Search

The objective of the study was to assess racial disparities in the treatment and outcomes among white, African American, and Hispanic patients with multiple myeloma (MM). Patients with an MM diagnosis from the Surveillance Epidemiology and End Results (SEER)-Medicare (2007-2013) database were included. Continuous Medicare enrollment for 6 months before (baseline) and after MM diagnosis was required unless death occurred. Time from MM diagnosis to novel therapy initiation and autologous stem cell transplant (ASCT), overall survival (OS), and MM-specific survival (MSS) was evaluated. Unadjusted and multivariable regressions compared African Americans and Hispanics vs whites. Trends of novel therapy and ASCT use across MM diagnosis years were assessed using linear regression models. The study included 3504 whites, 858 African Americans, and 468 Hispanics. African Americans and Hispanics had a longer time from MM diagnosis to novel therapy initiation vs whites (median: 5.2 and 4.6 vs 2.7 months, respectively). All cohorts had an increasing trend of novel therapy initiation within 6 months of MM diagnosis, particularly whites (all P < .05). Median MSS was significantly longer for African Americans (5.4 years) than whites (4.5 years; P < .05), and was comparable for Hispanics and whites. Median OS was similar overall (2.6-2.8 years). ASCT rate within 1 year of MM diagnosis rose among whites and African Americans (P < .05), but not Hispanics, who were less likely to receive ASCT vs whites. Significant variations in novel therapy and ASCT use were observed among different racial/ethnic groups with MM. Although OS was similar, both African Americans and Hispanics may not be fully benefitting from the introduction of novel therapies, as they receive them later than whites., (© 2019 by The American Society of Hematology.)

Introduction: Outcomes in multiple myeloma (MM) have improved significantly over time. This is true overall for all patients as well as patient subgroups based on age and race/ethnicity. Despite this, disparities are noted in outcomes when looking at racial subgroups., Materials and Methods: We performed an analysis from the population-based Surveillance, Epidemiology, and End Results (SEER) database to evaluate improvement in relative survival rates (RSRs) for young (≤ 40 years at the time of MM diagnosis) and older (> 40 years at the time of MM diagnosis) over time by race/ethnicity, specifically focusing on Hispanic patients with MM. Expected survival was estimated using the age- and gender-specific death rates from the United States population. RSR was provided as the ratio of the observed to expected survival at individual time points. Five-year and 10-year RSRs were calculated for patients based on treatments modalities available in various time periods., Results: We identified a total of 89,451 patients with MM in SEER, of which 1460 patients formed the young patients with MM (≤ 40 years) cohort. Five- and 10-year RSR improved significantly over time for all patients and older patients (> 40 years) by race (all P < .001). Evaluating the younger patients, RSR improved significantly for non-Hispanic whites and non-Hispanic blacks, but not for Hispanics. This was true for the 5-year (P = .08) and 10-year (P = .13) RSRs., Conclusion: We report a lack of significant benefit in long-term outcomes for younger Hispanic patients with MM over time. This could be owing to multifactorial causes that need to be addressed to mitigate outcome disparities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is one of the most lethal cancers. Various prognostic factors impact the survival of GBM patients. To further understand this extremely poor prognosis disease, we evaluated the effect of the treatment facility volumes on overall survival (OS) over the years, especially after the approval of multimodality therapy using temozolomide (TMZ) in 2005. National Cancer Data Base (NCDB) was utilized to identify GBM cases from 2004 through 2013 using ICD-O-3 code 9440/3 to identify eligible patients. We focused on studying the association between treatment facility volume and OS after adjusting for the patient-, disease-, and facility-characteristics. A total of 60,672 eligible GBM patients with median age of 65 years, treated at 1166 facilities were included in this analysis. The median annual facility volume was 3 patients/year (range: 0.1-55.1) and median OS was 8.1 months. There was an improvement in OS across all facilities after 2005, when multimodality therapy with TMZ was approved. Treatment at quartile 4 centers (Q4; >7 patients/year) was independently associated with decreased all-cause mortality in a multivariate analysis (Q3 hazard ratio [HR]: 1.11, 95% CI 1.09, 1.13; Q2 HR: 1.15, 95% CI 1.12, 1.19; Q1 HR: 1.25, 95% CI 1.17, 1.33). Treatment facility volume independently affects OS among GBM patients. Factors that are variable in high- and low-volume centers should be addressed to mitigate outcome disparities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17-1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12-1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5-1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41-1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003-2015 (SIR 1.36; 95% CI:1.3-1.42) as compared to 1973-1982 (SIR 1.19; 95% CI:1.12-1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31-1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13-1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

