Browsing by Author "Hardin, James W."
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Item Effect of initial treatment on health-related quality of life in patients with newly diagnosed multiple myeloma without immediate stem cell transplant intent: results from the Connect ® MM Registry(Wiley, 2021-04) Abonour, Rafat; Rifkin, Robert M.; Gasparetto, Cristina; Toomey, Kathleen; Durie, Brian G.M.; Hardin, James W.; Terebelo, Howard R.; Jagannath, Sundar; Narang, Mohit; Ailawadhi, Sikander; Omel, James L.; Lee, Hans C.; Srinivasan, Shankar; Kitali, Amani; Agarwal, Amit; Wagner, Lynne; Medicine, School of MedicineAlthough new multiple myeloma (MM) therapies are effective in alleviating some disease-associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health-related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide-bortezomib-dexamethasone [RVd (n = 445)], bortezomib-melphalan-prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy-Multiple Myeloma subscale, EuroQol-5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real-world, largely community-based population of patients with NDMM.Item Effect of t (11;14) Abnormality on Outcomes of Patients With Newly Diagnosed Multiple Myeloma in the Connect MM Registry(Elsevier, 2022) Gasparetto, Cristina; Jagannath, Sundar; Rifkin, Robert M.; Durie, Brian G. M.; Narang, Mohit; Terebelo, Howard R.; Toomey, Kathleen; Hardin, James W.; Wagner, Lynne; Ailawadhi, Sikander; Omel, James L.; Srinivasan, Shankar; Dhalla, Mazaher; Catamero, Donna; Kitali, Amani; Agarwal, Amit; Abonour, Rafat; Connect MM Registry Investigators; Medicine, School of MedicineBackground: The t (11;14) (q13;32) translocation [t (11;14)] is present in ∼20% of patients with newly diagnosed multiple myeloma (NDMM), but studies examining its prognostic ability have yielded divergent results, and data are lacking on outcomes from first-line therapy. Patients and methods: Data from the Connect MM Registry, a large US, multicenter, prospective observational cohort study of patients with NDMM were used to examine the effect of t (11;14) status on first-line therapy outcomes in the Overall population (n = 1574) and race groups (African American [AA] vs. non-African American [NAA]). Results: Baseline characteristics were generally similar between patients with (n = 378) and without (n = 1196) t (11;14). Prevalence of t (11;14) was similar by race (AA, 27%; NAA, 24%). In the overall population, regardless of first-line therapy, t (11;14) status did not affect progression-free survival (hazard ratio, 1.02; P = 0.7675) or overall survival (hazard ratio, 0.99; P = .9417). AA patients with t (11;14) had higher likelihood of death (Nominal Cox regression P = .0298) vs. patients without t (11;14). Conclusions: Acknowledging observational study and inferential limitations, this exploratory analysis of a predominantly community-based population suggests that t (11;14) is a neutral prognostic factor in the general MM population but may be a negative factor for overall survival in AA patients.Item Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta(Elsevier, 2017-03) Labarrere, Carlos A.; DiCarlo, Hector L.; Bammerlin, Elaine; Hardin, James W.; Kim, Yeon Mee; Chaemsaithong, Piya; Haas, David M.; Kassab, Ghassan S.; Romero, Roberto; Obstetrics and Gynecology, School of MedicineBACKGROUND: Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. OBJECTIVE: We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. STUDY DESIGN: A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025). RESULTS: We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker (P < .001). A significant correlation (R2 = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were intercellular adhesion molecule-1-positive, in none of the 14 placentas with failure of physiologic transformation that were intercellular adhesion molecule-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure (P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation. CONCLUSION: Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies.Item Heterogeneity of Second-Line Treatment for Patients With Multiple Myeloma in the