trial or a RCT compromised by control arm early withdrawal or noncompliance in order to estimate treatment effects. This research explores whether the treatment effect (difference between arms) based on an SCA can mimic the treatment effect from a RCT. Tipping point analyses were explored to assess the impact of unobserved confounders on the SCA-based demonstration of efficacy. Methods: This case study is based on patient-level data from previous clinical trials in R/R MM. The SCA patients satisfied key eligibility criteria of the target RCT and were further selected using propensity score methods to balance the baseline characteristics in the SCA with the target randomized treatment group (TRT) from the original RCT. Sensitivity analyses utilizing methods proposed by Lin (1998) illustrate the robustness of the treatment effect to unobserved covariate(s). Results: Comparable balance was achieved in observed baseline characteristics between SCA and the matched patients from TRT. The treatment effect utilizing SCA is similar to the original RCT. The Kaplan Meier curve of overall survival for the SCA overlaps with that of the randomized control and the quantified differences between SCA and the matched patients from TRT are very similar to the original RCT. Tipping point analyses show changes in HRs under representative sets of assumptions regarding the unobserved confounder (results not shown). Conclusions: This case study demonstrates an SCA built from previous clinical trials, can be well-balanced at baseline with TRT and can provide similar treatment effect estimates as a RCT. Tipping point analyses can elucidate whether treatment effects are reliable despite a reasonable degree of confounding expected in a clinical setting. This suggests, in some settings, SCA can be used to augment or replace a randomized control in future trials without loss of understanding of the treatment effect. [Table: see text]
Error propagation in simulated treatment comparisons for multiple myeloma: Results from a simulation.
Authors: Mackay Eric , Slater Justin , Arora Paul , Thorlund Kristian , Beliveau Audrey , Boyne Devon J , Brenner Darren 
Published: May 2020

e20523 Background: Comparing the effectiveness of multiple myeloma treatments presents a challenge due to the limited number of head-to-head trials with which to conduct indirect treatment comparisons. This is particularly true when subgroup analysis is of interest. In comparative effectiveness research Simulated Treatment Comparisons (STCs) are becoming increasingly common in the absence of head-to-head trials. STCs use estimates from limited IPD to adjust for covariate imbalance between trials, however the uncertainty from these estimates is generally ignored when estimating relative treatment effects. This study demonstrates the need to account for this uncertainty when conducting STCs for indications such as multiple myeloma. We introduce an STC method that accounts for the uncertainty due to covariate adjustment, and demonstrate its effectiveness via simulation. Methods: We simulated two single arm studies (N = 300 for both), each containing age and overall survival. We assume study 1 has individual patient data available, and study 2 only has aggregate age data and a digitized Kaplan-Meier curve. We compute a covariate adjustment term based on the mean age difference between the studies and the age coefficients from fitting a parametric survival model to the observed study 1 IPD. We then estimate the variance of this adjustment term via bootstrapping and incorporate this uncertainty into a Bayesian STC model which estimates the relative treatment effect for the two study datasets converted to a digitized Kaplan-Meier format. Results: The proportion of 95% credible intervals (CrI) that captured the true treatment effect was 86.8% without error propagation, whereas 92.0% of CrI’s captured the true treatment with error propagation. 94.9% of CrI’s contained the true treatment effect when using survival regression with the complete IPD. Conclusions: Failing to account for uncertainty from the covariate adjustment when conducting simulated treatment comparisons generally leads to underestimating the uncertainty of the relative treatment effect. This method better captures the uncertainty introduced when conducting an STC and has the potential to yield more reliable estimates of the comparative effectiveness of multiple myeloma treatments.
Medical resource utilization among multiple myeloma (MM) patients who were triple-exposed to a proteasome inhibitor, an immunomodulatory agent, and daratumumab.
Authors: Mehra Maneesha , Crivera Concetta , Valluri Satish , Nair Sandhya , Vogel Martin , Nesheiwat Tonia , Potluri Ravi C. , Jagannath Sundar , Shah Nina 
Published: May 2020

