Publications by authors named "Manisha Bhutani"

65 Publications

Thromboembolism Incidence and Risk Factors in Multiple Myeloma After First Exposure to Immunomodulatory Drug-Based Regimens.

Clin Lymphoma Myeloma Leuk 2021 Mar 28;21(3):188-198.e2. Epub 2020 Nov 28.

Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC.

Background: We evaluated time to thromboembolism (TE) and risk factors in multiple myeloma (MM) patients after first exposure to immunomodulatory therapy, stratified by thromboprophylaxis.

Patients And Methods: We retrospectively analyzed adult MM patients who received immunomodulatory therapy with or without dexamethasone between February 2012 and October 2017. Thromboprophylaxis included aspirin, anticoagulants (low-molecular-weight heparin, direct oral anticoagulants, or warfarin), or none. Primary endpoint was time to on-treatment TE by thromboprophylaxis type. Time to TE using death as a competing risk censored at 12 months was used in univariate and multivariable analyses to identify risk factors.

Results: Of 485 evaluable patients, 57% were white and 36% African American; median age was 66. Most received lenalidomide (97.5%) and dexamethasone (90%). Half presented with ≥ 1 comorbidities. Sixty-nine had no documented receipt of prophylaxis, 357 aspirin, and 59 anticoagulation. More patients receiving anticoagulants had ≥ 1 comorbidities compared to aspirin or no-prophylaxis groups (P < .001). There was no difference in 12-month estimated cumulative incidence of TE (7.3%; 95% confidence interval, 5.2-9.9) between thromboprophylaxis groups (none 4.4%, aspirin 8.5%, anticoagulant 3.4%) (P = .24). In multivariable analyses, male sex (hazard ratio, 2.50; 95% confidence interval, 1.21-5.17; P = .014) and presence of any comorbidity (hazard ratio, 2.35; 95% confidence interval, 1.17-4.73; P = .016) were associated with TE incidence; thromboprophylaxis type was not (P = .12).

Conclusion: Male sex and presence of any comorbidity were associated with time to TE. There were no differences in TE incidence between thromboprophylaxis groups despite a higher proportion of those in the anticoagulant group having ≥ 1 comorbidities.
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http://dx.doi.org/10.1016/j.clml.2020.11.015DOI Listing
March 2021

Daratumumab subcutaneous formulation for the treatment of multiple myeloma.

Expert Opin Biol Ther 2020 11 16;20(11):1253-1259. Epub 2020 Aug 16.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: Intravenous daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of daratumumab was approved for use in both the United States and European Union based on data which showed shorter infusion times and decreased rate of infusion reactions while maintaining non-inferior efficacy.

Areas Covered: We cover the physiology behind subcutaneous daratumumab and summarize the relevant clinical data with a particular focus on the pharmacokinetics, pharmacodynamics, safety, and clinical efficacy. Articles used to generate this review were obtained by searching pubmed (https://pubmed.ncbi.nlm.nih.gov/) with the search terms 'subcutaneous daratumumab' and 'daratumumab hyaluronidase'.

Expert Opinion: Subcutaneous daratumumab is associated with lower risk of infusion reactions and decreased administration time while maintaining non-inferior efficacy. We support the use of subcutaneous daratumumab for all approved indications and for investigational use moving forward.
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http://dx.doi.org/10.1080/14712598.2020.1806231DOI Listing
November 2020

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

Clin Lymphoma Myeloma Leuk 2020 10 7;20(10):e777-e781. Epub 2020 Jun 7.

Department of Hematologic Oncology and Blood Disorders, Atrium Health, Levine Cancer Institute, Charlotte, NC.

Background: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs.

Patients And Methods: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion.

Results: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations.

Conclusion: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.
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http://dx.doi.org/10.1016/j.clml.2020.05.024DOI Listing
October 2020

An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma.

Expert Rev Hematol 2020 08 20;13(8):795-802. Epub 2020 Sep 20.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: A subcutaneous formulation of daratumumab, a human immunoglobulin G1 kappa monoclonal antibody targeting CD38, recently achieved FDA approval for both newly diagnosed and relapsed refractory multiple myeloma amid promises to decrease infusion times and rates of infusion reactions in myeloma patients.