Background: Palliative treatment may be associated with prolonged survival and improved quality of life, but remains underutilized in stage IV colorectal (CRC). We examined a national cohort of stage IV CRC patients to determine the factors associated with palliative treatment., Methods: Stage IV CRC patients, classified based on their survival length (<6 months, 6-24 months, and 24 + months), were analyzed using the American College of Surgeons National Cancer Data Base (2004-2013). Multivariable analysis was performed to evaluate factors associated with palliative treatment., Results: Of 85,981 patients analyzed, 10.9% received palliative treatment. For 6-24 months survival, a more recent year of diagnosis, Medicaid, uninsured status, Mountain and Pacific regions were associated with higher odds of palliative treatment. For those who survived < 6months, older patients had lower odds, while academic centers and residence > 20 miles from treating institutions were associated with increased likelihood of palliative treatment., Conclusions: Palliative treatment in stage IV CRC is associated with a more recent year of diagnosis, Medicaid, academic centers, Mountain and Pacific regions of the US., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study analyzed 91 multiple myeloma patients who received two monoclonal antibodies, Daratumumab and Elotuzumab, over a year and report the adverse event profile, infusion practices and utilization of these drugs in the real world. All current reported data on monoclonal antibodies is from clinical trials, without any real-world experience. Patients from Mayo Clinic Florida or Arizona diagnosed with relapsed or refractory multiple myeloma who were treated with Daratumumab or Elotuzumab alone or in combination between 1 January 2016 and 31 December 2016 were included in the analysis. Daratumumab-treated patients (n = 78) were more heavily pre-treated than that in published clinical trials, whereas the elotuzumab patient (n = 13) profile was similar to that published before. Infusion time was on average 2 hours less than the prescribing guidelines and premedication use varied noticeably after the initial monoclonal antibody infusion, with an overall decrease over time. We noted higher than reported haematologic adverse events, especially neutropenia and fewer non-haematologic adverse events. 91.7% infusion-related reactions were observed during the first monoclonal antibody infusion, with a subsequent decrease. All infusion-related reactions were grade 2 or less, and none of the patients discontinued treatment due to infusion-related reactions. Baseline allergy profile or laboratory tests were not associated with the likelihood of developing monoclonal antibody-related infusion-related reactions. The real-world safety profile of monoclonal antibodies showed varying adverse event patterns than those reported in previous clinical trials. The infusion-related reaction patterns were similar to previous reports. Despite changes in premedication regimens safety was maintained in succeeding infusions. Such treatment utilization data is vital to broaden our knowledge of approved therapeutic agents and maximize their benefits for patients.

Purpose: CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied., Experimental Design: We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT., Results: In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model., Conclusions: Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications., (©2019 American Association for Cancer Research.)

Background: Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138, which is overexpressed on multiple myeloma (MM) cells., Patients and Methods: We report from 2 clinical studies of patients with relapsed and/or refractory MM previously treated with an immunomodulatory drug and a proteasome inhibitor. Single- and multi-dosing schedules were investigated to define dose-limiting toxicities, maximum tolerated dose (MTD), recommended phase II dose, and to describe safety, efficacy, and pharmacokinetics., Results: In the first-in-human study, indatuximab ravtansine was administered to 32 patients on day 1 of each 21-day cycle. The MTD was 160 mg/m 2 . In the phase I/IIa study, indatuximab ravtansine was administered to 35 patients on days 1, 8, and 15 of each 28-day cycle, and the MTD/recommended phase II dose was 140 mg/m 2 . Most (88%) adverse events were grade 1 or 2, the most common being diarrhea and fatigue. There was rapid clearance of indatuximab ravtansine and no relevant accumulation. Over 75% of heavily pretreated patients achieved stable disease or better. With the multi-dose schedule, minor and partial responses occurred in 14.7% of patients, the median time to progression was 3 months, and the median overall survival was 26.7 months., Conclusion: Our data support further investigation of indatuximab ravtansine as part of a combination regimen for relapsed and/or refractory MM., (Copyright © 2019. Published by Elsevier Inc.)

Over the last two decades, the utilization of various novel therapies in the upfront or salvage settings has continued to improve survival outcomes for patients with Multiple Myeloma (MM). Thus, the conventional role for hematopoietic stem cell transplantation (HSCT) in MM either in the form of an autologous stem cell transplant (ASCT) or an allogeneic stem cell transplant (Allo-SCT) warrants re-evaluation, given the aforementioned clinical advances. Here, we present a consensus statement of our multidisciplinary group of over 30 Mayo Clinic physicians with a special interest in the care of patients with MM and provide evidence-based recommendations on the use of HSCT in MM. We specifically address topics that include the role and timing of an ASCT for MM in the era of novel agents, eligibility for an ASCT, post-ASCT consolidation, and maintenance options, and finally the utility of an upfront tandem ASCT, salvage second ASCT, and an allo-SCT in MM.