e20539 Background: MM patients undergo several lines of treatment (LOT), mainly involving ≥1 proteasome inhibitor (PI), immunomodulatory (IMiD), and novel agents such as daratumumab (dara). Research is underway to address the need of patients previously exposed to a PI, an IMiD, and dara (triple-exposed). This retrospective cohort analysis assessed costs and healthcare resource (HR) utilization in triple-exposed patients. Methods: A pooled cohort of patients from Optum’s Humedica Electronic Health Records and Clinformatics claims data with an index MM diagnosis between 2008-2018 and who 1) had ≥12 months of activity/insurance coverage prior to index MM diagnosis, 2) did not have any other cancer during this period, 3) were aged ≥18 years at index diagnosis, 4) were triple exposed and 5) had ≥1 LOT subsequent to triple-exposure were studied. Costs per LOT after triple-exposure, broken down into cost categories, were analyzed in patients from Optum claims data (N = 94), while HR utilization (hospitalization, ER/outpatient visits, lab tests and MM drugs) was analyzed in the pooled cohort (N = 517). Descriptive statistics are reported. Results: 53% of patients were male; mean follow-up was 8.9 months (272 days). At LOT1 following triple-exposure, mean age was 68 yrs, mean time from index MM diagnosis was 37 months, and median prior LOTs were 4. 50% were penta-exposed (2 PIs + 2 IMiDs + dara) following triple exposure. 42% received a pomalidomide-containing regimen in LOT1 after triple-exposure. 56% of patients had ≥2 LOTs after triple-exposure; 28% had ≥3. Mean duration of LOT1, LOT2, and LOT3 in claims data patients was 132, 102 and 101 days, respectively, with associated mean cost per LOT of $165,453, $131,759, and $116,915. Over the follow-up, patients had a mean of 1.75 hospitalizations, 0.92 ER visits, 32.1 outpatient/office visits and 28.8 lab tests; post triple-exposure mean cost per patient per month was $38,214 (Table). Conclusions: Substantial MM drug costs, inpatient stays and frequent outpatient visits contribute to high cost per month of post triple-exposure treatment, underscoring the need for effective MM treatments with durable response. [Table: see text]
Patient characteristics and treatment patterns in relapsed/refractory multiple myeloma patients after exposure to a proteasome inhibitor, an immunomodulatory agent and daratumumab.
Authors: Mehra Maneesha , Vogel Martin , Valluri Satish , Nair Sandhya , Schecter Jordan , Jagannath Sundar , Weisel Katja , Usmani Saad Zafar 
Published: May 2020

e20540 Background: Many novel agents, such as a Chimeric Antigen Receptor T-Cell (CAR-T) therapy, are under investigation for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) who have been exposed to a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and daratumumab (triple-exposed). However, limited data are available on treatment patterns in these pts. Here, we aim to study characteristics and treatment patterns after triple-exposure in RRMM pts. Methods: Data from triple-exposed RRMM pts from the Flatiron MM core registry (Jan 1, 2011 - Oct 2019) who received ≥3 prior lines of therapy (LOT) were used for the analyses. Descriptive statistics for pt characteristics and treatment patterns were assessed at end of triple exposure LOT (time T0) and after triple exposure by LOT. Results: Of the 10,011 MM pts in the Flatiron registry, 1,029 were triple-exposed; of these, 362 had a LOT after triple-exposure. Median age at T0 was 68 years and time to triple-exposure was 3.5 years from index MM diagnosis (Table). 52% were male, 81% (of 250 with available ECOG data) had ECOG status < 2, and 54% had a stem cell transplant. In 96% of pts, daratumumab was part of the triple-exposure regimen. Median follow-up from triple-exposure (LOT end date) was 7.4 months. 49% and 23% of pts had ≥2 LOTs and ≥3 LOTs after triple-exposure. Pomalidomide-, carfilzomib-, or daratumumab-containing regimens accounted for 71% and 49% of all LOT1-post-triple and LOT3 post-triple treatments, respectively; non-novel treatments accounted for 18% and 30% of LOT1 post-triple and LOT3 post-triple treatments. Conclusions: Triple-exposed RRMM pts accounted for approximately 10% of the population in the Flatiron MM core registry. Triple-exposed RRMM pts progress to multiple LOT in which they continue to be treated with PIs, IMiDs, and daratumumab; therefore, there is a need for new treatments with novel mechanisms of action for this pt population. [Table: see text]
Treatment patterns in multiple myeloma: Real-world experience of the triple-class exposed (TCE) patient.
Authors: Shah Nina , Crivera Concetta , Mehra Maneesha , Mohammadi Iman , Kilgore Karl M. , Wong Anny C. , Jagannath Sundar 
Published: May 2020