Areas Covered: In this article the biology behind subcutaneous administration of oncologic antibody therapies is reviewed and the subcutaneous formulation of daratumumab is covered in depth. The most recent results from the PAVO, COLUMBA, and PLEIADES clinical trials evaluating subcutaneous daratumumab as a single agent, and in combination, in both newly diagnosed, and relapsed and refractory myeloma patients are summarized. The efficacy, safety, and PK data from these trials are reviewed, and the potential of the subcutaneous formulation to improve quality of life in myeloma patients and decrease healthcare resource use is discussed.

Expert Opinion: Subcutaneous daratumumab is non-inferior to conventional intravenous daratumumab with lower risk of infusion-related reactions and decreased administration time. Based on these data, and the recent FDA and European Commission approvalsthe widespread use of the subcutaneous formulation for both conventional and investigational practice is supported.
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http://dx.doi.org/10.1080/17474086.2020.1795829DOI Listing
August 2020

Management of newly diagnosed transplant ineligible multiple myeloma.

Leuk Lymphoma 2020 11 4;61(11):2549-2560. Epub 2020 Jul 4.

Department of Hematologic Oncology & Blood Disorders, Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Multiple myeloma (MM) is a chronically managed blood cancer with a median age of 69 years at the time of diagnosis. Although high dose melphalan and autologous stem cell transplantation (ASCT) remains a standard of care for eligible patients, more than half of the newly diagnosed MM patients are deemed ineligible due to comorbidities or complications of the disease by itself. In this setting, where ASCT is deemed inappropriate, patients could still achieve durable and deep responses if given the appropriate treatment plan. The key concepts of optimizing induction and maintenance strategies while minimizing side-effects are discussed in this review, especially in the context of employing novel agent combinations. It is important to understand the balance between safety and efficacy for each regimen, utilizing maintenance strategy and the best supportive care measures (bone health, infection prevention, and treatment, pain management, etc.). Here, we examine the evidence behind each of those principles and review results from clinical trials for transplant-ineligible (TI) MM.
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http://dx.doi.org/10.1080/10428194.2020.1786558DOI Listing
November 2020

Summary of the 2019 Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling.

Biol Blood Marrow Transplant 2020 10 24;26(10):e247-e255. Epub 2020 Jun 24.

Roswell Park Comprehensive Cancer Center, Buffalo, New York.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529908PMC
October 2020

Safety and Cost Benefits of the Rapid Daratumumab Infusion Protocol.

Clin Lymphoma Myeloma Leuk 2020 08 7;20(8):526-532.e1. Epub 2020 Mar 7.

Plasma Cell Disorders Division, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC. Electronic address:

Introduction: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol.

Patients And Methods: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity.

Results: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively.

Conclusion: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.clml.2020.02.014DOI Listing
August 2020

Quadruplets come of age for newly diagnosed multiple myeloma.

Lancet 2020 01 10;395(10218):94-96. Epub 2019 Dec 10.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute-Atrium Health, Charlotte, NC 28204, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(19)33063-6DOI Listing
January 2020

Extramedullary multiple myeloma.

Leukemia 2020 01 27;34(1):1-20. Epub 2019 Nov 27.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Extramedullary multiple myeloma (EMM) is an aggressive subentity of multiple myeloma, characterized by the ability of a subclone to thrive and grow independent of the bone marrow microenvironment, resulting in a high-risk state associated with increased proliferation, evasion of apoptosis and treatment resistance. Despite improvement in survival for most patients with multiple myeloma over recent decades, outcomes are generally poor when EMM develops. Understanding the molecular underpinnings leading to homing of plasma cells in ecosystems outside the bone marrow will be crucial for therapeutically manipulating the microenvironment and targeting key signaling pathways. Herein, we discuss the evolutionary biology of EMM, underscore the importance of a uniform definition, discuss prognostic significance, and provide current and emerging treatment strategies for managing this rare subentity of multiple myeloma.
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http://dx.doi.org/10.1038/s41375-019-0660-0DOI Listing
January 2020

A Review of Growth Factor Support in Bloodless Autologous Hematopoietic Stem Cell Transplant.

Biol Blood Marrow Transplant 2019 10 8;25(10):e305-e309. Epub 2019 Jul 8.

Pennsylvania Hospital, Center for Bloodless Medicine and Surgery, Philadelphia, , Pennsylvania.

Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.003DOI Listing
October 2019

Viral, immunologic, and clinical features of primary effusion lymphoma.

Blood 2019 04 19;133(16):1753-1761. Epub 2019 Feb 19.

HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent, and ∼80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, virologic, and immunologic features vs 20 patients with HIV-associated diffuse large B-cell lymphoma and 19 patients with symptomatic interleukin (IL)-6 related KSHV-associated multicentric Castleman disease. Survival analyses of treated patients with PEL were then performed to identify prognostic factors and cancer-specific mortality. Compared with HIV-associated diffuse large B-cell lymphoma, PEL was associated with significant hypoalbuminemia ( < .0027), thrombocytopenia ( = .0045), and elevated IL-10 levels ( < .0001). There were no significant differences in these parameters between PEL and KSHV-associated multicentric Castleman disease. Median overall survival in treated patients with PEL was 22 months, with a plateau in survival noted after 2 years. Three-year cancer-specific survival was 47%. EBV-positive tumor status was associated with improved survival (hazard ratio, 0.27; = .038), and elevated IL-6 level was associated with inferior survival (hazard ratio, 6.1; = .024). Our analysis shows that IL-6 and IL-10 levels contribute to the natural history of PEL. Inflammatory cytokines and tumor EBV status are the strongest prognostic factors. Pathogenesis-directed first-line regimens are needed to improve overall survival in PEL.
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http://dx.doi.org/10.1182/blood-2019-01-893339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473499PMC
April 2019

Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma.

Br J Haematol 2019 07 11;186(1):140-144. Epub 2018 Dec 11.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.

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http://dx.doi.org/10.1111/bjh.15716DOI Listing
July 2019

Peripheral Immunotype Correlates with Minimal Residual Disease Status and Is Modulated by Immunomodulatory Drugs in Multiple Myeloma.

Biol Blood Marrow Transplant 2019 03 24;25(3):459-465. Epub 2018 Nov 24.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina. Electronic address:

Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug-mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRD versus MRD status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRD response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRD group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRD versus MRD patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRD patients. Put together, these observations provide a distinctive signature for MRD and MRD groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.015DOI Listing
March 2019

Daratumumab, pomalidomide, and dexamethasone as a bridging therapy to autologous stem cell transplantation in a case of systemic light-chain amyloidosis with advanced cardiac involvement.

J Oncol Pharm Pract 2019 Jun 26;25(4):1021-1025. Epub 2018 Nov 26.

2 Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.

Systemic light-chain (AL) amyloidosis is a rare hematologic disorder where proteins infiltrate tissues leading to organ failure and death. Cardiac involvement, present in ∼70% of patients, determines stage and prognosis of the disease, with advanced involvement having a median survival of six months. The treatment of light-chain amyloidosis is directed at recovering organ function with therapeutic strategies following those of multiple myeloma with plasma cell-directed therapies. The use of single agent daratumumab has been reported in light-chain amyloidosis achieving rapid and deep responses. The combination of daratumumab, pomalidomide, and dexamethasone (DaraPomD) is particularly interesting for severe AL based on success in multiple myeloma. A 43-year-old female with light-chain amyloidosis and concomitant multiple myeloma presented with severe bowel dysmotility causing abdominal pain, anemia, and a 100-pound unintentional weight loss. A combination of cyclophosphamide, bortezomib, and dexamethasone was initiated but after five cycles her symptoms were progressing and therapy was switched to DaraPomD to optimize response. At the conclusion of two cycles she had achieved an amyloid complete-hematologic response, with her recurring ileus and abdominal pain significantly improved. Additionally, cardiac markers also suggested a rapid response without a common paradoxical worsening of congestive heart failure, and was overall well tolerated. Given the severe symptoms and refractory nature of our patient's disease DaraPomD was reasonable. With the tolerability and response seen, this patient experience supports a formal clinical trial evaluating the safety and efficacy of DaraPomD in light-chain amyloidosis.
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http://dx.doi.org/10.1177/1078155218815305DOI Listing
June 2019

Summary of the Second Annual BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling.

Biol Blood Marrow Transplant 2019 03 5;25(3):e89-e97. Epub 2018 Nov 5.