Purpose: Multiple new regimens are available for the treatment of relapsed/refractory multiple myeloma (RRMM). In this context, it is increasingly important to understand the differential costs of regimens used to treat RRMM., Methods: A treatment journey for RRMM during a 12-month period of therapy was developed to reflect real-world clinical practice based on current treatment guidelines and input from hematologists/oncologists. The journey incorporated prescreening visits, laboratory tests, regimen-specific premedication, treatment-related costs, medical costs, and indirect costs. A cost model was constructed from the standard RRMM treatment pathway to compare overall, direct, and indirect costs across therapies over a 12-month period from initiation of second-line therapy and to determine cost offsets (incremental costs) associated with use of ixazomib-based therapy versus comparator regimens. According to the clinical input, the standard pathway was modified for patients with high unmet need to determine specific cost offsets in these subgroups., Findings: Total costs ranged from $93,683 for bortezomib-cyclophosphamide-dexamethasone to $315,296 for daratumumab-bortezomib-dexamethasone. Drug cost comprised the highest proportion (83%-98%) of total costs of second-line therapy across regimens, which were generally highest for regimens based on recently approved agents. Indirect costs were higher for regimens that required more frequent or longer durations of drug administration, and lower for all-oral regimens. Costs were reduced among frail patients because of the use of adjusted dosing, whereas indirect costs were increased for regimens that required a greater number of clinic visits among patients with barriers to physician access., Implications: Cost model analyses highlight the differential direct and indirect costs associated with multiple regimens for the treatment of RRMM, including many recent new regimens. The results indicate the lower treatment burden and indirect costs associated with administering all-oral regimens compared with regimens that require frequent and/or lengthy subcutaneous or intravenous infusions. Understanding comparative costs associated with the treatment journeys of different patients with RRMM may help inform payer and patient therapeutic choices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

Proteasome inhibition is an established treatment strategy for patients with multiple myeloma as proteasome inhibitors (PIs) selectively target and disrupt the protein metabolism of aberrant plasma cells. Since the introduction of the first-in-class PIs bortezomib, the therapeutic landscape for multiple myeloma has shifted with the development of next-generation PIs (carfilzomib and ixazomib) and new classes of agents. Treatment with modern combination therapies has been shown to result in deep responses and improved outcomes, and these potent regimens are increasingly used as frontline therapy. As patients continue to live longer with modern frontline therapy, there will be an increased need for effective regimens after initial treatment failure. Several recent studies have shown that treatment with combination therapy incorporating PIs induces deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this review, we review pivotal data and discuss the role of PIs-based doublet and triplet regimens for the management of relapsed/refractory multiple myeloma in the era of modern combination therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Treatment of multiple myeloma (MM) has notably evolved with improved patient outcomes over the past few years. Several new drugs have become available, and large national and international clinical trials have set the stage for evidence-based medicine guidelines for the treatment of patients with MM. Although patient outcomes have undoubtedly improved, data increasingly show that several disparities exist at varying levels of health care and that these disparities make the care of patients heterogenous and potentially result in inferior outcomes. These disparities have been described with regard to patient age, race/ethnicity, rural-urban residence, socioeconomic status, and insurance type, among other factors. Looking at the global picture of MM care, there is substantial variation among different countries, primarily depending on the disparate availability of anti-MM drugs and access to quality health care across the world, limiting the delivery of innovative therapeutic approaches at the individual patient level. The causes of these national and international disparities could be multifactorial, intricate, and difficult to isolate. Yet the ongoing research in this field is encouraging, and there seems to be growing momentum to understand such disparities and their causes. It is hoped that this research will lead to solutions that can be implemented in the near future. This review focuses on certain aspects of disparities in MM care, highlighting disparities among different racial/ethnic subgroups, rural-urban differences in America, and global disparities at an international level.