e20543 Background: Recent advances in medical treatments have improved survival in multiple myeloma (MM), but relapse is a near certainty. TCE MM patients, i.e. treated with a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and anti-CD38, have been shown to have improved outcomes compared to patients with prior regimens, but patients who subsequently relapse have limited options. Objective: To describe the course of treatment in a real-world, TCE sample of patients with MM with an emphasis on treatments occurring after triple-exposure. Methods: This retrospective descriptive study used 100% Medicare Fee-for-Service claims data and Inovalon’s MORE² Registry, a commercial multi-payor claims database, to identify patients ≥ 18 years of age, newly diagnosed with MM in 2009-2017, and with ≥ 12 months continuous enrollment post-diagnosis. Patients with ≥ 3 lines of treatment (LOT) were considered relapsed/refractory MM (RRMM), and the TCE subset of those were analyzed in terms of number and timing of LOT. Results: 9534 patients were identified with RRMM and 29.2% (N = 2787) were TCE. TCE patients had a mean age of 70.8 and 50.1% were male. Treatment characteristics are shown in Table. Median number of LOT prior to TCE was 3, median time from diagnosis to TCE was 37 months, and 27.3% had a stem-cell transplant (SCT) prior to TCE. Patients had a median of 10 months of follow-up (range: 0-35) from end of the TCE LOT to end of follow-up. Nearly half (N = 1290, 46.3%) of the patients had at least 1 LOT post TCE, and 8% had at least 3. Over their entire post-TCE course of treatment, 826 (64%) received daratumumab, 443 (34%) received carfilzomib, and 356 (28%) received pomalidomide. 35.5% proceeded to penta-exposure (2 different PIs, 2 different IMiDs and an anti-CD38). Conclusions: While triple-exposure drug regimens have demonstrated improved outcomes, nearly half of the patients in this study received additional treatments beyond TCE and over 1/3 progressed to penta-exposure. Given the findings of this study, fundamentally new approaches are needed to close the gap and unmet medical need. [Table: see text]
Investigating macrophage function as a mechanism of resistance to daratumumab in relapsed refractory multiple myeloma patients.
Authors: Kambhampati Swetha , Wen Kwun Wah , Sung Victoria , Wong Sandy Wai Kuan , Martin Thomas G. , Wolf Jeffrey Lee , Shah Nina , Wiita Arun 
Published: May 2020

e20547 Background: Daratumumab (Dara), an anti-CD38 antibody, has a variety of Fc-dependent immune effector mechanisms of action including macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). However, it remains unclear which mechanism, when disrupted, drives in vivo resistance. Given widespread use of this agent for treatment of multiple myeloma, identifying how to overcome Dara resistance has become an urgent clinical need. We hypothesized that inhibiting macrophage activity, via increased plasma cell surface expression of the CD47 “don’t eat me” signal, could be a mechanism of acquired Dara resistance. Methods: We retrospectively identified 11 patients with relapsed refractory multiple myeloma who progressed on Dara and had sequential bone marrow core biopsies before and after Dara with both samples containing > 20% plasma cells. Nine patients had sufficient material for analysis. Core biopsy slides were stained and analyzed for expression of CD47 (H-scoring for total intensity on plasma cells, as well as annotation of membrane vs. cytosolic localization), CD68 (cell counts of macrophages), and CD4/CD8/FOXP3 triple stain (cell counts of CD4 and CD8 effector and regulatory T-cells). Results: Median age was 57 years. Median R-ISS stage was 2. Two patients had high-risk cytogenetics at diagnosis. Median time from diagnosis to progression on Dara was 56.3 months (95% CI 37.43 – 88.92). Median overall survival was 69.5 months (95% CI: 46.5 – 97.1). Plasma cells in all samples expressed CD47 (H-score median = 96, range 43 - 290). However, in contrast to our hypothesis, there was no significant change in CD47 H-score at progression on Dara (H-score median = 100, range 29 – 140). Furthermore, we observed no significant change in CD68+ macrophage counts nor CD68+ localization at Dara progression. We did note a trend toward CD47 expression shifting from membrane to cytosol at Dara resistance ( p = 0.14). Consistent with prior studies, in our cohort we observed no influx in Tregs but a markedly increased CD8/CD4 ratio at resistance ( p = 0.01). Conclusions: In vitro and murine studies have proposed ADCP as an important mechanism of Dara efficacy. However, we did not observe signatures of resistance in patients being driven by this pathway. Our work suggests that anti-CD47 therapy, leading to activation of macrophages to eliminate tumor cells, will potentially be efficacious for both the Dara-naïve and Dara-refractory settings.
Heparanase in myeloma related renal dysfunction: Role in promoting nephrotoxicity and potential as a novel biomarker for early detection.
Authors: Rangarajan Sunil , Tripathi Kaushlendra , Bandari Shyam Kumar , Brown Elizabeth E , Sanderson Ralph D 
Published: May 2020