The Transplant & Cellular Therapy Center, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

The second annual Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 7, 2017, at the American Society of Hematology (ASH) meeting. During this workshop, investigators from around the world presented their latest research involving assessment of minimal residual disease (MRD) and immune profiling (IP) in myeloma. This document summarizes the workshop presentations as well as relevant ASH abstracts and focuses on the regulatory issues involved in the integration of MRD and IP assessment in clinical trial design and practice.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445685PMC
March 2019

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma.

Bone Marrow Transplant 2018 11 4;53(11):1445-1449. Epub 2018 May 4.

Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection.
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http://dx.doi.org/10.1038/s41409-018-0170-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6740327PMC
November 2018

Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma.

Blood Adv 2017 Oct 29;1(22):1911-1918. Epub 2017 Sep 29.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Early results of a prospective phase 2 clinical trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance in high-risk smoldering myeloma showed promising results that were previously published. Here, we provide novel insights into the genetic landscape of high-risk smoldering myeloma and information on sustained minimal residual disease (MRD) negativity with an expanded cohort of patients. Eighteen patients with high-risk smoldering myeloma were enrolled between 29 May 2012, and 14 January 2014. We included patients with newly diagnosed multiple myeloma enrolled in a parallel trial who received the same therapy (reference group). The overall response rate was 100%. With median potential follow-up of 43.3 months, 10 (63%) remain in MRD negativity, and the estimated 4-year progression-free and overall survival rates are 71% and 100%, respectively. Importantly, we report differences in mutational patterns in patients with high-risk smoldering myeloma and newly diagnosed multiple myeloma, reflected in a lower frequency of mutations in significant myeloma genes (6.6% vs 45%) and pathway genes (6.6% vs 25%). Treatment with carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance was associated with a 100% response rate and 63% MRD negativity with a safety profile consistent with previous reports for this regimen. This study had a small numbers of participants, but there seemed to be important differences in the genetic landscape of patients with high-risk smoldering myeloma and those with newly diagnosed multiple myeloma, suggestive of a more treatment-responsive biology in early disease.
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http://dx.doi.org/10.1182/bloodadvances.2017005934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728141PMC
October 2017

Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials.

Lancet Haematol 2017 Sep;4(9):e443-e451

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC, USA. Electronic address:

Background: Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key components of treatment regimens for multiple myeloma. Nonetheless, outcomes vary among treated individuals. Drug-specific gene-expression profile (GEP) signatures that aid the prediction of favourable and unfavourable outcomes can provide patients with the most effective therapy for their individual disease. We aimed to develop and validate a gene expression signature to suggest which patients would benefit most from IMiD-based therapies.

Methods: For this exploratory retrospective study, we selected a cohort of patients with newly diagnosed or relapsed or refractory multiple myeloma who were treated in clinical trials with IMiD-containing regimens. Cohorts were eligible if they had publicly available GEP data from patients' bone marrow plasma cells, with long-term follow-up and clinicopathological data. In the development stage of the model, we identified 176 IMiD response genes that were differentially expressed before and after IMiD exposure using pharmacogenomic GEP data from patients who had bone marrow samples taken before and 48 h after a test dose exposure with thalidomide (n=42), lenalidomide (n=18), or pomalidomide (n=18). 14 of these genes had p values less than 0·05 for associations with progression-free survival in patients who received thalidomide in induction and maintenance therapy in the Total Therapy (TT) 2 trial (ie, the training cohort). We combined the 14 genes to create a continuous IMiD-14 score and an optimal cutoff. The subgroup with an IMiD-14 score higher than the cutoff was deemed to be IMiD-resistant. We obtained validation cohorts from four studies of IMiD combination regimens: the TT3a trial (thalidomide in induction and maintenance), the TT3b trial (thalidomide in induction and lenalidomide in maintenance), the TT6 trial (thalidomide in induction and lenalidomide in maintenance), and the vincristine, doxorubicin, and dexamethasone (VAD) group of the HOVON65/GMMG-HD4 trial (thalidomide in maintenance). The primary endpoint was to show the prognostic value of the IMiD-14 gene signature for progression-free survival.