Connect MM Registry (2010-2016)(Elsevier, 2018-07-01) Jagannath, Sundar; Abonour, Rafat; Durie, Brian G. M.; Gasparetto, Cristina; Hardin, James W.; Narang, Mohit; Terebelo, Howard R.; Toomey, Kathleen; Wagner, Lynne; Srinivasan, Shankar; Kitali, Amani; Yue, Lihua; Flick, E. Dawn; Agarwal, Amit; Rifkin, Robert M.; Medicine, School of MedicineBackground The treatment landscape for multiple myeloma (MM) has undergone recent changes with the regulatory approval of several new therapies indicated for second- and later-line disease. Using data from Connect MM, the largest multisite, primarily community-based, prospective, observational registry of MM patients in the United States, selection of second-line treatments was evaluated during a 5-year period from 2010 to 2016. Patients and Methods Eligible patients were aged ≥ 18 years, had newly diagnosed MM ≤ 2 months before study entry, and were followed for up to 8 years. Patients who received ≥ 2 lines of therapy were analyzed. “Tepee” plots of stacked area graphs differentiated treatments by color to allow visualization of second-line treatment trends in MM patients. Results As of February 2017, 855 of 2897 treated patients had progressed to second-line treatment. Treatment selection was heterogeneous; shifting patterns of treatment choices coincided with the approval status of newer agents. The most common treatment regimens in the early part of the decade were lenalidomide and/or bortezomib, with or without dexamethasone, with increasing use of newer agents (carfilzomib, pomalidomide, daratumumab, and elotuzumab) and triplet combinations over time. The influence of the baseline patient characteristics of age, history of diabetes, peripheral neuropathy, and renal function on treatment choice was also examined. Conclusion These findings indicate that community physicians are current in their MM management practices, with uptake of new drugs and acquaintance with results of randomized clinical trials using combinations almost concurrent with their regulatory approval and publication.Item Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect® MM Registry(Springer, 2018-12) Abonour, Rafat; Wagner, Lynne; Durie, Brian G.M.; Jagannath, Sundar; Narang, Mohit; Terebelo, Howard R.; Gasparetto, Cristina J.; Toomey, Kathleen; Hardin, James W.; Kitali, Amani; Gibson, Craig J.; Srinivasan, Shankar; Swern, Arlene S.; Rifkin, Robert M.; Medicine, School of MedicineMaintenance therapy after autologous stem cell transplantation (ASCT) is recommended for use in multiple myeloma (MM); however, more data are needed on its impact on health-related quality of life (HRQoL). Presented here is an analysis of HRQoL in a Connect MM registry cohort of patients who received ASCT ± maintenance therapy. The Connect MM Registry is one of the earliest and largest, active, observational, prospective US registry of patients with symptomatic newly diagnosed MM. Patients completed the Functional Assessment of Cancer Therapy-MM (FACT-MM) version 4, EuroQol-5D (EQ-5D) questionnaire, and Brief Pain Inventory (BPI) at study entry and quarterly thereafter until death or study discontinuation. Patients in three groups were analyzed: any maintenance therapy (n = 244), lenalidomide-only maintenance therapy (n = 169), and no maintenance therapy (n = 137); any maintenance and lenalidomide-only maintenance groups were not mutually exclusive. There were no significant differences in change from pre-ASCT baseline between any maintenance (P = 0.60) and lenalidomide-only maintenance (P = 0.72) versus no maintenance for the FACT-MM total score. There were also no significant differences in change from pre-ASCT baseline between any maintenance and lenalidomide-only maintenance versus no maintenance for EQ-5D overall index, BPI, FACT-MM Trial Outcomes Index, and myeloma subscale scores. In all three groups, FACT-MM, EQ-5D Index, and BPI scores improved after ASCT; FACT-MM and BPI scores deteriorated at disease progression. These data suggest that post-ASCT any maintenance or lenalidomide-only maintenance does not negatively impact patients' HRQoL. Additional research is needed to