Background: Despite therapeutic advancements that have significantly improved outcomes in multiple myeloma (MM), it remains an incurable disease. Patients with relapsed and/or refractory MM have an aggressive disease course, with inferior outcomes, necessitating the need for agents with novel therapeutic mechanisms. We present the results of a completed phase I trial of single-agent lorvotuzumab mertansine, a unique antibody-drug conjugate targeting CD56, which is frequently expressed in MM., Patients and Methods: Thirty-seven patients with relapsed MM were enrolled in a dose-escalation phase I clinical trial to determine the maximum tolerated dose of lorvotuzumab mertansine (112 mg/m 2 ), followed by an expansion phase at the maximum tolerated dose., Results: Despite a high proportion of patients with relapsed and/or refractory MM (56.8%), stable disease or better was noted in 42.9% of patients, and these patients had a long duration of response (median, 15.5 months). The adverse event profile was favorable, with a low incidence of grade 3/4 adverse events and no infusion-related reactions. No humoral responses were detected against the study drug., Conclusion: This completed phase I trial of single-agent lorvotuzumab mertansine provides ample evidence of safety and signals of clinical activity for this agent, warranting its further clinical development as part of combination regimens for the management of MM., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cholangiocarcinoma (CCA) is a rare, lethal cancer with 5-year survival of less than 10%. Although incidence rates have been increasing in the United States, ethnic variations in survival have not been investigated. We examined multi-ethnic variation in overall survival (OS) and CCA-specific survival (CSS) using data from the population-based Surveillance Epidemiology and End Results (SEER) program in the 4-year period after introduction of gemcitabine/cisplatin (GC) as treatment for CCA, compared with prior years., Methods: The study included data from 5,616 advanced, intrahepatic CCA cases reported in SEER between 1990 and 2013. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated to examine OS and CSS by ethnicity, age, gender and in the pre- and post-GC era (1990-2000, 2001-2009 vs. 2010-2013)., Results: Compared to non-Hispanic Whites, Hispanics had poorer 3-year OS (HR 1.11, 95% CI: 1.03-1.20) and 3-year CSS (HR 1.15, 95% CI: 1.05-1.25). Similarly, non-Hispanic Blacks had 3-year OS (HR 1.21, 95% CI: 1.10-1.34) and 3-year CSS (HR 1.21, 95% CI: 1.09-1.35). Males and older patients had shorter survival compared to females and younger patients. OS and CSS were both improved for patients' post-advent of GC. Statistically significant improvement in CSS pre- and post-advent of GC was noted in non-Hispanic Whites, while Hispanics actually had worsened survival., Conclusions: Hispanics and non-Hispanic Blacks have worse survival after diagnosis with advanced, intrahepatic CCA. Further studies are needed to determine determinants of poor survival among these groups., Competing Interests: Conflicts of Interest: Kabir Mody: (I) research support: Senwha Biociences Inc; Tracon Pharmaceuticals; Genentech; Astrazeneca/Medimmune; Arqule, Inc; Agios; Taiho Oncology; Boston Biomedical; Ipsen; (II) consulting/advisory board: Eisai Co, Ltd.; Bayer Pharmaceuticals; Sikander Ailawadhi: (I) research support: Pharmacyclics, Inc; (II) consulting/advisory board: Takeda Oncology; Novartis Pharmaceuticals; Amgen; Tanios Bekaii-Saab: (I) research support: Boston Biomedical; Bayer; Celgene; Merrimack; (II) consulting/advisory board: Taiho; Bayer; Boehringer Ingelheim; Merrimack; Glenmark; Amgen; Genentech. The other authors have no conflicts of interest to declare.

Background: Treatment of non-small-cell lung cancer (NSCLC) has been rapidly advancing over the last decade. Academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported., Methods: The National Cancer Database (NCDB) was used to identify NSCLC incident cases from 2004 to 2013. Overall survival (OS) was plotted by year of diagnosis and type of initial treatment center, accounting for several factors available in NCDB., Results: A total of 1 150 722 NSCLC patients were included and separated by initial treatment center type (academic: 31.5%; nonacademic: 68.5%). Median follow-up and OS for all patients were 11.8 months (range: 0-133.6 months) and 13.1 months (95% CI: 13.08-13.17), respectively. Median OS improved significantly for those diagnosed in 2010-2013 (14.8 months [95% CI: 14.7-14.9]) as compared to 2004-2009 (12.4 months [95% CI: 12.3-12.5]) (P < 0.001). Treatment at academic centers was associated with improved OS (multivariate HR for OS = 0.929 [95% CI: 0.92-0.94], P < 0.0010). Four-year OS for academic and nonacademic cohorts was 28.5%% and 22.1%, respectively (P < 0.001), and the difference was more pronounced in stage I to III NSCLC., Conclusion: In this largest analysis, thus far, NSCLC survival has improved over time, and type of initial treatment center significantly influences survival. Identifying and removing barriers to obtaining initial treatment of NSCLC at academic medical centers could improve OS., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Palliative care is associated with improved survival and quality of life, but its use among patients with colorectal cancer varies nationwide and the determinants of those variations are not clear., Objective: To determine the factors associated with palliative care use among patients who died of colorectal cancer., Methods: Deceased patients treated for colorectal cancer (2004-2013) were identified within the National Cancer Database. Multivariable logistic regression was used to evaluate patient and institutional characteristics associated with palliative care use. Patients were classified based on their length of survival (<6 months, 6-24 months, and 24+ months) to provide timing context., Results: A total of 287 923 patients were analyzed. Overall, 4.3% of the patients received palliative care. Patients who received palliative care were more likely to be younger, recently diagnosed, treated at academic hospitals, and have stage IV disease. Patients living in Mountain and Pacific regions had higher odds of palliative care receipt than those in the East Coast. Patients without insurance had higher odds of palliative care if they survived <24 months. Insurance coverage through Medicaid was associated with increased palliative care use among patients who survived 6 to 24 months. Patients who survived <6 months and lived >9 miles from the institution received more palliative care., Conclusion: Palliative care use among patients with colorectal cancer is associated with a younger age, a more recent year of diagnosis, insurance status, academic hospitals, and living in Mountain and Pacific regions.

CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Multiple myeloma (MM) occurs in all races, but the incidence in non-Hispanic black patients (NHBs) is two to three times higher than in non-Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p  < .0001) and Hispanic patients (EF 0.04%, p  < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Introduction: The present study analyzed the trends in secondary cancer (SC) risks among Hodgkin lymphoma (HL) patients in the United States., Materials and Methods: Patients with HL diagnosed from 1973 to 2014 were identified from the Surveillance, Epidemiology, and End Results database. We compared the risk of SCs in HL patients relative to the risk in the US general population across 3 periods: 1973 to 1986, 1987 to 2000, and 2001 to 2014 to study the effect of treatment practices on the development of SCs., Results: In a follow-up study of 23,864 HL survivors for 284,730 person-years, 3260 SCs were diagnosed with a standardized incidence ratio (SIR) of 1.97 (95% confidence interval [CI], 1.9-2.04). A statistically significant decrease was found in the overall SIRs of SCs diagnosed in HL patients from 1987 to 2000 (SIR, 1.82; 95% CI, 1.72-1.93) and from 2001 to 2014 (SIR, 1.66; 95% CI, 1.51-1.82) relative to patients with SCs diagnosed from 1973 to 1986 (SIR, 2.24; 95% CI, 2.13-2.35). The decline in the overall SIR mostly resulted from declines in digestive tract and breast cancers. The SIRs of most other solid tumors and hematologic malignancies did not decrease. After adjusting for age, gender, and race, patients with a diagnosis from 1973 to 1986 had a 12% greater risk of developing SCs (hazard ratio, 1.12; 95% CI, 1.03-1.23; P = .01) compared with the patients with a diagnosis from 1987 to 2000., Conclusion: Although the overall risk of SCs in patients with HL declined after modifications in HL treatment, the risk did not change significantly at most individual sites. Thus, close follow-up with active surveillance for SCs is crucial for long-term survivors of HL., (Copyright © 2018. Published by Elsevier Inc.)

The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients' MYD88 L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naïve setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p = 0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p = 0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p = 0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p = 0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p = 0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥ 3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients' MYD88 mutation status.

Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities. Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal. We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM. Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002-2011). African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase. Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents. While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival. While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials. Improved minority accrual in therapeutic clinical trials needs to be a priority.

Background: Palliative care has been increasingly recognized as an important part of cancer care but remains underutilized in patients with solid cancers. There is a current gap in knowledge regarding why palliative care is underutilized nationwide., Objective: To identify the factors associated with palliative care use among deceased patients with solid cancer tumors., Methods: Using the 2016 National Cancer Data Base, we identified deceased patients (2004-2013) with breast, colon, lung, melanoma, and prostate cancer. Data were described as percentages. Associations between palliative care use and patient, facility, and geographic characteristics were evaluated through multivariate logistic regression., Results: A total of 1 840 111 patients were analyzed; 9.6% received palliative care. Palliative care use was higher in the following patient groups: survival >24 months (17% vs 2%), male (54% vs 46%), higher Charlson-Deyo comorbidity score (16% vs 8%), treatment at designated cancer programs (74% vs 71%), lung cancer (76% vs 28%), higher grade cancer (53% vs 24%), and stage IV cancer (59% vs 13%). Patients who lived in communities with a greater percentage of high school degrees had higher odds of receiving palliative care; Central and Pacific regions of the United States had lower odds of palliative care use than the East Coast. Patients with colon, melanoma, or prostate cancer had lower odds of palliative care than patients with breast cancer, whereas those with lung cancer had higher odds., Conclusions: Palliative care use in solid cancer tumors is variable, with a preference for patients with lung cancer, younger age, known insurance status, and higher educational level.

Approximately one third of cancer patients suffer from comorbid mood disorders that are associated with increased cost and poorer outcomes. The majority of patients with multiple myeloma (MM) are treated with corticosteroids; as many as three fourths of those taking corticosteroids develop neuropsychiatric complications, likely increasing morbidity and cost of care. MM patients diagnosed between 1991 and 2010 and reported in the Surveillance Epidemiology, and End Results-Medicare database were characterized as MM-Only, MM+Psychiatric (any psychiatric condition, preexisting or post-MM), or MM+Depression (depression as the only psychiatric diagnosis, preexisting or post-MM). Differences in demographic characteristics, occurrence of clinical myeloma-defining events (MDEs), health care utilization (inpatient, outpatient, ambulatory claims), and cost of care during the first 6 months of MM diagnosis were analyzed. Psychiatric comorbidities were reported more frequently in females, and racial minorities had lower rates of psychiatric comorbidities. All clinical MDEs were more common in the MM+Psychiatric and MM+Depression groups; within them, the majority were more common in patients diagnosed with the psychiatric condition or depression after MM compared with it being a preexisting condition. Health care utilization in all treatment settings was higher in those with psychiatric comorbidities. Cost of care within the first 6 months after MM diagnosis was significantly higher in the MM+Psychiatric and MM+Depression groups. This increase in cost was more pronounced for patients from racial minorities diagnosed with a psychiatric condition, including depression. Psychiatric comorbidities significantly impact the clinical presentations, health care utilization, and cost among patients with MM. These findings need to be addressed for improved survivorship of MM patients., (© 2018 by The American Society of Hematology.)