Findings: In the training cohort, progression-free survival was significantly shorter in the 83 patients with IMiD-14 high scores than in the 92 patients with IMiD-14 low scores; 3 year progression-free survival was 52% (95% CI 42-64) for the IMiD-14 high group versus 85% (78-92) for the IMiD-14 low group, with a hazard ratio (HR) of 2·51 (95% CI 1·72-3·66; p<0·0001). These findings were supported by the results in the validation cohorts, TT3a (115 patients with IMiD-14 high vs 160 patients with IMiD-14 low; 3 year progression-free survival 63% [95% CI 55-73] vs 87% [82-92]; HR 1·54 [1·11-2·15], p=0·010), TT3b (77 patients with IMiD-14 high vs 89 patients with IMiD-14 low; 62% [52-74] vs 80% [72-89]; HR 2·07 [1·28-3·34], p=0·0024), TT6 (20 patients with IMiD-14 high vs 36 patients with IMiD-14 low; 39% [22-68] vs 74% [61-90]; HR 2·40 [1·09-5·30], p=0·026), and the VAD group of HOVON65/GMMG-HD4 (65 patients with IMiD-14 high vs 77 patients with IMiD-14 low; 16% [9-28] vs 54% [44-67]; HR 2·29 [1·52-3·45], p<0·0001).

Interpretation: Our results suggest that the IMiD-14 model has prognostic value in patients with multiple myeloma who are treated with IMiDs. Some genes in the model could provide novel targets for IMiD resistance and therapeutic intervention. The IMiD-14 model warrants evaluation in prospective studies.

Funding: Conquer Cancer Foundation ASCO Young Investigator Award and the Carolinas Myeloma Research Fund.
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http://dx.doi.org/10.1016/S2352-3026(17)30143-6DOI Listing
September 2017

Host-related immunodeficiency in the development of multiple myeloma.

Leuk Lymphoma 2018 05 9;59(5):1127-1132. Epub 2017 Aug 9.

b Myeloma Service, Department of Medicine , Memorial Sloan-Kettering Cancer Center , New York , NY, USA.

Host-related immunodeficiency is known to play a role in the development of multiple myeloma (MM) from its precursor conditions (monoclonal gammopathy of undetermined significance, MGUS, smoldering multiple myeloma, SMM). In order to understand the underlying immune changes in this process, we characterized immune patterns from MGUS to SMM to MM. We further sought to identify potential novel immune biomarkers that may predict progression of SMM to MM. We characterized patterns of circulating lymphocytes in 181 patients using multiparametric flow cytometry. We found decreased B- (p = .0003), increased T- (p = .037) and unaltered NK cell proportions from MGUS to SMM to MM. To gain insights into functional variability, we further characterized immunophenotypic lymphocyte subsets, which uncovered differences in CD57 subsets. Specifically, we found that SMM patients who eventually progressed to MM showed decreased proportions of CD57-CD56 + (p = .0061) and CD57-CD16 + (p = .035) lymphocyte subsets. We thus report novel data characterizing the nature of host-related immunodeficiency in the development of MM. We show sequential changes in lymphocyte subsets from MGUS to SMM to MM. We further suggest that CD57 subsets may serve as potential markers of progression from SMM to MM. Our findings support the study of lymphocyte subsets in the search for immune biomarkers. Such markers could provide clinical guidance in managing myeloma precursor disease.
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http://dx.doi.org/10.1080/10428194.2017.1361026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750254PMC
May 2018

Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma.

Drug Des Devel Ther 2017 20;11:893-900. Epub 2017 Mar 20.

Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute, Carolinas Healthcare System, UNC School of Medicine, Charlotte, NC, USA.

Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGκ) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations.
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http://dx.doi.org/10.2147/DDDT.S98053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367738PMC
May 2017

Practical Considerations in Managing Relapsed Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2017 02 23;17(2):69-77. Epub 2016 Nov 23.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC. Electronic address:

Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma, with numerous novel agents and combination strategies receiving regulatory approval worldwide during the past several years. An increasing body of phase III data has clearly demonstrated increased overall response rates, improved depths of response, and more durable responses when a third novel agent is incorporated into lenalidomide-dexamethasone and bortezomib-dexamethasone platforms, in most cases with acceptable toxicity. The carfilzomib-dexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. We review the data supporting the use of these novel treatment paradigms for relapsed/refractory multiple myeloma, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space, and propose strategies to best use these regimens, considering the disease, host, and previous treatment factors.
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http://dx.doi.org/10.1016/j.clml.2016.11.010DOI Listing
February 2017

Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone.

Leuk Lymphoma 2017 03 9;58(3):639-645. Epub 2016 Aug 9.

a Multiple Myeloma Section , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.