verify these findings.Item Ischemia considerations for the development of an organ and tissue donor derived bone marrow bank(BMC, 2020-08-05) Woods, Erik J.; Sherry, Aubrey M.; Woods, John R.; Hardin, James W.; LaFontaine, Michael; Brandacher, Gerald; Johnstone, Brian H.; Medical and Molecular Genetics, School of MedicineBackground Deceased organ donors represent an untapped source of therapeutic bone marrow (BM) that can be recovered in 3–5 times the volume of that obtained from living donors, tested for quality, cryopreserved, and banked indefinitely for future on-demand use. A challenge for a future BM banking system will be to manage the prolonged ischemia times that are inevitable when bones procured at geographically-dispersed locations are shipped to distant facilities for processing. Our objectives were to: (a) quantify, under realistic field conditions, the relationship between ischemia time and the quality of hematopoietic stem and progenitor cells (HSPCs) derived from deceased-donor BM; (b) identify ischemia-time boundaries beyond which HSPC quality is adversely affected; (c) investigate whole-body cooling as a strategy for preserving cell quality; and (d) investigate processing experience as a variable affecting quality. Methods Seventy-five bones from 62 donors were analyzed for CD34+ viability following their exposure to various periods of warm-ischemia time (WIT), cold-ischemia time (CIT), and body-cooling time (BCT). Regression models were developed to quantify the independent associations of WIT, CIT, and BCT, with the viability and function of recovered HSPCs. Results Results demonstrate that under “real-world” scenarios: (a) combinations of warm- and cold-ischemia times favorable to the recovery of high-quality HSPCs are achievable (e.g., CD34+ cell viabilities in the range of 80–90% were commonly observed); (b) body cooling prior to bone recovery is detrimental to cell viability (e.g., CD34+ viability < 73% with, vs. > 89% without body cooling); (c) vertebral bodies (VBs) are a superior source of HSPCs compared to ilia (IL) (e.g., %CD34+ viability > 80% when VBs were the source, vs. < 74% when IL were the source); and (d) processing experience is a critical variable affecting quality. Conclusions Our models can be used by an emerging BM banking system to formulate ischemia-time tolerance limits and data-driven HSPC quality-acceptance standards. Keywords: Deceased-donor bone marrow, Bone marrow banking, Bone marrow ischemia time, Hematopoietic stem cell transplantItem Recognition of early mortality in multiple myeloma by a prediction matrix(Wiley, 2017) Terebelo, Howard; Srinivasan, Shankar; Narang, Mohit; Abonour, Rafat; Gasparetto, Cristina; Toomey, Kathleen; Hardin, James W.; Larkins, Gail; Kitali, Amani; Rifkin, Robert M.; Shah, Jatin J.; Department of Medicine, IU School of MedicineEarly mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes.Item Treatment Outcomes and Health Care Resource Utilization in Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide-only Maintenance, Any Maintenance, or No Maintenance: Results from the Connect MM Registry(Elsevier, 2018-07-01) Rifkin, Robert M.; Jagannath, Sundar; Durie, Brian G. M.; Narang, Mohit; Terebelo, Howard R.; Gasparetto, Cristina J.; Toomey, Kathleen; Hardin, James W.; Wagner, Lynne; Parikh, Kejal; Abouzaid, Safiya; Srinivasan, Shankar; Kitali, Amani; Zafar, Faiza; Abonour, Rafat; Medicine, School of MedicinePurpose Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown. Methods Here we present an analysis of HCRU and clinical outcomes in a cohort of patients from the Connect MM registry, the largest, ongoing, observational, prospective US registry of patients with symptomatic newly diagnosed MM. In this study, patients with newly diagnosed MM who completed induction and single ASCT without subsequent consolidation received lenalidomide-only maintenance (n = 180), any maintenance (n = 256), or no maintenance (n = 165). HCRU (hospitalization, surgery/procedures, and concurrent medications [growth factors, bisphosphonates, or neuropathic pain medication]) was assessed starting from 100 days post-ASCT