Background: Outcomes have improved significantly in multiple myeloma (MM), but racial disparities in health care access and survival exist. A comprehensive analysis exploring MM care and racial disparities is warranted., Methods: Patients with MM from 1991 to 2010 in the Surveillance, Epidemiology, and End Results-Medicare database were evaluated for racial trends in clinical myeloma-defining events (MDEs), the receipt of treatment (drugs and stem cell transplantation; [SCT]), the cost of care, and overall survival (OS)., Results: Among 35,842 patients, the frequency of all MDEs at diagnosis increased over time; whereas, in recent years (2006-2010), all MDEs with the exception of renal dialysis decreased. Blacks had highest rates for all MDEs except bone fractures, which were highest in whites. Over time, the proportion of patients who received any treatment, multiple agents, and SCT increased significantly, and the largest increase was observed in the receipt of immunomodulatory drugs and steroids. There was greater receipt of bortezomib and SCT among whites and blacks and higher receipt of immunomodulatory drugs among Hispanics and Asians (P < .001). Medicare claims were highest during first 6 months after MM diagnosis for blacks and at any time after MM diagnosis for Hispanics. Over time, Medicare claims increased most steadily for Hispanics (P < .001). Hypercalcemia, renal dysfunction, and bone fractures were associated with inferior OS. Blacks and Asians had superior OS compared with whites, but racial differences in OS became less pronounced during 2006 through 2010 (P = .182) compared with prior years (P < .01). Better OS was noted among patients who had higher median incomes., Conclusions: The current results indicate that there have been significant changes in the management of patients with MM over time and provide an in-depth understanding of the factors that may help explain racial disparities. Cancer 2018;124:1710-21. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML)., Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy., Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905)., Setting: 63 centers in 18 countries., Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR., Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment., Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point)., Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation., Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment., Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib., Primary Funding Source: Novartis Pharmaceuticals Corporation.

Background: Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma., Methods: We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed., Findings: Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients., Interpretation: Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma., Funding: Sanofi., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A quarter of cancer patients struggle with distress or depression during their illness. Multiple organizations including the National Comprehensive Cancer Network recommend universal screening for distress and depression. Herein, we describe a universal screening program in patients with hematologic malignancies and factors associated with distress and depression. Between December 2013 and February 2015, patients with hematologic malignancies took the Patient Health Questionnaire 9 (PHQ-9) and Distress Thermometer (DT) prior to receiving their first outpatient parenteral chemotherapy. Patient demographic information as well as information regarding visit burden and baseline use of psychiatric medications were recorded. A PHQ-9 score of ≥ 9 and a DT score ≥ 4 suggested a high risk of major depression and distress. Intergroup comparisons of categorical and continuous variables were performed via chi-square and Wilcoxon rank-sum tests. Multivariate models were constructed using the stepwise selection technique using all potential variables. Two hundred forty-six patients with a median age at diagnosis 65 years (range 18-94 years) were included. In the multivariate analysis, a PHQ-9 score ≥ 9 was associated with living alone (P = 0.007), positive PHQ-2 (P = 0.003), and high Charlson comorbidity index (CCI; P = 0.02), while a DT score ≥ 4 was associated with being married (P = 0.03) and female (P = 0.03). There was no other association with high scores on either questionnaire. Patients with hematologic malignancies often have prolonged treatment and surveillance. We identified subpopulations within this group who may be at high risk of developing distress and depression and who should be aggressively screened even when universal screening programs are not available.

Introduction: Optimal scheduling and calendar management in an outpatient chemotherapy unit is a complex process that is driven by a need to focus on safety while accommodating a high degree of variability. Primary constraints are infusion times, staffing resources, chair availability, and unit hours., Methods: We undertook a process to analyze our existing management models across multiple practice settings in our health care system, then developed a model to optimize safety and efficiency. The model was tested in one of the community chemotherapy units. We assessed staffing violations as measured by nurse-to-patient ratios throughout the workday and at key points during treatment. Staffing violations were tracked before and after the implementation of the new model., Results: The new model reduced staffing violations by nearly 50% and required fewer chairs to treat the same number of patients for the selected clinic day. Actual implementation results indicated that the new model leveled the distribution of patients across the workday with an 18% reduction in maximum chair utilization and a 27% reduction in staffing violations. Subsequently, a positive impact on peak pharmacy workload reduced delays by as much as 35 minutes. Nursing staff satisfaction with the new model was positive., Conclusion: We conclude that the proposed optimization approach with regard to nursing resource assignment and workload balance throughout a day effectively improves patient service quality and staff satisfaction.