The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p <0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma.
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http://dx.doi.org/10.1080/10428194.2016.1214953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357961PMC
March 2017

Cutaneous manifestations of multiple myeloma and other plasma cell proliferative disorders.

Semin Oncol 2016 06 23;43(3):395-400. Epub 2016 Feb 23.

Plasma Cell Disorders Program, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC. Electronic address:

Plasma cell proliferative disorders cause rare but extremely varied dermatologic manifestations that may occur as an accompaniment to established diagnoses, or may be a first clue of an underlying neoplasm in the setting of clinical suspicion. In some instances skin lesions result from aggregation of misfolded monoclonal immunoglobulins or their fragments, as in light chain-related systemic amyloidosis. On other occasions the cutaneous lesions result from deposits of malignant plasma cells or monoclonal proteins. In still others, the dermatologic manifestations are related to antibody activity of monoclonal protein, as in many cases of cryoglobulinemia. This report provides insights into the well-recognized cutaneous manifestations associated with plasma cell disorders.
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http://dx.doi.org/10.1053/j.seminoncol.2016.02.017DOI Listing
June 2016

Bone marrow abnormalities and early bone lesions in multiple myeloma and its precursor disease: a prospective study using functional and morphologic imaging.

Leuk Lymphoma 2016 May 7;57(5):1114-21. Epub 2016 Apr 7.

a Multiple Myeloma Section , Lymphoid Malignancies Branch, CCR, NCI, NIH , Bethesda , MD , USA ;

The incidence and importance of bone marrow involvement and/or early bone lesions in multiple myeloma (MM) precursor diseases is largely unknown. This study prospectively compared the sensitivity of several imaging modalities in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM. Thirty patients (10 each with MGUS, SMM and MM) were evaluated with skeletal survey, [18F]FDG-PET/CT, [18F]NaF-PET/CT and morphologic dynamic contrast enhanced (DCE)-MRI. An additional 16 SMM patients had skeletal surveys and FDG-PET/CT. Among MGUS patients, DCE-MRI found only one focal marrow abnormality; other evaluations were negative. Among 26 SMM patients, five (19%) were re-classified as MM based on lytic bone lesions on CT and six had unifocal or diffuse marrow abnormality. Among MM, marrow abnormalities were observed on FDG-PET/CT in 8/10 patients and on DCE-MRI in nine evaluable patients. Abnormal NaF uptake was observed only in MM patients with lytic lesions on CT, providing no additional clinical information.
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http://dx.doi.org/10.3109/10428194.2015.1090572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576169PMC
May 2016

∆ DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis.

EBioMedicine 2015 Oct 7;2(10):1340-50. Epub 2015 Sep 7.

Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD 21201, USA ; Marlene and Stewart Greenebaum Cancer Center, University of Maryland, 22 S Greene St, Baltimore, MD 21201, USA.

Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. We have previously shown that ∆DNMT3B is the predominantly expressed form of DNMT3B. In this study, we found that most of the lung cancer cell lines tested predominantly expressed DNMT3B isoforms without exons 21, 22 or both 21 and 22 (a region corresponding to the enzymatic domain of DNMT3B) termed DNMT3B/∆DNMT3B-del. In normal bronchial epithelial cells, DNMT3B/ΔDNMT3B and DNMT3B/∆DNMT3B-del displayed equal levels of expression. In contrast, in patients with non-small cell lung cancer NSCLC), 111 (93%) of the 119 tumors predominantly expressed DNMT3B/ΔDNMT3B-del, including 47 (39%) tumors with no detectable DNMT3B/∆DNMT3B. Using a transgenic mouse model, we further demonstrated the biological impact of ∆DNMT3B4-del, the ∆DNMT3B-del isoform most abundantly expressed in NSCLC, in global DNA methylation patterns and lung tumorigenesis. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation patterns during lung tumorigenesis and suggest that ∆DNMT3B4-del may be a target for lung cancer prevention.
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http://dx.doi.org/10.1016/j.ebiom.2015.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634842PMC
October 2015

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

JAMA Oncol 2015 Sep;1(6):746-54

Multiple Myeloma Section, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, New York, New York2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival.

Objective: To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM).

Design, Setting, And Participants: Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM).

Interventions: Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing.

Main Outcomes And Measures: Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed.