for up to 2 years. Findings Although the rates of hospitalization per 100 person-years were similar across groups at the end of years 1 and 2, the median duration of hospitalization was numerically longer with no maintenance. The rates of use of growth factors, bisphosphonates, and neuropathic pain medication were generally similar in all 3 groups. The receipt of any maintenance was associated with significantly reduced use of neuropathic pain medications during year 1. Of note, lenalidomide-only maintenance was associated with significantly longer progression-free survival (54.5 vs 30.4 months; hazard ratio [HR] = 0.58; 95% CI, 0.43–0.79; P = 0.0005) and overall survival (OS) (median OS not reached in either group; HR = 0.45; 95% CI, 0.28–0.73; P = 0.001) compared with no maintenance. Likewise, the group treated with any maintenance had significantly longer median progression-free survival (44.7 vs 30.4 months; HR = 0.62; 95% CI, 0.47–0.82; P = 0.0008) and OS (median OS not reached in either group; HR = 0.50; 95% CI, 0.33–0.76; P = 0.001) than did the group that did not receive maintenance. Implications These findings suggest that in this largely community-based study population, post-ASCT maintenance therapy, including lenalidomide-only maintenance, improves clinical outcomes without negatively affecting HCRU. ClinicalTrials.gov identifier: NCT01081028.Item Treatment patterns and outcomes in elderly patients with newly diagnosed multiple myeloma: results from the Connect® MM Registry(Springer Nature, 2021-07-23) Lee, Hans C.; Ailawadhi, Sikander; Gasparetto, Cristina J.; Jagannath, Sundar; Rifkin, Robert M.; Durie, Brian G. M.; Narang, Mohit; Terebelo, Howard R.; Toomey, Kathleen; Hardin, James W.; Wagner, Lynne; Omel, James L.; Dhalla, Mazaher; Liu, Liang; Joshi, Prashant; Abonour, Rafat; Connect® MM Registry; Medicine, School of MedicineItem Treatment Patterns, Survival, Quality of Life, and Healthcare Resource Use Among Patients With Triple-Class Refractory Multiple Myeloma in US Clinical Practice: Findings From the Connect MM Disease Registry(Elsevier, 2023) Lee, Hans C.; Ramasamy, Karthik; Weisel, Katja; Abonour, Rafat; Hardin, James W.; Rifkin, Robert M.; Ailawadhi, Sikander; Terebelo, Howard R.; Durie, Brian G. M.; Tang, Derek; Joshi, Prashant; Liu, Liang; Jou, Ying-Ming; Che, Min; Hernandez, Gabriela; Narang, Mohit; Toomey, Kathleen; Gasparetto, Cristina; Wagner, Lynne I.; Jagannath, Sundar; Medicine, School of MedicineBackground: Adults with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognosis, but the burden of TCR MM has not been well characterized. This study evaluated treatment patterns, overall survival (OS), health-related quality of life (HRQoL), and healthcare resource use (HCRU) among patients with TCR MM in US clinical practice. Patients and methods: Patients with TCR MM in the Connect MM Registry (NCT01081028; a large, US, multicenter, prospective observational cohort study of patients with newly diagnosed MM) were included. Patient characteristics, treatment patterns, HRQoL, and HCRU were analyzed using descriptive statistics. OS was calculated using Kaplan-Meier methodology for the overall cohort and for patients with/without ≥1 post-TCR line of therapy (LOT). Results: A total of 232 patients with TCR MM were included; 155 (67%) had ≥1 post-TCR LOT (post-TCR-Treated subgroup; median 9.9 months of follow-up). Most common post-TCR treatments were carfilzomib (47%), pomalidomide (40%), and daratumumab (26%); median treatment duration was 3.3 months. Median OS was 9.9 months in the overall population, 10.8 months in post-TCR-Treated patients, and 2.6 months for those with no new post-TCR LOT. HRQoL deteriorated and pain increased over 1 year of follow-up, with clinically meaningfully changes in EQ-5D (mean, -0.06 points) and FACT-G (mean, -9.9 points). 124 (53%) patients had ≥1 all-cause hospitalization and 58 (25%) had ≥1 MM-related hospitalization; median annualized length of stay was 35.3 and 42.9 days, respectively. Conclusion: The burden of TCR MM is substantial, emphasizing the need for more effective treatment options in the TCR setting.