We conducted a surveillance epidemiology and end results (SEER)-based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5-year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de-novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5-year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10-1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58-1.95, P < 0.001). Hematological-1M sites had significantly higher SIRs (hematological-SIR 7.35; solid-SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5-year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Outcomes have improved considerably in multiple myeloma (MM), but disparities among racial-ethnic groups exist. Differences in utilization of novel therapeutics are likely contributing factors. We explored such differences from the SEER-Medicare database. A utilization analysis of lenalidomide, thalidomide, bortezomib, and stem cell transplant (SCT) was performed for patients diagnosed with MM between 2007 and 2009, including use over time, use by race, time-dependent trends for each racial subgroup, and survival analysis. A total of 5338 MM patients were included with median 2.4-year follow-up. Within the first year of MM diagnosis, utilization of lenalidomide, bortezomib, SCT, and more than one novel agent increased over time while utilization of thalidomide decreased. There was significantly lower utilization of lenalidomide among African-Americans (P < 0.01), higher thalidomide use among Hispanics and Asians (P < 0.01), and lower bortezomib use among Asians (P < 0.01). Hispanics had the highest median number of days to first dose of bortezomib (P = 0.02) and the lowest utilization of SCT (P < 0.01). Hispanics and Asians were the only groups without notable increases in lenalidomide and bortezomib use, respectively. SCT utilization increased over time for all except African-Americans. SCT use within the first year after diagnosis was associated with better overall survival (HR 0.52; 95% CI: 0.4-0.68), while bortezomib use was associated with inferior survival (HR 1.14; 95% CI 1.02-1.28). We noted considerable variability in MM therapeutics utilization with seeming inequity for racial-ethnic minorities. These trends should be considered to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all races., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: We assessed the economic value of carfilzomib 56 mg/m 2 and dexamethasone (Kd56) vs. bortezomib and dexamethasone (Vd) for relapsed/refractory multiple myeloma (R/RMM) using ENDEAVOR trial results., Methods: Cost-effectiveness of Kd56 vs. Vd was assessed using a partitioned survival model by estimating progression-free survival, overall survival, and direct costs over a lifetime horizon. Surveillance Epidemiology and End Results (SEER) survival data were extrapolated after matching registry and ENDEAVOR patients. Utilities were sourced from the literature and mapped from patient-reported quality of life in ENDEAVOR to estimate quality-adjusted life-years (QALYs) from life-years (LYs)., Results: The model predicted an average gain of 1.66 LYs and 1.50 QALYs with Kd56 vs. Vd, and lifetime additional costs of $182,699, resulting in an incremental cost-effectiveness ratio (ICER) of $121,828/QALY gained. The ICER was $114,793/QALY in patients with 1 prior treatment; $99,263/QALY in those not transplanted, and <$150,000/QALY up to an 85% discount in bortezomib price., Conclusions: Kd56 is cost-effective for patients with R/RMM at a willingness-to-pay threshold of $150,000/QALY. Trial data in the model may limit generalizability; however, SEER registry data mitigates this challenge. Kd56 provides additional value in key subgroups, and remains cost-effective after steep comparator discounts.

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88 WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88 L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 (95% confidence interval [CI]: 15-51) and 50 (95% CI: 35-60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23-not reached [NR]) and NR (95% CI: 37-NR), respectively. Twenty-five (86%) of 29 genotyped patients harbored MYD88 L265P . The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well-tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients' MYD88 status., (© 2017 John Wiley & Sons Ltd.)

Objective: Neuropathy is an important complication that may limit treatment options for patients with multiple myeloma. Previous studies have focused on treatment efficacy and have shown that retreatment with bortezomib (BTZ) is an effective treatment option. The goal of this study was to focus on the clinical manifestations of peripheral neuropathy (PN) and to retrospectively compare the incidence and severity of PN between the initial BTZ regimen and upon retreatment. Furthermore, this study evaluated how certain factors affect BIPN, which will help determine what conditions should be considered prior to retreatment., Methods: Charts were reviewed from 93 patients who were retreated with a BTZ-containing regimen after previously being treated with this drug., Results: Among the patients who developed PN, most patients in the study had low-grade neuropathy during the initial BTZ treatment (n = 52, 68%). The results showed no evidence of cumulative toxicity, and there was no significant difference in the incidence and severity of PN upon retreatment. Factors such as the presence of baseline PN, number of prior treatments, dose of BTZ, and comorbidities did not increase the severity of PN upon retreatment. The lapse of time between the two regimens also did not affect the severity of PN., Conclusion: The results suggest that retreatment with BTZ may be a feasible option, without additional risks of PN, for MM patients even with peripheral neuropathy during their initial treatment with this drug.