Results: Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively.

Conclusions And Relevance: Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.
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http://dx.doi.org/10.1001/jamaoncol.2015.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662597PMC
September 2015

Expanding role of lenalidomide in hematologic malignancies.

Cancer Manag Res 2015 2;7:105-19. Epub 2015 May 2.

Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.

Lenalidomide is an immunomodulatory agent that has been approved by the US Food and Drug Administration for treatment of multiple myeloma, deletion 5q myelodysplastic syndrome, and mantle cell lymphoma. In addition, it has clinical activity in lymphoproliferative disorders and acute myeloid leukemia. The mode of action includes immunomodulatory, anti-inflammatory, antiangiogenic, and antiproliferative mechanisms. The antitumor effect is a result of direct interference of key pathways in tumor cells and indirect modulation of the tumor microenvironment. There has been no recent collective review on lenalidomide in multiple myeloma, myelodysplastic syndrome/acute myeloid leukemia, and lymphoma. This review summarizes the results of current clinical studies of lenalidomide, alone and in combination with other agents, as a therapeutic option for various hematologic malignancies.
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http://dx.doi.org/10.2147/CMAR.S81310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427066PMC
May 2015

Multiple myeloma: is it time for biomarker-driven therapy?

Am Soc Clin Oncol Educ Book 2015 :e493-503

From the Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC; Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Remarkable strides have been made in understanding the molecular mechanisms by which multiple myeloma develops, leading to more sophisticated classification that incorporates not only the traditional diagnostic criteria, but also immunophenotype, genetic, and molecular features. However, even with this added information, considerable heterogeneity in clinical outcomes exists within the identified subtypes. The present paradigm for myeloma treatment is built on the basic step of defining transplant eligibility versus noneligibility, as determined by age, performance status, and cumulative burden of comorbidities. An incredibly complex heterogeneous disease is, therefore, treated in a generalized way with the result that large interpatient variability exists in the outcome. As antimyeloma therapeutics continue to expand it is becoming even more crucial to personalize treatment approaches that provide the most value to a specific patient. Development of biomarkers, either individually or as larger sets or patterns and ranging from analysis of blood or bone marrow to biomedical imaging, is a major focus in the field. Biomarkers such as involved serum free light chain ratio and MRI focal lesions have been implemented in the new definition of multiple myeloma and guide clinicians to initiate treatment in otherwise asymptomatic individuals. Currently, however, there is not enough evidence to support intensifying the treatment for high-risk disease or reducing the treatment for low-risk disease. Minimal residual disease-negative status is an important biomarker that holds promise for monitoring the effectiveness of response-adapted strategies. This article sheds light on the forward landscape and rear-mirror view of biomarkers in myeloma.
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http://dx.doi.org/10.14694/EdBook_AM.2015.35.e493DOI Listing
February 2016

Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment.

Semin Oncol 2015 Apr 31;42(2):223-46. Epub 2014 Dec 31.

HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD. Electronic address:

Kaposi sarcoma associated herpesvirus (KSHV), a γ2-herpesvirus, also known as human herpesvirus-8, is the etiologic agent of three virally associated tumors: Kaposi sarcoma, a plasmablastic form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These malignancies are predominantly seen in people with acquired immunodeficiencies, including acquired immunodeficiency syndrome and iatrogenic immunosuppression in the setting of organ transplantation, but can also develop in the elderly. Kaposi sarcoma (KS) is most frequent in regions with high KSHV seroprevalence, such as sub-Saharan Africa and some Mediterranean countries. In the era of combination antiviral therapy, inflammatory manifestations associated with KSHV-infection, including KSHV-MCD, a recently described KSHV-associated inflammatory cytokine syndrome and KS immune reconstitution syndrome also are increasingly appreciated. Our understanding of viral and immune mechanisms of oncogenesis continues to expand and lead to improved molecular diagnostics, as well as novel therapeutic strategies that employ immune modulatory agents, manipulations of the tumor microenvironment, virus-activated cytotoxic therapy, or agents that target interactions between specific virus-host cell signaling pathways. This review focuses on the epidemiology and advances in molecular and clinical research that reflects the current understanding of viral oncogenesis, clinical manifestations, and therapeutics for KSHV-associated tumors.
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http://dx.doi.org/10.1053/j.seminoncol.2014.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309362PMC
April 2015