e20554 Background: Our laboratory previously demonstrated that heparanase (HPSE), an enzyme that cleaves heparan sulfate, upregulates growth factors and their receptors, resulting in enhanced multiple myeloma (MM) growth, chemoresistance, and metastasis. Targeting HPSE therapeutically decreases chemoresistance and relapse. Renal dysfunction is a major problem in MM patients with nearly 50% having renal dysfunction at diagnosis of which 19% are advanced, and 8% require dialysis. There is no specific therapy for myeloma associated renal dysfunction highlighting the need to identify novel mechanisms that lead to the development of targeted therapies. This is the first study to investigate the association between HPSE activity and renal dysfunction in MM patients by utilizing high-sensitivity biomarkers. Methods: Human Kidney 2 (HK-2) cells were treated with HPSE. Necrosis and apoptosis were assessed by flow cytometry. Cell lysates were examined for expression of kidney injury biomarkers by western blotting. HK-2 clusters were co-cultured with MM-spheroids with low or high HPSE. SCID mice were injected with 3 million luciferase-positive myeloma cells with low or high level of HPSE. Kidneys were harvested after 3 weeks and processed for studies. HPSE activity and biomarkers using multiplex magnetic bead ELISA were assessed in peripheral blood from a MM patient with serum creatinine 1.2 mg/dL and a healthy control donor. Results: HPSE induced HK-2 cell necrosis and apoptosis. HPSE induced significant expression by HK-2 cells of KIM-1, NGAL and IGFBP-7. Co-culturing HK-2 organoids with MM-spheroids expressing high HPSE compromised HK-2 organoids survival over 7 days. Damage to HK-2 cells was prevented by HPSE inhibitors Roneparstat or OGT-2115. Kidney tissues from mice harboring HPSE-high myeloma tumors expressed more KIM-1 and NGAL than those harboring HPSE-low myeloma tumors. HPSE activity was 6-fold higher and kidney injury biomarkers were many fold (range 2 – 84) higher in the plasma of a MM patient than in plasma from healthy control. Conclusions: HPSE causes kidney cellular injury which can be detected early by the measurement of high sensitivity biomarkers and can be prevented by treatment with HPSE inhibitors, Roneparstat and OGT-2115. Further studies are ongoing to investigate the association between HPSE activity and renal dysfunction in a larger cohort of MM patients which have been accrued as a part of the UAB-Integrative Molecular And Genetic Epidemiology (IMAGE) Study of Myeloma.
Effect of daratumumab based four drug combinations on surrogate endpoints and high-risk features in newly diagnosed multiple myeloma: A systematic review.
Authors: Ammad Ud Din Mohammad , Hussain Syed Ather , Boppana Leela Krishna Teja , Liaqat Hania , Farooqui Arafat Ali , Razzaq Faryal , Ahmed Zahoor , Anwer Faiz 
Published: May 2020

e20561 Background: Daratumumab (DARA) has shown benefit in combination with standard of care regimens in newly diagnosed multiple myeloma (NDMM). Methods: A literature search of PubMed, EmCare, clinicaltrials.gov, and Cochrane Library was performed on January 27, 2020 for DARA in NDMM. Six phase I/II and III trials met inclusion criteria out of 696 studies per PRISMA guidelines (n = 2146). Results: The median age was 58.5 – 71 years. DARA based quadruplet regimens were evaluated by Moreau et al (2019) and Mateos et al (2018) in stem cell transplant (SCT) eligible and ineligible patients respectively. These trials along with Voorhees et al (2019), Yimer et al (2019), Kapoor et al (2019) and Jakubowiak (2017) all reported improved surrogate endpoints (Table). African Americans were underrepresented and Hazard Ratio for disease progression in high-risk MM did not significantly improve by adding DARA. Conclusions: Combining DARA in the treatment of NDMM with/without SCT achieved improved surrogate endpoints without increased toxicity. With limited data, improvement is not noted in high-risk cytogenetics NDMM. Long term data is awaited. [Table: see text]