Purpose: Pomalidomide plus low-dose dexamethasone (POM-d), daratumumab monotherapy (DARA), and carfilzomib monotherapy (CAR) have been approved for use in the treatment of patients with heavily pretreated relapsed-refractory multiple myeloma (RRMM) in the US, based on findings from the MM-002, SIRIUS, and PX-171-003-A1 studies, respectively. The objective of this study was to assess the cost-effectiveness of POM-d, DARA, and CAR in this patient population from a US payer's perspective., Methods: A cost-effectiveness model was developed to estimate the cost and health outcomes over a 3-year time horizon in 3 health states: progression-free, post-progression, and death. The main efficacy data source was a matching-adjusted indirect comparison using data from the aforementioned studies. Direct medical costs were considered, including: treatment acquisition and administration (initial line and subsequent line), pre- and post-medication, prophylaxis treatment, adverse event management, and health care resource utilization. Sensitivity analyses were conducted. A scenario analysis that assumed equal efficacy across all 3 treatments was conducted. Costs, life-years, and quality-adjusted life-years were estimated and discounted at 3% per annum., Findings: Over 3 years, the use of POM-d was associated with similar life-years and quality-adjusted life-years gained compared with DARA and CAR (incremental: life-years, +0.02 and +0.07, respectively; quality-adjusted life-years, +0.01 and +0.05), and with a cost less than that of DARA (-$8,919) and similar to that of CAR (-$195). Sensitivity analyses illustrated that the results were sensitive to progression-free survival, treatment duration, and drug costs. An equal efficacy scenario resulted in cost-savings relative to those of both DARA and CAR (-$11,779 and -$12,595)., Implications: POM-d may be a cost-effective treatment option relative to DARA or CAR in heavily pretreated patients with RRMM in the US., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m 2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m 2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952., (© 2017 by The American Society of Hematology.)

Importance: Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system., Observations: Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant., Conclusions and Relevance: Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.

Multiple myeloma treatment has changed tremendously over recent years leading to overall improvement in patient outcomes. With therapeutic advancements, patient care has become increasingly complex and variability is seen in healthcare delivery as well as outcomes when various patient subgroups are analyzed based on sociodemographic factors. It is imperative to understand this variability so that while overall the outcomes get better, specific focus is placed on subgroups that may remain disadvantaged and may not be able to fully access the advancements in therapeutics. Research in multiple myeloma has specifically looked at several such patient subgroups based on socioeconomic status, age, race/ethnicity, insurance carrier, and geographic location that may affect healthcare utilization and patient outcomes. Exploring and understanding these would certainly help address disparities and lead to further equity in healthcare access and, hopefully, patient outcomes.

Background & Objectives: Rheumatic fever (RF) and rheumatic heart disease (RHD) are the autoimmune sequelae caused by Group A Streptococcus. RHD still remains a major concern in the developing countries due to its poor diagnosis, lack of vaccines and social awareness among population. This study was aimed to identify the plausible early- and late-stage disease markers associated with RF/RHD., Methods: A total of 84 patients with confirmed pharyngitis (n=18), RF (n=23) and RHD (n=43) were included in the comparative analysis of different factors involved in host-pathogen interaction during RF/RHD pathogenesis., Results: This study revealed high titre of serum antistreptolysin O (ASO) antibody in pharyngitis compared to RF and RHD patients, whereas procollagen type 1 C-peptide (PICP) level was elevated in RHD which showed an inverse correlation with serum ASO titre. The significant elevation of serum anti-peptide associated with RF (PARF) antibody in RF patients was correlated as a probable stage-specific determinant. In addition, pro-inflammatory cytokine profile revealed high levels of interleukin-12 (IL-12)/IL-23p40, IL-17A in RF, whereas IL-6 concentration was higher in RHD compared to healthy controls., Interpretation & Conclusions: The overall assessment of the factors/ disease markers involved in host-pathogen interaction in RF/RHD may be suggestive of plausible disease marker in different groups of patients. Further studies with larger sample need to be done to better understand RF/RHD pathogenesis.

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTK C481S and CXCR4 WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTK C481S and CXCR4 WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

Life expectancy in patients with multiple myeloma is increasing because of the availability of an increasing number of novel agents with various mechanisms of action against the disease. However, the disease remains incurable in most patients because of the emergence of resistant clones, leading to repeated relapses of the disease. In 2015, 5 novel agents were approved for therapy for relapsed multiple myeloma. This surfeit of novel agents renders management of relapsed multiple myeloma more complex because of the occurrence of multiple relapses, the risk of cumulative and emergent toxicity from previous therapies, as well as evolution of the disease during therapy. A group of physicians at Mayo Clinic with expertise in the care of patients with multiple myeloma regularly evaluates the evolving literature on the biology and therapy for multiple myeloma and issues guidelines on the optimal care of patients with this disease. In this article, the latest recommendations on the diagnostic evaluation of relapsed multiple myeloma and decision trees on how to treat patients at various stages of their relapse (off study) are provided together with the evidence to support them., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Granulocytic Sarcomas (GS) also called as Myeloid Sarcomas (MS) or chloromas are the representatives of extramedullary infiltrates of immature myeloid cells including myeloblasts, promyelocytes and myelocytes. Primary cardiac malignancies per se are rare and infiltration of cardiac muscles by secondary malignant cells is also an uncommon finding. Out of these cardiac tumors, contribution of Cardiac Myeloid Sarcoma (CMS) is even more smaller thereby limiting our knowledge about this rare entity. Because of its very lower incidence, an exact guideline for diagnosis and management is still missing and usually haematologists around the world are treating CMS based on their clinical acumen. Aim of this review is to briefly discuss the presenting clinical feature, differential diagnosis, diagnostic workup and management based on published articles related to CMS till date.